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Introduction: Despite initial efficacy, most patients (pts) with HR+/HER2– advanced breast cancer (BC) eventually progress on endocrine therapy (ET) plus a CDK4/6 inhibitor (CDK4/6i). In preclinical models, resistance to ET + CDK4/6i can be overcome by concomitant inhibition of CDK2. Therefore, simultaneous inhibition of CDK2/4/6 may provide a new therapeutic strategy to prolong clinical benefit. This first-in-human dose escalation/expansion study (NCT03519178) is evaluating the safety, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary antitumor activity of the first-in-class selective CDK2/4/6 inhibitor PF-06873600 (PF-3600) as monotherapy and combined with ET. The results of Part 1 monotherapy dose escalation and initial combination with ET are presented.Methods: This is a phase 1/2a, open-label, non-randomized, study of PF-3600 as monotherapy and combined with letrozole or fulvestrant (F). Pts with locally advanced/metastatic HR+/HER2– BC whose tumor progressed on previous ET + CDK4/6i and with ≤2 prior lines of chemotherapy (Cx), triple-negative breast cancer (TNBC) with ≤2 prior lines of Cx, and platinum-resistant ovarian cancer (OVCA) with ≤3 prior lines of treatment (Tx) were eligible for Part 1 dose escalation. Pts received escalating doses of PF-3600 (1–50 mg) BID orally. Dose escalation followed the modified toxicity probability interval method. Tx continued until disease progression, toxicity requiring discontinuation or pt withdrawal. Primary objectives for Part 1 were to evaluate safety including dose-limiting toxicities (DLTs) in the 1st 28-day cycle, adverse events (AEs), and laboratory abnormalities; and to select the recommended dose for expansion (RDE) in combination with ET. Results: As of 24 June 2021, 67 pts (HR+/HER2– BC, n=59; TNBC, n=2; OVCA, n=6) received PF-3600 (n=58) or PF-3600 + F (n=9). In the PF-3600 group, 22 (38%) and 36 (62%) pts had ECOG performance status (PS) 0 and 1, respectively. In the PF-3600 + F group, 6 (67%) and 3 (33%) pts had ECOG PS 0 and 1, respectively. The median (range) number of prior Tx in the metastatic setting was 4.0 (1, 8) for PF-3600 and 4.0 (3, 6) for PF-3600 + F. The most frequently reported treatment-related AEs (all grade/grade ≥3) for PF-3600 alone and PF-3600 + F, respectively, were nausea (50%/0% and 67%/0%), anemia (38%/14% and 44%/11%) and neutropenia (29%/16% and 22%/11%). Six (13%) of 48 DLT-evaluable pts treated with monotherapy had DLTs; all occurred at the highest doses (35 and 50 mg BID). At the RDE of 25 mg BID (PF-3600 alone, n=17; PF-3600 + F, n=9), there were no DLTs. PF-3600 exposure increased with dose, was not significantly impacted by F and at the RDE remained above the preclinical efficacious concentrations in most of the tested models for >70% of the dosing interval. The disease control rate was 48% (28/58, PF-3600) and 67% (6/9, PF-3600 + F) including 3 pts who remained stable for >13 mos with one ongoing for >28 mos. Three heavily pre-treated pts with HR+/HER2– BC (including prior ET + CDK4/6i and Cx) treated with PF-3600 alone had partial responses (2 confirmed), including 1 pt who remained on Tx for >13 mos. Modulation of cell cycle PD biomarkers (pRb and Ki-67) in paired tumor biopsies was observed. Data are not final and subject to change. Updated data will be presented.Conclusions: PF-3600 can be combined with ET with a manageable AE profile and demonstrates promising preliminary antitumor activity in heavily pretreated pts, including those with HR+/HER2– BC progressing on ET + CDK4/6i and Cx. Dose expansion in combination with ET in pts with HR+/HER2– BC with and without prior CDK4/6i Tx is ongoing. Citation Format: Timothy A. Yap, Cynthia Basu, Jonathan W. Goldman, Michael Gordon, Erika Hamilton, Adrianne Kelly, Feng Liu, Allison R. Moreau, Heather Neumann, Kyriakos Papadopoulos, Hope S. Rugo, Geoffrey I. Shapiro, Shaveta Vinayak, Li Zhou, Komal Jhaveri. A first-in-human phase 1/2a dose escalation/expansion study of the first-in-class CDK2/4/6 inhibitor PF-06873600 alone or with endocrine therapy in patients with breast or ovarian cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-16-06.

Background: Eganelisib is a first-in-class, oral, immuno-oncology macrophage reprogramming agent. The IMpassion130 randomized trial in 1L advanced TNBC has demonstrated improved efficacy with the addition of atezo to nab-pac in patients with PD-L1+ tumors. Adding eganelisib to the approved doublet of atezo and nab-pac is expected to improve patient benefit regardless of PD-L1 status. Methods: Eligible patients (pts) had measurable unresectable locally advanced or metastatic TNBC and no prior systemic therapy for advanced disease. A safety run-in assessed the safety of the triplet of oral eganelisib 30 mg daily in combination with IV nab-pac 100 mg/m2 given on days 1, 8, & 15, and IV atezo 840 mg given on days 1 & 15 of a 28 day cycle. After establishing tolerability and confirmation of the 30 mg dose in the safety run-in (n=6), the expansion phase of the phase II study was initiated to enroll approximately 60 pts (30 PD-L1+ and 30 PD-L1-). Cycles are repeated until loss of clinical benefit, unacceptable toxicity or consent withdrawal. The primary efficacy endpoint is confirmed complete response (CR) rate per RECIST v1.1. Secondary endpoints include the overall response rate (ORR), progression free survival and safety assessment. Results: As of 6/26/2021, data from the safety run-in and the expansion cohorts are reported for 43 pts evaluable for safety and 38 evaluable for efficacy defined as having at least one post-baseline tumor assessment. 2 CRs (2/38), 19 PRs (19/38), and 11 SDs (11/38) were observed with an ORR of 55.3% (21/38) and a disease control rate (DCR) of 84.2% (32/38). Responses were seen irrespective of PD-L1 status; in PD-L1+ pts, ORR is 66.7% (8/12) and DCR is 91.7% (11/12), and in PD-L1- pts, ORR is 47.8% (11/23) and DCR is 78.3% (18/23). The most common all-grade adverse events were nausea (51.2%), fatigue (48.8%), alopecia (32.6%), diarrhea (32.6%), rash maculo-papular (30.2%), ALT increased (27.9%), and AST increased (25.6%). The most common grade ≥3 adverse events were ALT increased (18.6%), AST increased (14.0%), neutrophil count decreased (9.3%) and rash maculo-papular (9.3%). The safety profile is acceptable and in line with expectations of component drugs with no additive or new safety signals. Translational data from paired biopsies show a shift in tumor associated macrophages towards an immune activated state as well as an increase in cytotoxic T cells. In addition, a subset of tumors with baseline PD-L1 negative status show conversion to PD-L1 positive status post treatment. Consistent with immune activation, increased interferon gamma signature, increased proinflammatory cytokines and T cell invigoration were observed in peripheral blood cells. Conclusions: The novel triplet regimen of eganelisib, atezo, and nab-pac shows promising anti-tumor activity (ORR 55.3% and DCR 84.2%) irrespective of PD-L1 status and has manageable toxicity. . Translational data from paired biopsies and peripheral blood show evidence of immune activation regardless of PD-L1 status as well as conversion from PD-L1 negative to PD-L1 positive subtype within a subset of patients treated with the triplet regimen. The expansion phase of the phase II study is currently enrolling. At the time of presentation, we will have updated efficacy, safety and translational data. Citation Format: Soliman Hatem, Jeffrey Hargis, Anthony Elias, Arielle Lee, Rachel Swart, Shaker Dahkil, Alexandra Drakaki, Vu Phan, Frederic Kass, Melody Cobleigh, Sanil Babu, Katherine Tkaczuk, Brenda O'Connell, Jennifer Roberts, Nora Zizlsperger, Erika Hamilton. Updated efficacy, safety and translational data from MARIO-3, a phase II open-label study evaluating a novel triplet combination of eganelisib (IPI-549), atezolizumab (atezo), and nab-paclitaxel (nab-pac) as first-line (1L) therapy for locally advanced or metastatic triple-negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-16-02.

Background: Despite the success of multiple HER2-targeted agents in HER2+ breast cancer (BC), resistance remains a challenge and novel therapies are needed. DHES0815A is a THIOMABTM antibody-drug conjugate consisting of a humanized IgG1 anti-HER2 monoclonal antibody (mAb) conjugated to the DNA alkylating agent PBD-MA. The reduced potency of PBD-MA compared to PBD dimers and the stability of the conjugation site and linker were designed to improve tolerability, whereas the binding of the mAb to a HER2 epitope distinct from trastuzumab and pertuzumab was designed to enable combination therapy with existing HER2 therapies. Methods: This first-in-human, Phase I, open-label, multicenter, dose escalation study used a 3+3 dose escalation design to assess the safety, pharmacokinetics (PK), and preliminary anti-tumor activity of DHES0815A in patients with metastatic HER2-positive BC refractory to established therapies (NCT03451162). DHES0815A (0.6-6.0 mg/kg) was administered intravenously every 3 weeks (Q3W) until intolerable toxicity or disease progression. Results: A total of 14 patients were treated with DHES0815A; all had ≥3 prior lines of therapy. Thirteen patients discontinued treatment due to progressive disease (43%), adverse events (AE; [29%]) symptomatic deterioration (14%) or other (7%); 1 patient remains on treatment. DHES0815A was initially well-tolerated for doses up to 2.4 mg/kg. At 4.0 mg/kg and 6.0 mg/kg, the first dose was also well-tolerated with no dose limiting toxicities, however, following 3 or more cycles at 4.0 mg/kg or 2 or more cycles at 6.0 mg/kg, safety events involving skin, eyes, and lung emerged. Skin events were reported in 50% of patients (all doses) and related events occurring in n≥2 patients included pruritus (36%), rash (36%), and skin hyperpigmentation (21%). Ocular toxicities were reported in 57% and related events occurring in n≥2 patients included photophobia (21%), conjunctivitis, eye pain, and dry eye (each 14%). Lung toxicities were reported in 36% of patients; events occurring in n≥2 included pneumonitis (14%). Other related skin, ocular, and pulmonary events occurring in 1 patient (7%) included palmar-plantar erythrodysaesthesia, macular rash, blurred vision, eyelid edema, periorbital edema, blepharitis, punctate keratitis, wheezing, allergic rhinitis, and pneumothorax. Most events were grade 1 or 2 although 3 patients experienced grade 3 ocular events (blepharitis, eye pain, photophobia). Due to these AEs, DHES0815A dose was decreased to 2.4 mg/kg Q3W for all enrolled patients and accrual was stopped. All 5 patients receiving doses of 4.0 mg/kg and 6.0 mg/kg discontinued due to AEs. At lower doses, 1 patient receiving 2.4 mg/kg developed grade 2 rash at Cycle 21 and 1 patient receiving 1.2 mg/kg developed grade 1 rash, pruritis, and skin hyperpigmentation between Cycles 28-30. Nonlinear PK of antibody-conjugated PBD-MA (acPBD-MA) was observed due to target mediated drug disposition at 0.6, 1.2, and 2.4 mg/kg; PK approached linear at 4.0 mg/kg. Minimal systemic exposure of unconjugated PBD-MA was observed. Overall, 1 patient (7%) in the 1.2 mg/kg cohort achieved a confirmed complete response. As of 10Jun21, this patient remains on study after more than 32 months on treatment. Ten patients (86%) showed a confirmed best overall response of stable disease (86%). Conclusion: Despite some anti-tumor activity observed with DHES0815A, development in HER2-positive BC has been discontinued due to safety concerns and the narrow therapeutic window. Toxicities observed in skin, lung, and eyes are clinically apparent only after repeated dose administration. If future exploration of PBD-MA-based constructs is performed in the clinic, close monitoring for delayed toxicities is warranted. Citation Format: Ian Krop, Erika Hamilton, Kyung Hae Jung, Shanu Modi, Kevin M Kalinsky, Gail Phillips, Rong Shi, Sharareh Monemi, Michael Mamounas, Ola Saad, Voleak Choeurng, Renee Commerford, Eunpi Cho, Alexander Ungewickell, Patricia LoRusso. A phase I dose-escalation study of DHES0815A, a HER2-targeting antibody-drug conjugate with a DNA monoalkylator payload, in patients with HER2-positive breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-25.

Background: ER+, HER2- metastatic breast cancer (MBC) patients will receive sequential, endocrine based therapy, either as monotherapy or in combination with a targeted agent until endocrine resistance develops. OP-1250 is a small molecule Complete Estrogen Receptor Antagonist (CERAN) that completely inactivates ER by blocking the 2 activation functions of ER transcription (AF-1 & AF-2). While complete antagonism is believed to be the most critical mechanism of action, OP-1250 is also a strong degrader of the ER. OP-1250 demonstrates anti-cancer activity in preclinical models, including activity against brain metastases and in tumors with activating mutations in ESR1. OP-1250 is orally bioavailable with favorable pharmacokinetics (PK) yielding high and steady drug levels in multiple species. The characteristics of OP-1250 including PK, ability to cross the blood brain barrier, and complete antagonism of the ER suggest that OP-1250 may have superior efficacy over standard of care and experimental agents, both as a monotherapy and in combination with other targeted therapies. Methods: OP-1250-001 is a phase I/II first-in-human study to determine the Dose Limiting Toxicity (DLT), Maximum Tolerated Dose (MTD) and/or Recommended Phase II Dose (RP2D) and to characterize the safety, PK profile and preliminary efficacy in subjects with ER+, HER2- MBC. Eligible patients received prior endocrine therapy. OP-1250 was given orally, once a day continuously in 28-day cycles. Using a rolling 6 design, cohorts of 3 - 6 subjects were sequentially enrolled and monitored for DLTs. The study allows for expansion of 1 or 2 doses for further evaluation of safety and PK to best inform selection of the RP2D. The phase II portion will evaluate the preliminary activity of OP-1250 in 3 cohorts: 1) measurable disease; and 2 exploratory cohorts: 2) evaluable & non-measurable; and 3) central nervous system metastasis. Plasma is being collected for ctDNA sequencing to evaluate ESR1 and other relevant mutations. Results: Between August 5, 2020 and June 4, 2021, 28 subjects with a median age of 63 (range 37-82) have been enrolled. Of the 27 subjects for whom detailed data on prior therapy was reported, all subjects received > 1 prior endocrine therapy for MBC (74% received > 2 and 37% received > 3; range 1-6). All of the 27 subjects received a CDK4/6 inhibitor and 23 of 27 (85%) had received fulvestrant. 20 subjects of 28 (71%) subjects had visceral disease affecting the liver, lung, peritoneum, and/or pleura. OP-1250 was escalated through 5 dose cohorts (range 30 - 300 mg qd). 26 patients were evaluable for a DLT. As of the data cut-off date, no DLTs occurred. Most of the TEAE were grade 1 or 2. OP-1250 is orally bioavailable and extensively distributed with an effective half-life of approximately 2-3 days. Cmax and AUC show dose proportional increase. By cycle 2, exposure levels are at steady state with limited fluctuations and at all doses significantly higher than those seen with fulvestrant. Importantly, OP-1250 has now demonstrated clinical activity at doses that were well tolerated and within the predicted exposure windows where maximum efficacy was observed in preclinical models. Detailed response and safety data will be presented. Conclusion: OP-1250 is continuing evaluation in a phase I/II study. The population enrolled reflects the evolving standard of care in that all pts received prior CDK4/6 inhibitors and the majority also received fulvestrant. OP-1250 is well tolerated with a favorable PK across dose levels ensuring target coverage throughout the dosing interval. No MTD has been identified and selection of the RP2D will be based on consideration of long-term tolerability, efficacy, and the ability to combine with targeted agents. (NCT04505826) Citation Format: Manish Patel, Carlos Alemany, Zahi Mitri, Della Makower, Virginia Borges, Joseph Sparano, Trinh Le, Pamela Klein, Julia Lawrence, Peter Kushner, Demiana Faltaos, Cyrus Harmon, David Myles, JoAnne Zujewski, Erika Hamilton. Preliminary data from a phase I/II, multicenter, dose escalation study of OP-1250, an oral CERAN/SERD, in subjects with advanced and/or metastatic estrogen receptor (ER)-positive, HER2-negative breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-17-12.

Background: SG is an antibody-drug conjugate composed of an anti-Trop-2 antibody coupled to the cytotoxic SN-38 payload via a proprietary, hydrolyzable linker. SG is FDA approved for pts with mTNBC who received ≥2 prior chemotherapies (≥1 in the metastatic setting). The confirmatory phase 3 ASCENT study (NCT02574455) in pts treated in second line or greater (2L+) mTNBC demonstrated significant progression-free survival (PFS) and overall survival (OS) benefit of SG over single-agent chemotherapy treatment of physician’s choice (median PFS: 4.8 vs 1.7 months, HR 0.43, P Citation Format: Javier Cortés, Aditya Bardia, Delphine Loirat, Sara M. Tolaney, Kevin Punie, Mafalda Oliveira, Sara A. Hurvitz, Adam Brufsky, Sagar Sardesai, Kevin M Kalinsky, Tiffany Traina, Erika Hamilton, Joyce O’Shaughnessy, Véronique Diéras, Lisa A. Carey, Martine Piccart, Sibylle Loibl, Hope S. Rugo, Yanni Zhu, See Phan, Luca Gianni. Post-progression therapy outcomes in patients (pts) from the phase 3 ASCENT study of sacituzumab govitecan (SG) in metastatic triple-negative breast cancer (mTNBC) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-16-15.

Background: Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate consisting of a humanized anti-TROP2 IgG1 monoclonal antibody conjugated to a potent topoisomerase I inhibitor payload via a stable tetrapeptide-based cleavable linker. Preliminary results from the phase 1 TROPION-PanTumor01 study demonstrate that Dato-DXd has encouraging antitumor activity and a manageable safety profile in patients with non-small cell lung cancer (NSCLC) (Meric-Bernstam, ASCO 2021) and those with triple-negative breast cancer (TNBC) (Bardia, ESMO BC 2021). Updated results from the TNBC cohort are presented here. Methods: TROPION-PanTumor01 (NCT03401385) is a phase 1, multi-center, open-label, 2-part study evaluating Dato-DXd in previously treated patients with solid tumors. Based on the dose-escalation results in patients with NSCLC, Dato-DXd 6 mg/kg intravenously every 3 weeks is being evaluated in patients with advanced/metastatic TNBC and HR+/HER2− breast cancer who relapsed/progressed on standard therapies. Two patients with TNBC received Dato-DXd 8 mg/kg prior to selection of 6 mg/kg for dose expansion. Safety and efficacy were assessed, including objective response rate (ORR) per RECIST version 1.1 by blinded independent central review (BICR). Results: As of the April 6, 2021, data cutoff, 43 patients with TNBC had received ≥1 dose of Dato-DXd, with 27 patients (63%) continuing and 16 patients (37%) discontinuing treatment all due to disease progression. The median age was 53 years (range, 32-82 years). Forty-one patients (95%) had received ≥2 prior lines of therapy; 19 patients (44%) had received prior immunotherapy and 7 (16%) had received prior sacituzumab govitecan. The median duration of treatment was 2.8 months (range, 0.7-6.9 months). The median follow-up was 3.9 months (range, 0.3-9.2 months). Among 38 patients evaluable for response, the ORR by BICR was 39% (15 partial responses [PR]), with 12 confirmed and 3 pending confirmation. The disease control rate was 84% (32/38). The median time to response was 1.35 months (1.2-3.2 months) for the 12 confirmed PRs. All-cause treatment-emergent adverse events (TEAEs; any grade, grade ≥3) were observed in 95% and 35% of patients, respectively; 2 events were grade 4 and 0 grade 5. The most common TEAEs (any grade [≥30%], grade ≥3) included nausea (58%, 0%), stomatitis (53%, 9%), alopecia (35%, N/A), vomiting (35%, 2%), and fatigue (33%, 7%). One patient had grade 3 decreased neutrophil count; no cases of grade ≥3 diarrhea were observed. No cases of treatment-related interstitial lung disease as adjudicated by an independent committee were reported. Serious TEAEs were observed in 5 patients (12%); no TEAEs were associated with death. Dose reductions occurred in 9 patients due to stomatitis, fatigue, mucosal inflammation, dry eye, retinal exudates, and blurred vision (multiple counts per TEAE). Three patients had dose interruptions due to stomatitis, mucosal inflammation, bronchitis, and musculoskeletal chest pain. No patients discontinued treatment due to adverse events. Conclusions: Preliminary results showed that Dato-DXd demonstrates promising antitumor activity with a manageable safety profile in patients with previously treated advanced/metastatic TNBC; confirmatory studies in patients with breast cancer are warranted. Citation Format: Ian Krop, Dejan Juric, Toshio Shimizu, Anthony Tolcher, Alexander Spira, Toru Mukohara, Aaron E. Lisberg, Takahiro Kogawa, Kyriakos P. Papadopoulos, Erika Hamilton, Senthil Damodaran, Jonathan Greenberg, Wen Gu, Fumiaki Kobayashi, Ferdinand Guevara, Takahiro Jikoh, Yui Kawasaki, Funda Meric-Bernstam, Aditya Bardia. Datopotamab deruxtecan in advanced/metastatic HER2- breast cancer: Results from the phase 1 TROPION-PanTumor01 study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS1-05.

Background: More than two thirds of patients with advanced breast cancer (ABC) have estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2−) tumors. In most countries, current standard-of-care first-line treatments include an aromatase inhibitor or fulvestrant, a selective ER degrader, combined with cyclin-dependent kinase 4/6 inhibitors. Concurrent use of luteinizing hormone-releasing hormone agonists is recommended for men and premenopausal women with ABC. Nevertheless, almost all ABCs eventually become resistant to endocrine therapy and the disease is incurable in these cases. New therapies are needed to combat endocrine therapy resistance, maintain patient health-related quality-of-life, and delay the need for chemotherapy. AZD9833 (camizestrant) is a highly potent, next-generation selective ER degrader and pure ER antagonist that has demonstrated anticancer properties across a range of preclinical models, including those with ER-activating mutations (Scott et al, AACR 2020). A Phase I dose-escalation and expansion study (SERENA-1) has demonstrated that AZD9833 is well tolerated and has a promising antitumor activity when administered alone or in combination with the cyclin-dependent kinase 4/6 inhibitor palbociclib (Baird et al, SABCS 2020). SERENA-4 (NCT04711252) is a randomized, multicenter, double-blind, Phase III trial to evaluate the safety and efficacy of AZD9833 in combination with palbociclib for patients with ER+/HER2− ABC who have not received systemic treatment in the advanced disease setting. Methods: SERENA-4 will enroll 1342 patients with de novo or recurrent ER+/HER2− ABC who have not previously received systemic treatment for their locoregionally recurrent or metastatic disease. Patients with recurrent disease must have received adjuvant aromatase inhibitor or tamoxifen therapy for at least 24 months without relapse. Patients will be randomized 1:1 to receive oral treatment with either (a) AZD9833 75 mg once daily, palbociclib 125 mg once daily for 21 days followed by 7 days off treatment and a placebo for anastrozole 1 mg once daily or (b) anastrozole 1 mg once daily, palbociclib (same as active arm) and a placebo for AZD9833 75 mg once daily. Men and premenopausal women will also receive a luteinizing hormone-releasing hormone agonist. The primary endpoint is progression-free survival (PFS; up to 5 years). Secondary endpoints include overall survival (up to 8 years), second PFS, time to chemotherapy, objective response rate, and changes in health-related quality-of-life measures. Enrollment began in January 2021. As of 02 July 2021, the number of open sites is 57 across 15 countries. Acknowledgments: We thank Julia Mawer, PhD, of Oxford PharmaGenesis, Oxford, UK, for providing medical writing support funded by AstraZeneca Funding: The SERENA-4 trial is funded and overseen by AstraZeneca. © 2021 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2021 ASCO Annual Meeting. All rights reserved. Citation Format: Fabrice André, Seock-Ah Im, Patrick Neven, Richard D Baird, Johannes Ettl, Matthew P Goetz, Erika Hamilton, Hiroji Iwata, Zefei Jiang, Anil Abraham Joy, Vincent Haddad, Andrew Walding, Manuel Selvi Miralles, Cynthia Huang Bartlett, Antonio Llombart-Cussac. SERENA-4: A Phase III comparison of AZD9833 (camizestrant) plus palbociclib, versus anastrozole plus palbociclib, for patients with ER-positive/HER2-negative advanced breast cancer who have not previously received systemic treatment for advanced disease [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-11-06.

Background Zenocutuzumab is a humanized bispecific full-length IgG1 antibody targeting both HER2 and HER3 with enhanced ADCC activity. The unique Dock & Block mechanism inhibits HER3 from interacting with its ligands by targeting HER2 at a different epitope than trastuzumab, that optimally positions it to block HER2/HER3 dimerization and downstream PI3K/AKT/mTOR signaling. In MBC, HER3 overexpression and/or HER3 ligand upregulation are important drivers of carcinogenesis leading to trastuzumab resistance, indicating a potential role for zenocutuzumab. Preclinical activity was seen in HER2+ breast cancer models when zenocutuzumab was combined with trastuzumab. Single-agent zenocutuzumab showed consistent antitumor activity in heavily pretreated HER2+ MBC pts. This phase 2, open-label study explored zenocutuzumab/trastuzumab/vinorelbine in MBC. Methods This open-label study planned to enroll up to 40 evaluable pts with HER2+ MBC progressing after up to 5 anti-HER2 lines of therapy including trastuzumab, pertuzumab, and an anti-HER2 ADC. This sample size with a clinical benefit rate (CBR) of 45% would provide adequate precision to exclude 30% (lower limit of 90% CI > 30%). The threshold for the CBR rate at 24 w was based on the assumption that progression-free survival (PFS) follows an exponential distribution with a median of 5 months (clinically relevant) and 3.5 months (not clinically relevant).Pts received zenocutuzumab (750 mg, 2h IV), trastuzumab (8 mg/kg loading, then 6 mg/kg), and vinorelbine (25 mg/m², D1 and 8), q3w. A safety run-in of zenocutuzumab + trastuzumab ± vinorelbine was performed. The primary endpoint of the study was CBR at 24 w (tumor assessment [TA] by RECIST 1.1, per investigator), secondary endpoints include CBR at 24 w (TA by RECIST 1.1, per central review), overall response rate (ORR), safety, biomarkers, and pharmacokinetics. Cutoff date for the efficacy endpoints was 31Mar2021. This is an updated analysis of the 2020 ASCO abstract after all patients had completed at least 6 months of treatment or discontinued. Result total of 39 pts with a median of 3 lines (range 2-5) of prior anti-HER2 therapy including TDM1 received a median of 6 (range 1-23) cycles of zenocutuzumab. In the 37 pts evaluable for efficacy and with locally confirmed HER2 overexpression (3+ IHC or 2+ IHC confirmed by FISH), CBR at 24 w per investigator was 49% (90% CI: 34-63%); ORR was 27% (95% CI: 15-42%). The CBR at 24 w was consistent across different methods of HER2 overexpression/amplification detection (local vs central laboratory) and response assessment (investigator and central independent radiological review; see table below). As of a 12Jan2021 safety data update, the most common related AEs (all grades; G3-4) were neutropenia/neutrophil count decrease (61%; 46%), diarrhea (61%; 4%), asthenia/fatigue (46%; 0), and nausea (29%; 0). The PK half-life was 117h. The correlation of HER2-HER3 pathway activation at baseline with best ORR, duration of response, PFS, and overall survival was analyzed and will be presented in the poster. Conclusion Updated analyses confirm that the efficacy of zenocutuzumab combinations with trastuzumab/vinorelbine in heavily pretreated, HER2+ MBC, with progression after TDM-1, met prespecified protocol criteria for success. The regimen is safe and well tolerated with AEs mostly related to chemotherapy. CBR with zenocutuzumab, trastuzumab, and vinorelbinePopulationNCBR at 24 wks, %. (90% CI)HER2+ by local test/TA by RECIST1.1 per investigator3749 (34-63)HER2+ by central test/TA by RECIST1.1 per investigator2955.1 (38-71)HER2+ by local test/TA by RECIST1.1 by central independent radiologist review3644 (30-59)HER2+ by central test/TA by RECIST1.1 by central independent radiologist review2850.0 (33-67) Citation Format: Erika Hamilton, Thierry Petit, Barbara Pistilli, Anthony Goncalves, Ana Alexandra Ferreira, Florence Dalenc, Fatima Cardoso, Monica M Mita, Luis Manso, Syed M Karim, Francois-Clement Bidard, Philippe Aftimos, Santiago Escriváa-de-Romaníi, Noemia Afonso, Ernesto Wasserman, Kees Bol, Viktoriya Stalbovskaya, Anastasia Vliet, Anastasia Murat, Mohamed Bekradda, Thomas Bachelot. Updated analysis of MCLA-128 (zenocutuzumab), trastuzumab, and vinorelbine in patients (pts) with HER2 positive/amplified (HER2+) metastatic breast cancer (MBC) who progressed on previous anti-HER2 ADCs [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-15-01.

Background: Despite the availability of multiple HER2-targeted therapies, most patients (pts) with advanced HER2-positive BC experience disease progression, and an unmet medical need remains. Zanidatamab (zani) binds to HER2 across a range of expression levels and induces formation of receptor clusters, resulting in receptor internalization and downregulation that affect signal transduction. Zani potently activates antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and complement-dependent cytotoxicity. In this ongoing phase 1 study (NCT02892123), data from BC pts treated with zani monotherapy have been previously reported. Here, we evaluated the safety and antitumor activity of zani in combination with chemo in HER2-positive BC pts. Methods: Pts with locally advanced and/or metastatic HER2-positive (immunohistochemistry [IHC] 3+ or IHC 2+/fluorescence in situ hybridization+) BC who received prior trastuzumab (tras), pertuzumab (pert), and T-DM1 were enrolled. Eligibility criteria included Eastern Cooperative Oncology Group performance status ≤1 and adequate organ function. Prior history of treated stable brain metastases was allowed. Zani (20 mg/kg Q2W or 30 mg/kg Q3W) was administered in combination with paclitaxel (pac), capecitabine (cap), or vinorelbine (vin). Zani + chemo was continued until disease progression or toxicity; if chemo was discontinued due to toxicity, zani treatment could be continued. Primary endpoints were safety and tolerability assessments; secondary efficacy endpoints included objective response rate (ORR) and disease control rate (DCR; complete response [CR] + partial response [PR] + stable disease [SD]) per RECIST v1.1, and progression-free survival (PFS). Clinical benefit rate (CBR) was defined as SD ≥24 weeks or best overall response of CR or PR. Results: As of 3 May 2021, 20 HER2-positive BC pts had enrolled (zani + pac, n=4; zani + cap, n=9; zani + vin, n=7). Ten pts were hormone receptor positive (data available for 19 pts), and 7 pts had a prior history of brain metastases. Median age was 53 years (range, 38-72), with median prior systemic therapies of 4.5 (range, 2-7) and median of 2 regimens in the metastatic setting. Pts received a median of 3 prior HER2 regimens; all pts received tras and T-DM1, 17 received pert, and 6 received tyrosine kinase inhibitors. In the 16 response evaluable (measurable disease and either post-baseline assessments or earlier death/progression) pts, confirmed ORR was 37.5% (with 1 additional response pending confirmation), CBR was 50%, and DCR was 81.3%. Median duration of response was not reached (range, 1.8+ to 16.8+ mo), with 4 of 6 confirmed responses ongoing. Among all pts (n=20), the most common (≥30% of pts) zani- and/or chemo-related adverse events (AEs) were diarrhea (65%), nausea (45%), peripheral neuropathy (35%), and fatigue (30%). One pt experienced grade 3 diarrhea leading to dose reduction of zani, and 1 pt discontinued zani due to AEs (abdominal pain and nausea, both grade ≤2). Four grade 4 AEs were observed in 4 (20%) pts: neutrophil count decreased (2 pts) and neutropenia (1 pt), all related to chemo, and hyponatremia (1 pt, not related to study treatment). Serious AEs were observed in 2 (10%) pts (pleural effusion, 1 pt; pneumonitis and upper respiratory tract infection, 1 pt), none related to zani. No grade 5 AEs were reported. Conclusions: Zani in combination with chemo is well tolerated, with encouraging and durable antitumor activity in heavily pretreated (including prior tras, pert, and T-DM1) pts with HER2-positive BC. These data support further investigation of zani as a novel therapeutic for these pts. The cap and vin cohorts continue to enroll, and additional cohorts are evaluating zani ± chemo in combination with tucatinib. Citation Format: Philippe L Bedard, Seock-Ah Im, Elena Elimova, Sun Young Rha, Rachel Goodwin, Cristiano Ferrario, Keun-Wook Lee, Diana Hanna, Funda Meric-Bernstam, Jose Mayordomo, Murali Beeram, Erika Hamilton, Jorge Chaves, Melody Cobleigh, Tony Mwatha, Joseph Woolery, Do-Youn Oh. Zanidatamab (ZW25), a HER2-targeted bispecific antibody, in combination with chemotherapy (chemo) for HER2-positive breast cancer (BC): Results from a phase 1 study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-07.

Purpose: This study assessed the efficacy, safety, and pharmacokinetics of adavosertib in combination with four chemotherapy agents commonly used in patients with primary platinum-resistant ovarian cancer. Patients and Methods: Women with histologically or cytologically confirmed epithelial ovarian, fallopian tube, or peritoneal cancer with measurable disease were enrolled between January 2015 and January 2018 in this open-label, four-arm, multicenter, phase II study. Patients received adavosertib (oral capsules, 2 days on/5 days off or 3 days on/4 days off) in six cohorts from 175 mg once daily to 225 mg twice daily combined with gemcitabine, paclitaxel, carboplatin, or pegylated liposomal doxorubicin. The primary outcome measurement was overall response rate. Results: Three percent of patients (3/94) had confirmed complete response and 29% (27/94) had confirmed partial response. The response rate was highest with carboplatin plus weekly adavosertib, at 66.7%, with 100% disease control rate, and median progression-free survival of 12.0 months. The longest median duration of response was in the paclitaxel cohort (12.0 months). The most common grade ≥3 adverse events across all cohorts were neutropenia [45/94 (47.9%) patients], anemia [31/94 (33.0%)], thrombocytopenia [30/94 (31.9%)], and diarrhea and vomiting [10/94 (10.6%) each]. Conclusions: Adavosertib showed preliminary efficacy when combined with chemotherapy. The most promising treatment combination was adavosertib 225 mg twice daily on days 1–3, 8–10, and 15–17 plus carboplatin every 21 days. However, hematologic toxicity was more frequent than would be expected for carboplatin monotherapy, and the combination requires further study to optimize the dose, schedule, and supportive medications.

Introduction/Background This first-in-human, phase 1 study aimed to characterize the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetic (PK) profile, and antitumor activity of RAD140, an oral selective androgen receptor (AR) modulator (SARM). Patients and Methods This dose-escalation study with a 3 + 3 design and PK expansion cohort enrolled postmenopausal women with ER+/HER2- metastatic breast cancer (mBC). Serum sex hormone-binding globulin (SHBG) and prostate-specific antigen (PSA) were used as surrogate markers of AR engagement. Results Twenty-two (21 AR+) heavily pretreated mBC patients were enrolled. Dose levels included 50 mg (n = 6), 100 mg (n = 13), and 150 mg (n = 3) once daily (QD). Most frequent (> 10%) treatment-emergent adverse events (TEAEs) were elevated AST (59.1%), ALT (45.5%), and total blood bilirubin (27.3%), and vomiting, dehydration, and decreased appetite and weight (27.3% each). Grade 3/4 TEAEs occurred in 16 (72.7%) patients and included elevations in AST/ALT and hypophosphatemia (22.7% each). Treatment-related TEAEs occurred in 17 per 22 patients (77.3%); 7 (31.8%) were Grade 3; none were Grade 4. The half-life (t1/2) of 44.7 hours supported QD dosing. At the MTD of 100 mg/day, 1 patient with an ESR1 mutation at baseline had a partial response. Overall, clinical benefit rate at 24 weeks was 18.2%, and median progression-free survival was 2.3 months. SHBG decreased in 18 per 18 patients, and PSA increased in 16 per 20 patients. Paired baseline and on-treatment tumor biopsies demonstrated AR engagement. Conclusion RAD140 is a novel oral AR-targeted agent for the treatment of AR+/ER+/HER2- mBC with an acceptable safety profile and preliminary evidence of target engagement and antitumor activity.

Approved antibody-drug conjugates (ADCs) for HER2-positive breast cancer include trastuzumab emtansine and trastuzumab deruxtecan. To develop a novel HER2 ADC, we selected an antibody that does not compete with trastuzumab or pertuzumab for binding, conjugated to a reduced potency PBD (pyrrolobenzodiazepine) dimer payload. PBDs are potent cytotoxic agents that alkylate and cross-link DNA. We modified the PBD dimer to alkylate, but not cross-link DNA. This HER2 ADC, DHES0815A, demonstrated in vivo efficacy in models of HER2-positive and HER2-low cancers and was well-tolerated in cynomolgus monkey safety studies. Mechanisms of action include induction of DNA damage and apoptosis, activity in non-dividing cells, and bystander activity. A dose-escalation study in patients with HER2-positive metastatic breast cancer showed early signs of anti-tumor activity with limited toxicity. However, delayed dermal, ocular and pulmonary toxicities developed. The delayed onset, as well as non-resolvable nature of the toxicities resulted in termination of the phase 1 trial.

Background: In US clinical practice, GnRH agonists are widely used to suppress ovarian function in pre/perimenopausal patients with breast cancer that is moderate-to high-risk for recurrence. Despite extensive use of leuprolide acetate (LA) for ovarian suppression, regulatory approval for this indication has not been established in the US. Additionally, existing three month formulations may not reliably provide ovarian suppression, as demonstrated by escapes in estradiol (E2). An extended-release LA product with a 3-month dosing period specifically developed for ovarian suppression in patients with breast cancer could fill this unmet need. TOL2506 is a 3-month, extended-release formulation of 30 mg of LA. This combination of active drug and in situ polymeric extended release technology is expected to deliver higher exposure to drug than the currently available 3-month (22.5 mg) formulations of LA marketed for advanced prostate cancer and potentially reduce escapes in E2 over the dosing period. Methods: TOL2506A (OVELIA) is a phase 3, single arm, open-label study evaluating the effectiveness of TOL2506 to suppress ovarian function in premenopausal women with HR+, HER2-negative breast cancer. Approximately 250 subjects will be enrolled targeting 220 evaluable subjects, with 30% aged 40 years or younger. Subjects must be premenopausal women, age 18-49 (inclusive), with a diagnosis of Stage I, II, or III HR+, HER2-negative breast cancer (ER>1% and/or, PR>1%, HER2-negative per ASCO CAP guidelines), who are candidates for ovarian suppression with endocrine therapy. For subjects receiving chemotherapy, premenopausal status will be determined prior to initiating chemotherapy. Male subjects with HR+, HER2-negative breast cancer may also be eligible, but will be evaluated for safety analyses only. Eligible subjects will enter the 48 week Treatment Period in 2 groups: those receiving tamoxifen concurrently with TOL2506 or those who initiate therapy with an aromatase inhibitor (AI; letrozole, anastrozole, or exemestane) beginning 6 weeks after the first administration of TOL2506, if E2 < 20 pg/mL has been achieved. After Week 12, subjects will be allowed to switch from receiving an AI to receiving tamoxifen or from tamoxifen to AI at the Investigator’s discretion. Subjects will receive 4 doses of TOL2506 every 12 weeks over the 48 week study duration. The primary endpoint to be evaluated is ovarian suppression, defined as ≥ 90% of subjects with LH levels < 4 IU/L at Week 6. Secondary endpoints include suppression of LH, E2 (< 20 pg/mL for tamoxifen cohort and < 2.72 pg/mL for AI cohort) and absence of menses at weeks 6, 12, 24, 36, and 48. NCT04906395 Citation Format: Ryan Turncliff, Erika Hamilton, Kerlin Lynch, Stuart N. Atkinson. A Phase 3 study evaluating ovarian suppression following three-month leuprolide acetate in combination with endocrine therapy in premenopausal subjects with HR+, HER2-negative breast cancer (OVELIA) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT3-04-01.

There is growing interest in targeting the androgen receptor (AR) in advanced/metastatic breast cancer. It has been recently demonstrated preclinically that AR activation, rather than AR suppression, exerts potent antitumor activity across a number of ER+/AR+ breast tumors, including those resistant to standard-of-care endocrine therapy and CDK4/6 inhibitors (Hickey et al, Nature Medicine 2021 27: 310-320). Mechanistically, agonist activation of AR altered the genomic distribution of ER and essential co-activators resulting in repression of ER-regulated cell cycle genes and upregulation of AR target genes, including known tumor suppressors. EP0062 is an oral, non-steroidal, SARM currently being developed for the treatment of AR+/HER2-/ER+ advanced breast cancer. The efficacy and safety of EP0062 has previously been investigated in a Phase 1 clinical trial of AR+/HER2–/ER+ advanced breast cancer, and demonstrated that EP0062 has acceptable tolerability with evidence of clinical efficacy (LoRusso et al. Clinical Breast Cancer 2022 22;1 67-77). This new study is designed to further extend the evaluation of EP0062 as a potential therapy for AR+/HER2–/ER+ advanced breast cancer. The primary aim of the study is to assess tolerability and identify an optimal RP2D dose. The study will also explore the relationship between efficacy of EP0062 and AR expression, to establish a threshold for future patient selection, and undertake an initial evaluation of the safety and efficacy of EP0062 in combination with established standard of care therapies. The study will recruit up to 128 patients with AR+/HER2-/ER+ advanced breast cancer. Module A is a dose finding cohort to investigate safety, tolerability, PK and PD and to define the maximum tolerated dose (MTD) and/or Recommended Phase II Dose (RP2D). Dose finding will be based on a 3+3 design and is expected to recruit up to 32 patients. Once potential recommended doses are identified, approximately 60 evaluable patients will be randomised to two different dose cohorts in Module B in order to further optimise the RP2D dose, by further evaluation of safety and tolerability, as well as prospectively evaluate the relationship between efficacy and AR expression. In Module C, EP0062 will be combined with select standard of care targeted therapies in patients with relapsed AR+/HER2-/ER+ advanced breast cancer to confirm safety and explore efficacy. This will include approximately 36 patients across a number of single arm expansion cohorts. The key inclusion criteria are as follows: • Post-menopausal women, ≥18 years • ECOG performance status of 0 to 1 • Locally advanced or metastatic breast cancer • ER+, HER2- as per ASCO CAP guidelines • AR+, as defined as ≥ 10% AR nuclei staining by IHC • Endocrine-sensitive defined as greater than 3 years endocrine treatment prior to recurrence if recurrence occurred in the adjuvant setting, or ≥ 6 months treatment and response if recurrence occurred from primary treatment in the advanced setting • Relapsed, defined as clear and documented evidence of disease progression following ≥ 1 lines and ≤2 prior lines of previous endocrine therapy and ≤ 2 lines of chemotherapy in the advanced/metastatic setting • Measurable disease defined by RECIST version 1.1, or measurable bone-only disease EP0062 will be dosed to progression. Endpoints include incidence of DLTs during Cycle 1 of EP0062 treatment (28 days), MTD, RP2D (Module A), incidence and severity of AEs and SAEs, plasma PK parameters, Clinical Benefit Rate (complete response, partial response, or stable disease) at 24 weeks, ORR, duration of response, PFS, OS and quality of life. Clinic follow-up will be at 2 and 4 weeks, then every 4 weeks until disease progression. Recruitment is scheduled to initiate in Q4 2022. Citation Format: Elgene Lim, Erika Hamilton, Carlo Palmieri, Hendrik-Tobias Arkenau, Sue Brook, Geoff Fisher, Andrew Mazur. A phase 1/2 study to evaluate the safety and efficacy of EP0062, an oral Selective Androgen Receptor Modulator (SARM), for the treatment of AR+/HER2-/ER+ advanced breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT1-02-02.

PURPOSE Molecular biomarkers informing disease diagnosis, prognosis, and treatment decisions in patients with breast cancer are being uncovered by next-generation sequencing (NGS) technologies. In this study, we survey how NGS is used for patients with breast cancer in real-world settings with a focus on physician behaviors and sequencing results. METHODS We conducted a retrospective analysis of patients with breast cancer who received NGS testing from commercial vendors as part of standard of care from 2014 to 2019. A total of 2,635 NGS reports from 2,316 unique breast cancer patients were assessed. Hormone receptor and human epidermal growth factor receptor 2 statuses were abstracted from patient medical records. Comparative gene amplification and mutation frequencies were analyzed using Pearson's correlation and Lin's concordance statistics. RESULTS The number of physicians ordering NGS tests for patients with breast cancer increased more than six-fold from 2014 to 2019. Tissue- and plasma-based tests were ordered roughly equally by 2019, with plasma-based testing ordered most frequently in hormone receptor–positive subtypes. Patients with triple-negative breast cancer were most likely to receive NGS testing. Gene amplifications including ERBB2 were detected less frequently in our real-world data set as compared to previous genomic landscape studies, whereas the opposite was true for gene mutations including ESR1. Pathogenic mutations in the PI3K pathway (38.6%) and DNA damage repair pathway (11.0%) were frequently reported. Alterations were also reported across other cellular pathways. CONCLUSION Overall, we found that an increasing number of physicians in community settings are adopting NGS in the care of patients with breast cancer. Discrepancies between our real-world NGS data and previous genomic landscape studies are likely owed to the prevalence of plasma-based testing in community oncology clinics, as the reference data were from tissue-based NGS alone.

The checkpoint kinase 1 (CHK1) inhibitor prexasertib exhibited modest monotherapy antitumor activity in prior trials, suggesting that combination with chemotherapy or other targeted agents may be needed to maximize efficacy. The aim of this study was to determine the recommended phase II dose and schedule of prexasertib in combination with either cisplatin, cetuximab, pemetrexed, or 5-fluorouracil in patients with advanced and/or metastatic cancer, and to summarize preliminary antitumor activity of these combinations. This phase Ib, nonrandomized, open-label study comprised dose-escalation phase(s) with multiple sub-arms evaluating different prexasertib–drug combinations: Part A, prexasertib + cisplatin (n = 63); Part B, prexasertib + cetuximab (n = 41); Part C, prexasertib + pemetrexed (n = 3); Part D, prexasertib + 5-fluorouracil (n =8). Alternate dose schedules/regimens intended to mitigate toxicity and maximize dose exposure and efficacy were also explored in sub-parts. In Part A, the maximum tolerated dose (MTD) of prexasertib in combination with cisplatin (75 mg/m2) was declared at 80 mg/m2, with cisplatin administered on Day 1 and prexasertib on Day 2 of a 21-day cycle. The overall objective response rate (ORR) in Part A was 12.7%, and 28 of 55 evaluable patients (50.9%) had a decrease in target lesions from baseline. The most frequent treatment-related adverse events (AEs) in Part A were hematologic, with the most common being white blood cell count decreased/neutrophil count decreased, experienced by 73.0% (any grade) and 66.7% (grade 3 or higher) of patients. In Part B, an MTD of 70 mg/m2 was established for prexasertib administered in combination with cetuximab (500 mg /m2), both administered on Day 1 of a 14-day cycle. The overall ORR in Part B was 4.9%, and 7 of 31 evaluable patients (22.6%) had decreased target lesions compared with baseline. White blood cell count decreased/neutrophil count decreased was also the most common treatment-related AE (56.1% any grade; 53.7% grade 3 or higher). In Parts A and B, hematologic toxicities, even with the addition of prophylactic granulocyte colony-stimulating factor, resulted in frequent dose adjustments (> 60% of patients). In Part C, evaluation of prexasertib + pemetrexed was halted due to dose-limiting toxicities in two of the first three patients; MTD was not established. In Part D, the MTD of prexasertib in combination with 5-fluorouracil (label dose) was declared at 40 mg /m2, both administered on Day 1 of a 14-day cycle. In Part D, overall ORR was 12.5%. This study demonstrated the proof-of-concept that prexasertib can be combined with cisplatin, cetuximab, and 5-fluorouracil. Schedule was a key determinant of the tolerability and feasibility of combining prexasertib with these standard-of-care agents. Reversible hematologic toxicity was the most frequent AE and was dose-limiting. Insights gleaned from this study will inform future combination strategies for the development of prexasertib and next-generation CHK1 inhibitors. NCT02124148 (date of registration 28 April 2014).

A phase I study evaluated the safety, tolerability, and maximum-tolerated dose (MTD)/recommended phase II dose (RP2D) of FCN-437c, a novel, orally available cyclin-dependent kinase inhibitor (CDK4/6i), in participants with advanced/metastatic solid tumors (aSTs). FCN-437c was escalated from 50 mg (once daily [QD] on days 1–21 of 28-day cycles) to the MTD/RP2D. In the dose-expansion phase, patients with CDK4/6i-treated breast cancer, or KRAS-mutant (KRASmut) non-small-cell lung cancer (NSCLC) received the MTD. Twenty-two patients were enrolled. The most common tumors in the dose-escalation phase (n = 15) were breast, colorectal, and lung (each n = 4 [27.3%]). The dose-expansion phase included five (71.4%) patients with breast cancer and two (28.6%) with KRASmut NSCLC. Twenty (90.9%) participants experienced FCN-437c–related adverse events. Dose-limiting toxicities occurred in two (33.3%) participants (200-mg dose, dose-escalation phase): grade 3 neutropenia and grade 4 neutrophil count decreased. Due to toxicities reported at 150 mg QD, the MTD was de-escalated to 100 mg QD. One (4.5%) participant (KRASmut NSCLC, 100-mg dose) achieved a partial response lasting 724+ days, and five (22.7%) had stable disease lasting 56+ days. In conclusion, FCN-437c was well tolerated with encouraging signs of antitumor activity and disease control. Further exploration of FCN-437c in aSTs is warranted.

The long-sought discovery of HER2 as an actionable and highly sensitive therapeutic target was a major breakthrough for the treatment of highly aggressive HER2-positive breast cancer, leading to approval of the first HER2-targeted drug - the monoclonal antibody trastuzumab - almost 25 years ago. Since then, progress has been swift and the impressive clinical activity across multiple trials with monoclonal antibodies, tyrosine kinase inhibitors and antibody-drug conjugates that target HER2 has spawned extensive efforts to develop newer platforms and more targeted therapies. This Review discusses the current standards of care for HER2-positive breast cancer, mechanisms of resistance to HER2-targeted therapy and new therapeutic approaches and agents, including strategies to harness the immune system.

Dilpacimab (formerly ABT-165), a novel dual-variable domain immunoglobulin, targets both delta-like ligand 4 (DLL4) and VEGF pathways. Here, we present safety, pharmacokinetic (PK), pharmacodynamic (PD), and preliminary efficacy data from a phase I study (trial registration ID: NCT01946074) of dilpacimab in patients with advanced solid tumors. Eligible patients (≥18 years) received dilpacimab intravenously on days 1 and 15 in 28-day cycles at escalating dose levels (range, 1.25–7.5 mg/kg) until progressive disease or unacceptable toxicity. As of August 2018, 55 patients with solid tumors were enrolled in the dilpacimab monotherapy dose-escalation and dose-expansion cohorts. The most common treatment-related adverse events (TRAE) included hypertension (60.0%), headache (30.9%), and fatigue (21.8%). A TRAE of special interest was gastrointestinal perforation, occurring in 2 patients (3.6%; 1 with ovarian and 1 with prostate cancer) and resulting in 1 death. The PK of dilpacimab showed a half-life ranging from 4.9 to 9.5 days, and biomarker analysis demonstrated that the drug bound to both VEGF and DLL4 targets. The recommended phase II dose for dilpacimab monotherapy was established as 3.75 mg/kg, primarily on the basis of tolerability through multiple cycles. A partial response was achieved in 10.9% of patients (including 4 of 16 patients with ovarian cancer). The remaining patients had either stable disease (52.7%), progressive disease (23.6%), or were deemed unevaluable (12.7%). These results demonstrate that dilpacimab monotherapy has an acceptable safety profile, with clinical activity observed in patients with advanced solid tumors.

The majority of the over 250,000 new cases of invasive breast cancer diagnosed in the United States are driven by hormone receptor signaling (HR+). Since 2015, cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) have become the standard in combination with endocrine therapy (ET) for patients facing HR+ metastatic disease.There are now three approved agents in the HR+ metastatic setting such as abemaciclib, ribociclib, and palbociclib. Due to the almost doubling of progression-free survival (PFS) and improvement in overall survival (OS) in the metastatic setting, studies were conducted to examine the benefit of adding CDK4/6i in the adjuvant setting for those patients at high risk for recurrence. Despite negative results of PALLAS (palbociclib) in this setting, monarchE (abemaciclib) showed an improvement in invasive disease-free survival (IDFS) and distant recurrence-free survival (DRFS) at the 3-year time point for patients with high-risk tumor characteristics leading to its approval. Herein, we discuss the data, the population studied and for which abemaciclib is approved as well as safety, tolerability, and dose reductions for practical management of these patients.Abemaciclib is appropriate and beneficial for those patients with high-risk, node-positive, hormonally driven, human epidermal growth factor receptor 2 negative (HER2-) breast cancer.

Among breast cancers without human epidermal growth factor receptor 2 (HER2) amplification, overexpression, or both, a large proportion express low levels of HER2 that may be targetable. Currently available HER2-directed therapies have been ineffective in patients with these "HER2-low" cancers.We conducted a phase 3 trial involving patients with HER2-low metastatic breast cancer who had received one or two previous lines of chemotherapy. (Low expression of HER2 was defined as a score of 1+ on immunohistochemical [IHC] analysis or as an IHC score of 2+ and negative results on in situ hybridization.) Patients were randomly assigned in a 2:1 ratio to receive trastuzumab deruxtecan or the physician's choice of chemotherapy. The primary end point was progression-free survival in the hormone receptor-positive cohort. The key secondary end points were progression-free survival among all patients and overall survival in the hormone receptor-positive cohort and among all patients.Of 557 patients who underwent randomization, 494 (88.7%) had hormone receptor-positive disease and 63 (11.3%) had hormone receptor-negative disease. In the hormone receptor-positive cohort, the median progression-free survival was 10.1 months in the trastuzumab deruxtecan group and 5.4 months in the physician's choice group (hazard ratio for disease progression or death, 0.51; P

MEDI4276 is a biparatopic tetravalent antibody targeting two nonoverlapping epitopes in subdomains 2 and 4 of the HER2 ecto-domain, with site-specific conjugation to a tubulysin-based microtubule inhibitor payload. MEDI4276 demonstrates enhanced cellular internalization and cytolysis of HER2-positive tumor cells in vitro. This was a first-in-human, dose-escalation clinical trial in patients with HER2-positive advanced or metastatic breast cancer or gastric cancer. MEDI4276 doses escalated from 0.05 to 0.9 mg/kg (60- to 90-minute intravenous infusion every 3 weeks). Primary endpoints were safety and tolerability; secondary endpoints included antitumor activity (objective response, progression-free survival, and overall survival), pharmacokinetics, and immunogenicity. Forty-seven patients (median age 59 years; median of seven prior treatment regimens) were treated. The maximum tolerated dose was exceeded at 0.9 mg/kg with two patients experiencing dose-limiting toxicities (DLTs) of grade 3 liver function test (LFT) increases, one of whom also had grade 3 diarrhea, which resolved. Two additional patients reported DLTs of grade 3 LFT increases at lower doses (0.4 and 0.6 mg/kg). The most common (all grade) drug-related adverse events (AEs) were nausea (59.6%), fatigue (44.7%), aspartate aminotransferase (AST) increased (42.6%), and vomiting (38.3%). The most common grade 3/4 drug-related AE was AST increased (21.3%). Five patients had drug-related AEs leading to treatment discontinuation. In the as-treated population, there was one complete response (0.5 mg/kg; breast cancer), and two partial responses (0.6 and 0.75 mg/kg; breast cancer)—all had prior trastuzumab, pertuzumab, and ado-trastuzumab emtansine (T-DM1). MEDI4276 has demonstrable clinical activity but displays intolerable toxicity at doses >0.3 mg/kg.

Background: Epidermal growth factor receptor 2 (EGFR2 or HER2) has shown gene amplification/over-expression in more than 30% of all human cancers, including breast cancer, gastric, colon, salivary gland, bladder, and uterine serous carcinoma, and its overexpression in tumors is associated with poor prognosis. DB-1303 (developed by DUALITYBIO INC.) is an antibody-drug conjugate (ADC) comprised of a humanized anti-HER2 IgG1 monoclonal antibody (BAT0606), covalently linked to a proprietary DNA topoisomerase I inhibitor (P1003) via a cleavable linker containing maleimide tetrapeptide (GGFG), with a drug-to-antibody ratio (DAR) of approximately 8. Preclinical studies demonstrated a favorable safety profile and a potent antitumor activity of DB-1303 compared with approved HER2-ADC. These studies warrant further clinical development of the study drug. Methods: This is a global first-in-human Phase 1/2a study (NCT05150691) to assess the safety, tolerability, and anti-tumor activities of the study drug DB-1303 in patients with pretreated advanced/metastatic solid tumors. Patients should have histologically confirmed HER2-positive or HER2-expressing cancers who failed previously systemic therapies, ECOG 0-1, and adequate organ function. The dose escalation part will evaluate seven ascending dose levels of DB-1303 (accelerated titration design for the first dose level and “3+3” design for the rest dose levels) to determine recommended phase 2 dose (RP2D) or maximum tolerated dose (MTD). The study drug will be administrated iv infusion Q3W, and dose-limiting toxicity (DLT) will be assessed during Cycle 1 (1st 3 weeks). Phase 2a part will initiate after MTD and/or RP2D are determined. Phase 2a part only enrolls the patients with HER2-positive gastric, esophageal, or gastroesophageal junction adenocarcinoma, colorectal cancers, HER2 overexpression and HER2-low endometrial carcinoma, hormone receptor-positive (HR+)/HER2-low breast cancer, HER2-positive breast cancer, and activating HER2-mutated NSCLC. The study treatment of DB-1303 will continue until disease progression, withdrawal of consent, or unacceptable toxicity. Tumor responses will be assessed every 6-9 weeks with RECIST v1.1. The study planned to enroll 253 patients from sites in the United States, Australia, and China (88 patients in Phase I and 165 patients in Phase 2a). Citation Format: Erika Hamilton, Jian Zhang, Liming Liu, Jie Gao, Rong Shi, Shengxue Liu, Gu Wei, Yang Qiu, Kathleen Moore. A Phase 1/2a, multicenter, open-label, non-randomized first-in-human study to assess the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of DB-1303 in patients with advanced/metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT247.

Background: PRO1184 is an antibody-drug conjugate (ADC) directed to folate receptor alpha (FRα), a cell surface antigen overexpressed in multiple cancers including ovarian, endometrial, lung, mesothelioma, and breast cancer. PRO1184 consists of a human monoclonal antibody that selectively binds FRα, a novel cleavable hydrophilic linker, and a topoisomerase 1 inhibitor payload, exatecan. Previous studies demonstrated that the hydrophilic linker confers excellent physicochemical properties and pharmacokinetic (PK) profiles across a range of payload mechanisms and is superior to conventional linkers on these critical parameters for ADCs. In addition, exatecan is broadly active in many tumor types, is membrane permeable, and is not a substrate of multidrug resistance efflux pumps. It may thus lend a robust bystander effect and induce deeper or more durable responses in refractory tumors. Preclinical studies further established that PRO1184 exerts potent antitumor activity in mouse xenograft models with high, moderate, and low FRα expression, consistent with the inherent potency and expected bystander activity of the exatecan payload. PRO1184 is stable in plasma and retains the excellent PK properties and bioactivity of the unconjugated parent antibody. The preliminary safety profile of PRO1184 was more favorable than a benchmarking deruxtecan-based ADC in cynomolgus monkeys. PRO1184 is thus a promising development candidate with a potentially large therapeutic index to benefit a broad population of patients with FRα-expressing solid tumors. Methods: PRO1184-001 is an ongoing, phase 1/2, open-label dose escalation and expansion study. Eligible patients are adults with metastatic or unresectable solid tumors, including ovarian, endometrial, non-small cell lung, breast cancer, or mesothelioma. Patients must have measurable disease per the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, or mRECIST 1.1 for pleural mesothelioma. Patients must also have previously received therapies known to confer clinical benefit unless considered ineligible, refused by the patient, or not available in the region. PRO1184 is given by intravenous infusion on Day 1 of a 21-day cycle and treatment may continue until disease progression, unacceptable toxicity, or other reason for discontinuation. The primary objectives are to evaluate the safety and tolerability of PRO1184 and to identify the maximum tolerated dose, if reached, and recommended phase 2 dose (RP2D). Part A of the study consists of a dose escalation phase and Part B consists of 4 FRα-expressing tumor-specific expansion cohorts treated at the RP2D. PK, immunogenicity, and antitumor activity will also be evaluated. The study is currently enrolling at sites in the US, with future enrollment in China planned (NCT05579366). Citation Format: Justin Call, Douglas Orr, Ian Anderson, Debra L. Richardson, Zhu Chen, Sharon Ma, Naomi N. Hunder, Erika Hamilton. Phase 1/2 study of PRO1184, a novel folate receptor alpha-directed antibody-drug conjugate, in patients with locally advanced and/or metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT244.

Background: ELU001 is a novel, first-in-class, new molecular entity described as a C’Dot Drug Conjugate (CDC). ELU001 consists of ~13 folic acid targeting moieties and a payload of ~22 molecules of the topoisomerase-1 inhibitor, exatecan. Folic acid and exatecan are covalently bound by non-cleavable and cathepsin-B cleavable linkers, respectively, to short polyethylene glycol chains which surround the C’Dot’s silica core. CDCs are very small (~6 nm), allowing greater ability to penetrate more efficiently into solid tumors compared to ADCs. CDCs are rapidly eliminated by the kidneys, which is expected to lead to less toxicity than ADCs that have a longer half-life in circulation. ELU001’s high avidity is designed to promote binding to FRα on the surface on FRα overexpressing cancer cells with a wide range of antigen expression including high, moderate and low expressing tumor cells. Following antigen binding, ELU001 internalizes into the tumor cell, and traffics to the lysosome where enzymatic cleavage releases the exatecan payload. The first-in-human trial, ELU-FRα-1, is currently recruiting patients that have advanced, recurrent or refractory tumors associated with indications that are known to potentially overexpress FRα and have been shown to be topoisomerase 1 inhibitor-sensitive, and, in the opinion of the Investigator, have no satisfactory therapeutic options available. Methods: This is a Phase 1/2 multicenter, open label clinical trial with two parts: Part 1 Dose Escalation and Part 2 Tumor Group Expansion Cohort(s). Part 1 is a basket trial enrolling patients with cancer types with a high likelihood of having FRα overexpressing tumors, (specifically, ovarian, endometrial, colorectal, gastric, gastroesophageal junction, triple negative breast, or non-small cell lung cancers, or cholangiocarcinoma). Patients are receiving ELU001 weekly (QW) (once a week for 3 weeks, 1 week rest), every other week (Q2W, with no rest between cycles), or every three weeks (Q3W). Analysis of FRα expression will be retrospectively determined. Part 2 will use Simon’s Two-Stage design to evaluate 4-6 Expansion Cohorts, comprised of tumor histologies anticipated to have greatest activity to ELU001 treatment. FRα will be prospectively determined. The primary objective for Part 1 is to identify the MTD/RP2D. The primary objective for Part 2 is to determine the ORR. Secondary objectives include DOR, PFS, TFST, PFS2, OS, frequency, severity and tolerability of adverse events, PK, ADA, and FRα expression assessments. Part 1 Dose Escalation will recruit about 25 patients per dose regimen (QW; Q2W; Q3W). The first stage of Part 2 (Dose Expansion) will recruit about 15 patients per tumor group expansion cohort. The study is actively enrolling in the US and currently recruiting in Q2W Cohort 201 and Q3W Cohort A. QW Cohorts 1-3 and Q2W Cohort 101 are complete. Clinical trial information: NCT05001282. Citation Format: Wen Wee Ma, Anthony Tolcher, Cesar A. Perez, Douglass Orr, Erika Hamilton, Yujie Zhao, Yonina Murciano-Goroff, Carey Anders, Gregory P. Adams, Catherine W. Reddick, Eliel Bayever. ELU-FRα-1: a study to evaluate ELU001 in patients with solid tumors that overexpress folate receptor alpha (FRα) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT255.

Background: The current first-line (1L) standard of care (SOC) for human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC) is trastuzumab (T) plus pertuzumab (P) and a taxane. Despite advances in 1L SOC, most patients (pts) progress during maintenance therapy with T+P. Tucatinib is a tyrosine kinase inhibitor (TKI) approved in combination with T and capecitabine for adults with HER2+ MBC, with and without brain metastases (BM). In HER2CLIMB, the addition of tucatinib significantly prolonged progression-free survival (PFS) and overall survival (OS) in pts with HER2+ MBC and was well tolerated. Adding tucatinib also reduced the risk of disease progression or death in pts with untreated and/or active BM (Murthy et al. 2020, Curigliano et al. 2021). HER2CLIMB-05 investigates whether adding tucatinib to 1L SOC as maintenance therapy will extend PFS while maintaining quality of life (QOL). Methods: HER2CLIMB-05 (NCT05132582) is a phase 3, randomized, double-blind study evaluating tucatinib plus T+P as maintenance therapy for HER2+ MBC. Approximately 650 pts will be enrolled. Eligible pts will have advanced HER2+ disease, no progression on 4-8 cycles of prior 1L SOC, ECOG Performance Status of 0 or 1, and no or asymptomatic BM. Exclusion criteria include prior treatment with anti-HER2 and/or anti-epidermal growth factor receptor TKI (prior SOC for early BC is permitted) or inability to undergo contrast magnetic resonance imaging of the brain. Pts will be randomized 1:1 to receive either tucatinib or placebo twice daily, with T+P once every 21 days. Pts with HR+ disease may receive endocrine therapy. The primary endpoint is investigator-assessed PFS. Secondary endpoints include OS (key endpoint), PFS by blinded independent central review (BICR), time to deterioration of health-related QOL, central nervous system PFS, safety, and pharmacokinetic (PK) parameters. PFS and OS will be compared using a 2-sided stratified log-rank test between treatment groups. Time-to-event endpoints will be summarized using the Kaplan-Meier method. PK and safety data will be summarized using descriptive statistics. Enrollment is ongoing in the US, Canada, and several EU and APAC countries, with additional sites planned. This abstract was previously presented at ESMO-BC 2022, FPN (Final Publication Number): 415, by Veronique Dieras (reused with permission). Citation Format: Erika Hamilton, Junji Tsurutani, Joohyuk Sohn, Giuseppe Curigliano, Ciara C. O’Sullivan, Miguel Martín, Konstantinos Tryfonidis, Libero Santarpia, Shan Yang, Veronique Dieras. Phase 3 study of tucatinib or placebo in combination with trastuzumab and pertuzumab as maintenance therapy for HER2+ metastatic breast cancer (HER2CLIMB-05, trial in progress) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT065.

Background: The MONALEESA (ML) studies showed significant PFS & OS benefits for 1L ribociclib (RIB) + endocrine therapy (ET) in patients (pts) with pre/peri & postmenopausal advanced breast cancer. The benefit of RIB beyond study treatment (tx) was also observed, with improvements in PFS2 & delays in time to 1st subsequent chemotherapy (CT). While there is currently no preferred tx for the next line post-progression on a CDK4/6 inhibitor (CDK4/6i), except alpelisib in pts with a PIK3CA mutation, guidelines encourage multiple lines of ET or ET-based therapies before switching to CT (except for visceral crisis). This pooled exploratory analysis of the ML studies examined outcomes of various tx strategies post progression on RIB + ET. Methods: Data from pts receiving 1L therapy in ML-2, -3, & -7 (NSAI cohort only & excluding pts with early relapse [≤ 12 mo after end of (neo)adjuvant ET] whose prognosis is closer to that of 2L pts) were pooled & pts receiving 1st subsequent therapies after progression were analyzed. Three groups of subsequent therapies were assessed: ET only, CT, & targeted therapy. Subsequent CT comprises CT +/- any other therapy; targeted therapy includes CDK4/6i, mTORi, PI3Ki, AKTi, etc, +/- ET. Subsequent CT & targeted therapy groups are mutually exclusive. Median duration of study tx, 1st subsequent therapy, & OS (from randomization to death) were analyzed by KM methods. Weighted Cox regressions were performed using inversed propensity scoring matching method (inverse probability tx weighting [IPTW]) to ensure compatible pt characteristics between tx arms. These are not randomized comparisons; only baseline characteristics were used for the estimation of propensity scores in the IPTW, imbalance of prognostic factors at progression may exist. Results: Median follow-up time was 74 mo. 461 pts treated with RIB (81%) & 440 (86%) with PBO discontinued study tx & received a subsequent therapy. In the RIB arms, the most common 1st subsequent therapies were ET only (40%), CT (29%), combination with targeted therapy (28%), & other (4%); for the PBO arms, 34% received CT as a 1st subsequent therapy & 31% each received ET only or combination with targeted therapy (5% received other). In 14% & 20% of pts in the RIB & PBO arms, the 1st subsequent therapy was a CDK4/6i, of these 31% & 12% were RIB. In general, regardless of type of 1st subsequent therapy, the duration of both the study tx & the 1st subsequent therapy was longer for pts treated with RIB vs PBO (Table). In both RIB & PBO arms, pts who received subsequent CT had the shortest duration on study tx, whereas those who received subsequent targeted therapy combination had the longest. Among pts on 1L RIB + ET, after matching pre-randomization baseline characteristics, subsequent CDK4/6i use was associated with the longest mOS (84 [84-NE] mo), followed by ET only (60 [51-68] mo), then a non-CDK4/6i targeted therapy (52 [43-72] mo); post-progression CT was associated with the shortest mOS (37 [32-48] mo). Conclusions: This large, pooled analysis of the ML studies shows that, in general, duration of any subsequent therapy was numerically longer post-1L RIB + ET vs PBO + ET, & subsequent CT was used less frequently for pts on RIB vs PBO. Both findings confirm that upfront tx with RIB does not worsen pt outcomes. This trend in enhancement of outcomes of subsequent therapies seen with 1L RIB suggests a post-tx effect that merits further exploration. Citation Format: Erika Hamilton, Laura M. Spring, Peter A. Fasching, Sandra Franco, Richard H DeBoer, Javier Cortés, Kevin Kalinsky, Dejan Juric, Aditya Bardia, Sina Haftchenary, Agnes Lteif, Juan Pablo Zarate, Liyi Cen, Patrick Neven. Pooled analysis of post-progression treatments after first-line ribociclib + endocrine therapy in patients with HR+/HER2− advanced breast cancer in the MONALEESA-2, -3, and -7 studies [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-42.

Objectives: The addition of a CDK 4/6 inhibitors to endocrine therapy, in the first or second line setting, provides a significant improvement in progression free survival (PFS), and in some cases in overall survival (OS), with a tolerable toxicity profile. Regardless, most patients experience disease progression on these agents and ultimately develop endocrine resistance, thus, emphasizing the critical need for novel treatments. Elacestrant showed a statistically significant improvement in PFS when compared to standard of care endocrine therapy after progression on CDK4/6 inhibitors in combination with endocrine therapy (Bidard et al, 2022). Onapristone is a type I antiprogestin which prevents the progesterone receptor (PgR) from dimerizing and blocks ligand-induced protein kinase-mediated phosphorylation of the PgR. The clinical anticancer activity of onapristone, in immediate release formulation, has been previously documented in patients with hormone therapy-naïve (Robertson et al, 1999) or tamoxifen-resistant (Jonat et al, 2002) breast cancer (BC). More recently, onapristone, in extended release formulation, was evaluated in doses up to 50 mg BID in a phase 1 trial that enrolled 52 heavily pretreated patients with metastatic solid tumors, with no dose limiting toxicity observed. Among the 20 breast cancer patients enrolled, 7 (35%) had stable disease (Cottou et al, 2018). Methods: ELONA is a phase 1b/2, open-label, multicenter study. The phase 1b portion of the study will assess the safety, pharmacokinetics (PK), pharmacodynamics, and preliminary efficacy of elacestrant plus onapristone to determine the combinations’ recommended phase 2 dose. The primary endpoint of the phase 2 part of the trial is objective response rate and secondary endpoints will include safety, duration of response, clinical benefit rate, PFS, and OS, in addition to pharmacodynamics markers using ctDNA. Eligible patients are pre-, peri- and post-menopausal women and men aged ≥18 years with ER+/PgR+,HER2- tumors and an Eastern Cooperative Oncology Group performance status ≤2 with at least one measurable lesion at baseline, as per RECIST version 1.1. Prior therapy in the metastatic setting includes at least one anti-hormonal therapy in combination with a CDK4/6i. No prior chemotherapy regimen in the metastatic setting is allowed. The phase 1b dose-escalation portion of the study will evaluate dose-limiting toxicities (DLTs) of the combination in up to 4 cohorts of 6 patients each. Citation Format: Erika Hamilton, Lajos Pusztai, Hatem H. Soliman, Sara Hurvitz, Krzysztof Grzegorzewski, Nassir Habboubi, Priya Marreddy, Tarek Sahmoud, Nuhad Ibrahim. ELONA: An open-label, phase 1b-2 study of elacestrant, in combination with onapristone in patients with estrogen receptor-positive, progesterone receptor-positive, HER2-negative advanced or metastatic breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-01-04.

Background: Elacestrant demonstrated significantly prolonged progression-free survival (PFS) and a manageable safety profile compared with standard of care endocrine therapy in the phase 3 EMERALD trial that enrolled patients with estrogen-receptor positive (ER+)/HER2− mBC following disease progression on prior endocrine and cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) therapy. Benefit was observed in the overall population and in patients with ESR1 mutations. Combining elacestrant with targeted agents utilized in combination with endocrine therapy in mBC is of therapeutic interest. Methods: ELEVATE is a phase 1b/2 trial designed to evaluate the combination of elacestrant with alpelisib, everolimus, palbociclib, abemaciclib, or ribociclib. Eligible patients (pts) are women or men with ER+/HER2− locally advanced or mBC, measurable disease per RECIST v1.1 or ≥1 lytic or mainly lytic bone lesion, ECOG PS ≤1, no inflammatory breast cancer or uncontrolled central nervous system metastases, in addition to treatment-arm specific eligibility criteria as detailed below. In the phase 1b portion, pts who have received prior aromatase inhibitor (AI) and CDK4/6i will be enrolled in three 6-patient cohorts for each combination except abemaciclib (under study in a separate trial). Patients will receive elacestrant with the targeted agent at reduced or full doses. The primary endpoint of phase 1b is to determine the recommended phase 2 dose for each combination. Secondary endpoints are safety, pharmacokinetics, pharmacodynamics, and efficacy (objective response rate [ORR], duration of response [DoR], clinical benefit rate [CBR], PFS, and overall survival [OS]). The phase 2 portion will enroll 5 separate arms: A) pts with PIK3CA mutation(s) and prior AI + CDK4/6i: alpelisib + elacestrant, n=50; B) pts with prior AI + CDK4/6i: everolimus + elacestrant, n=50; C) pts with prior AI + CDK4/6i: abemaciclib or ribociclib (investigator’s [inv] choice) + elacestrant, n=60 (30 per combination); D) pts with prior AI only (no CDK4/6i): palbociclib, abemaciclib or ribociclib (inv choice) + elacestrant, n=90 (n=30 per combination); E) pts with no prior systemic therapy: palbociclib or ribociclib (inv choice) + elacestrant, n=90 (n=45 per combination). No prior fulvestrant or chemotherapy is allowed in any arm and no more than 2 prior hormonal therapies are permitted in arms A-D. Prior therapy restrictions apply to the mBC setting or within 12 months of adjuvant therapy. The primary endpoint for the phase 2 portion is the estimation of PFS at 6 months in arms A, B, and C and at 12 months in arms D and E. Secondary endpoints will include ORR, DoR, CBR, PFS, OS, and safety. The Kaplan-Meier method will be used to estimate PFS. Descriptive statistics will be used to evaluate response and safety. Citation Format: Hope Rugo, Aditya Bardia, Javier Cortés, Giuseppe Curigliano, Erika Hamilton, Sara Hurvitz, Sibylle Loibl, Simona Scartoni, Tarek Sahmoud, Krzysztof Grzegorzewski, Nassir Habboubi, Joyce O’Shaughnessy. ELEVATE: A phase 1b/2, open-label, umbrella study evaluating elacestrant in various combinations in women and men with metastatic breast cancer (mBC). [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-01-03.

Background Camizestrant (C), a next-generation oral selective estrogen receptor (ER) antagonist and degrader (ngSERD) has shown promising clinical activity in ER+ breast cancer (BC) in the Phase 1 SERENA-1 study1,2 with a dose-dependent safety profile. The Phase 2 randomized SERENA-2 study (NCT04214288) initially assessed three doses of C vs fulvestrant (F) in post-menopausal women with ER+ HER2˗ BC with disease recurrence or progression after ≤1 endocrine therapy (ET) in the advanced setting. Methods SERENA-2 evaluated efficacy and safety of C 75, 150 or 300 mg monotherapy QD vs F (per label). Eligible patients were randomized 1:1:1:1. The Primary objective was to determine clinical efficacy of C vs F by investigator-assessed progression-free survival (PFS). Secondary endpoints included objective response rate, response duration, clinical benefit rate at 24 weeks, overall survival and safety. Patients had no prior F or oral SERD and ≤1 ET and ≤1 chemotherapy (CTX) in the advanced setting. To assess the impact of prior CDK4/6 inhibitor (CDK4/6i) treatment, randomization was stratified so that 50% of patients had prior CDK4/6i. Planned enrolment of 288 patients began in April 2020. The C 300 arm was closed after 20 patients were enrolled, changing target enrolment to 236. By August 2021, 240 patients had been randomized. Primary analysis was triggered when 108 progression events (75% maturity) had occurred in the best performing pair (C vs F) in August 2022. Efficacy analyses compared C 75 and 150 mg doses with F, with no formal analyses of C 300 vs F. 108 events for pairwise comparison vs F gave 86% power at the 2-sided 10% significance level. Primary analyses used a Cox proportional hazards model to compare PFS, adjusting for prior CDK4/6i and lung/liver metastases. ESR1 mutations (ESR1m) were detected in plasma samples using next-generation sequencing. Results 119/240 (49.6%) patients had had prior CDK4/6i therapy. At baseline, 88 (36.7%) patients had detectable ESR1m and 140 (58.3%) had lung/liver metastases. Prior CTX or ET rates in the advanced setting were 19.2 and 65.4%. Treatment-emergent adverse events (AEs) (grade ≥3) occurred in 77.0 (12.2), 90.4 (21.9) and 68.5 (13.7) % of patients in the C 75, C 150 and F arms. AEs leading to treatment discontinuation occurred in 2.7, 0 and 0% of patients in the C 75, C 150 and F arms. The most common AEs considered by the investigator to be causally related to study drug were photopsia (18.4%) and (sinus) bradycardia (13.6%) – all were grade 1 or 2. Hot flush (2.7%) and myalgia (2.7%) were the most common AEs related to F. Conclusions SERENA-2 is the first Phase 2 trial investigating multiple dose levels of an ngSERD vs F in post-menopausal women with advanced ER+ HER2˗ BC with disease recurrence or progression after ≤1 ET in the advanced setting. C at both 75 and 150 mg dose levels showed a statistically significant and clinically meaningful benefit in PFS vs F in the overall study population, and was well tolerated. The results of SERENA-2 support the further development of C in ER+ HER2- BC. Acknowledgements AstraZeneca sponsored this trial and funded medical writing support from Helen Heffron (InterComm International). References 1. Baird R, Oliveira M, Ciruelos Gil EM, et al. SABCS 2020 Virtual Meeting. Abstract PS11-05; 2. Oliveira M, Hamilton EP, Incorvati J et al. ASCO 2022 Annual Meeting, Chicago, IL, USA. Abstract 1032. Citation Format: Mafalda Oliveira, Denys Pominchuck, Zbigniew Nowecki, Erika Hamilton, Yaroslav Kulyaba, Timur Andabekov, Yevhen Hotko, Tamar Melkadze, Gia Nemsadze, Patrick Neven, Yuriy Semegen, Vladmir Vladmirov, Claudio Zamagni, Hannelore Denys, Frederic Forget, Zsolt Horvath, Alfiya Nesterova, Maxine Bennett, Bistra Kirova, Teresa Klinowska, Justin Lindemann, Delphine Lissa, Alastair Mathewson, Christopher Morrow, Zuzana Traugottova, Ruaan Van Zyl, Ekaterine Arkania. GS3-02 Camizestrant, a next generation oral SERD vs fulvestrant in post-menopausal women with advanced ER-positive HER2-negative breast cancer: Results of the randomized, multi-dose Phase 2 SERENA-2 trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS3-02.

Background: Trastuzumab deruxtecan (T-DXd) is approved in the United States and European Union for use in patients (pts) with HER2+ unresectable/metastatic breast cancer (mBC) after ≥1 prior anti–HER2 regimen(s). Approval was based on the randomized, multicenter, open-label, phase 3 DESTINY-Breast03 study (NCT03529110), in which T-DXd demonstrated statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared with trastuzumab emtansine (T-DM1). At the primary interim analysis (data cutoff May 21, 2021), the risk of disease progression or death was reduced by 72% with T-DXd (P < 0.001; Cortes et al. N Engl J Med 2022). Overall survival (OS) data were immature for both treatment groups; although the prespecified cutoff for significance was not reached (NR), a trend toward benefit with T-DXd was observed. With further follow-up, we report results from the prespecified OS analysis of DESTINY-Breast03 (data cutoff July 25, 2022), including updated efficacy and safety. Methods: Pts with HER2+ mBC previously treated with trastuzumab and a taxane in either the metastatic setting or (neo)adjuvant setting with progression within 6 mo of therapy, who could have received pertuzumab, were randomly assigned 1:1 to receive T-DXd 5.4 mg/kg every 3 weeks (Q3W) or T-DM1 3.6 mg/kg Q3W until disease progression. The primary endpoint was PFS by blinded independent central review (BICR). The key secondary endpoint was OS (80% powered at 2-sided significance level of 5%); other secondary endpoints included objective response rate (ORR), duration of response (DoR), PFS based on investigator assessment, and safety. Results: 524 pts received either T-DXd (n = 261) or T-DM1 (n = 263). As of the updated data cutoff, median duration of study follow-up was 28.4 mo (range, 0.0-46.9 mo) for T-DXd and 26.5 mo (range, 0.0-45.0 mo) for T-DM1. Median treatment duration was 18.2 mo (range, 0.7-44.0 mo) for T DXd and 6.9 mo (range, 0.7-39.3 mo) for T-DM1. The risk of death was reduced by 36% (HR, 0.64; P = 0.0037) with T-DXd; median OS (mOS) was NR (95% CI, 40.5 mo-not evaluable [NE]), with 72 (27.6%) OS events, for T-DXd vs NR (95% CI, 34.0 mo-NE), with 97 (36.9%) OS events, for T-DM1. Landmark 12-mo OS rate was 94.1% (95% CI, 90.4-96.4) for T-DXd vs 86.0% (95% CI, 81.1-89.8) for T-DM1; 24-mo OS rate was 77.4% (95% CI, 71.7-82.1) for T-DXd vs 69.9% (95% CI, 63.7-75.2) for T-DM1. The P value for OS crossed the prespecified boundary (P = 0.013) and was statistically significant. mPFS by BICR was 28.8 mo (95% CI, 22.4-37.9 mo) with T-DXd, compared with 6.8 mo (95% CI, 5.6-8.2 mo) with T-DM1; HR, 0.33; nominal P < 0.000001. Key efficacy and safety results are shown in the table. Grade ≥3 treatment-emergent adverse events were experienced by 56.4% of T-DXd-treated pts and 51.7% of T DM1-treated pts. Drug-related interstitial lung disease/pneumonitis, as evaluated by an independent adjudication committee, was experienced by 39 pts (15.2%) in the T-DXd arm and 8 pts (3.1%) in the T DM1 arm; no adjudicated drug-related grade 4 or 5 events were observed in pts who received T-DXd. Conclusions: Updated results confirm the superiority of T-DXd compared with T-DM1 for pts with HER2+ mBC previously treated with an anti-HER2 therapy, with highly clinically meaningful and statistically significant benefit in OS and PFS and a manageable safety profile with longer treatment duration. Editorial Acknowledgment Under the guidance of authors, assistance in medical writing and editorial support was provided by Laura Halvorson, PhD, and Rachel Hood, PhD, of ApotheCom, and was funded by Daiichi Sankyo. Funding This study was funded by Daiichi Sankyo and AstraZeneca. Table. Summary of Efficacy Results for T-DXd and T-DM1 Citation Format: Sara Hurvitz, Roberto Hegg, Wei-Pang Chung, Seock-Ah Im, William Jacot, Vinod Ganju, Joanne Win Yang Chiu, Binghe Xu, Erika Hamilton, Srinivasan Madhusudan, Hiroji Iwata, Sevilay Altintas, Jan-Willem Henning, Giuseppe Curigliano, José Manuel Pérez-García, Anton Egorov, Yali Liu, Jillian Cathcart, Shahid Ashfaque, Javier Cortés. GS2-02 Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: Updated survival results of the randomized, phase 3 study DESTINY-Breast03 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS2-02.

Background: ARV-471 is a selective, orally administered PROteolysis TArgeting Chimera (PROTAC®) protein degrader that targets wild-type and mutant ER. ARV-471 is being evaluated in patients with ER+/HER2- locally advanced or metastatic breast cancer in a first-in-human phase 1/2 study (NCT04072952). In the phase 1 dose escalation, ARV-471 monotherapy (dose range: 30–700 mg total daily dose) showed a manageable safety profile in patients who had previously received endocrine therapy and a cyclin-dependent kinase (CDK) 4/6 inhibitor. The clinical benefit rate (CBR; rate of confirmed complete or partial response or stable disease ≥24 weeks) was 40% (95% CI: 26–56) in 47 evaluable patients. The phase 2 expansion portion of the study (VERITAC) evaluated 2 doses of ARV-471.Methods: In VERITAC, ARV-471 monotherapy was administered at doses of 200 mg once daily (QD) or 500 mg QD to patients with ER+/HER2- locally advanced/metastatic breast cancer who had received ≥1 prior endocrine therapy for ≥6 months, ≥1 CDK4/6 inhibitor, and ≤1 chemotherapy regimen. The primary endpoint of CBR was evaluated in patients enrolled ≥24 weeks prior to the data cutoff. Results: As of June 6, 2022, 71 patients received ARV-471 (200 mg QD [n=35]; 500 mg QD [n=36]) in VERITAC. Across all treated patients, 69 (97.2%) were female and median age was 60 y (range: 41–86). Patients had received a median of 4 prior regimens in all settings (range: 1–10); 100% had prior CDK4/6 inhibitors, 78.9% had prior fulvestrant, and 73.2% had prior chemotherapy. ARV-471 was well tolerated at both doses, with most treatment-related adverse events (TRAEs) grade 1/2; the most common TRAEs were fatigue and nausea (Table). In all, 3 patients (1 in the 200 mg QD cohort and 2 in the 500 mg QD cohort) discontinued ARV-471 due to treatment-emergent adverse events (TEAEs); 3 patients had ARV-471 dose reductions due to TEAEs (all from 500 mg QD to 400 mg QD). CBR was 37.1% (95% CI: 21–55) in 35 evaluable patients treated at 200 mg QD and 38.9% (95% CI: 23–57) in 36 evaluable patients treated at 500 mg QD. CBR in evaluable patients with mutant ESR1 in the 200 mg QD (n=19) and 500 mg QD (n=22) cohorts was 47.4% (95% CI: 24–71) and 54.5% (95% CI: 32–76), respectively. Conclusions: In the phase 2 VERITAC expansion cohorts of patients with ER+/HER2- locally advanced/metastatic breast cancer and prior CDK4/6 inhibitor treatment, ARV-471 monotherapy showed evidence of clinical activity based on CBR, which was further enhanced in the subgroup with ESR1 mutations. The manageable AE profile observed in the phase 1 portion of the study was maintained during cohort expansion at doses of 200 mg QD and 500 mg QD. Additional analyses are ongoing.Table. TRAEs reported in ≥10% of patients overall aNo grade 3/4 TRAE occurred in >1 patient. AST=aspartate aminotransferase Citation Format: Anne F. Schott, Sara Hurvitz, Cynthia Ma, Erika Hamilton, Rita Nanda, George Zahrah, Natasha Hunter, Antoinette R. Tan, Melinda Telli, Jesus Anampa Mesias, Rinath Jeselsohn, Pamela Munster, Haolan Lu, Richard Gedrich, Cecile Mather, Janaki Parameswaran, Hyo S. Han. GS3-03 ARV-471, a PROTAC® estrogen receptor (ER) degrader in advanced ER-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer: phase 2 expansion (VERITAC) of a phase 1/2 study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS3-03.

Background: CD166 is broadly expressed in normal epithelium and overexpressed in many types of malignancies, including breast cancer. Probody® therapeutic candidates are masked antibodies, conditionally activated by tumor-associated proteases, which restricts their activity to the tumor microenvironment and minimizes ‘off-tumor’ toxicity. CX-2009 is a conditionally activated humanized anti-CD166 monoclonal antibody conjugated to DM4 that showed clinical activity in ABC patients in a phase 1 study (Boni et al. Clin Cancer Res. 2022). This phase 2 study (NCT04596150) evaluates CX-2009 as monotherapy in patients with advanced HR+/HER2− BC (Arm A) and TNBC (Arm B), and in combination with pacmilimab (a conditionally activated PD-L1) in TNBC (Arm C). Methods: Key eligibility criteria for all cohorts include: ECOG 0-1, acceptable end-organ function, measurable disease, willingness to receive ocular prophylaxis for DM-4 related toxicity, and available tumor tissue for CD166 evaluation. Eligibility criteria for HR+ BC include: 2-4 prior regimens (excluding single-agent hormonal therapy with up to 2 prior cytotoxic regimens) and a prior CDK 4/6 inhibitor in the metastatic setting; eligibility criteria for TNBC include CD166 by IHC >1% by central assessment, 1-3 prior regimens in the metastatic setting and prior taxane. All patients initially received 7 mg/kg Q3W; the protocol was subsequently amended to enroll patients at 6 mg/kg Q3W. The primary endpoint was overall response rate (ORR) using RECIST v1.1 assessed by central review. Other key endpoints include ORR by investigator assessment, clinical benefit rate at 24 weeks (CBR24; defined as any response, confirmed or unconfirmed, or SD for 24 weeks), duration of response, and progression-free survival by investigator. Archival tumor specimens and blood samples were collected for correlative research including genomic analyses. Results: As of 13 May 2022, 60 patients were enrolled in Arm A (all patients started at 7 mg/kg); 52 were evaluable for efficacy by investigator. Median duration of follow-up was 29.1 weeks (range: 3.6-60.7). Median age was 60.5 years (36, 83); pts received a median of 3.5 (1, 6) prior treatments for ABC. CD166 H-Score > 200 was reported in 53.3% of patients. Arm A met the primary efficacy endpoint with a confirmed ORR by central radiology of 14.9% (n=47); by investigator, ORR was similar at 15.4% (n=52); an additional 9 patients (17.3%) had an unconfirmed response. CBR24 was 40.4%; using only confirmed responses, CBR24 was 23.1%. Median PFS was 11.4 weeks (95% CI 9.0, 13.9). Common treatment-related all-grade adverse events (TRAEs) included blurred vision (42%), nausea (35%), fatigue (35%), diarrhea (25%), peripheral neuropathy (27%), infusion-related reaction (23%) and decreased appetite (20%). Grade ≥3 ocular and neuropathic TRAEs were 15% and 10%, respectively. AEs resulting in treatment discontinuation (AEDC) were 25%. For Arm B and C, 55 and 10 patients were enrolled (the majority received a starting dose of 6 mg/kg). For Arm B, the futility boundary was crossed (ORR < 10%). Grade ≥3 ocular and neuropathic TRAEs and AEDC at 7 mg/kg in Arm B were similar to Arm A (11%, 11% and 21% respectively); whereas at 6 mg/kg, they were reduced at 3%, 0% and 0%, respectively. Biomarker data and correlation with outcomes will be presented. Conclusions: Praluzatamab ravtansine demonstrated single-agent activity in unselected heavily pretreated patients with HR+/HER2- ABC. Time to event analyses, such as PFS, were confounded by higher-than-expected toxicity at a starting dose of 7 mg/kg. The toxicity profile was generally consistent with a DM4 payload. The lower dose of 6 mg/kg appears to be better tolerated. Additional clinical studies in HR+ABC, incorporating a starting dose of 6 mg/kg and potentially including a biomarker strategy, are warranted. Citation Format: Kathy Miller, Sara Tolaney, Leisha A. Emens, Sung-Bae Kim, Erika Hamilton, Cristina Saura, Lucia Sanz, Valentina Boni, Filipa Lynce, Juan Miguel Cejalvo, Jennifer Crozier, Shirley Wang, Hirdesh Uppal, Alison L. Hannah, Sara Hurvitz. Preliminary results from a phase 2 study of praluzatamab ravtansine (CX-2009) in patients with advanced breast cancer (ABC) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-15.

Background T-DXd is a novel antibody-drug conjugate composed of an anti-HER2 antibody, cleavable tetrapeptide-based linker, and membrane-permeable topoisomerase I inhibitor payload. In a phase 2 study in patients (pts) with HER2+ (IHC 3+ or IHC 2+/ISH+), unresectable or metastatic breast cancer (MBC) previously treated with trastuzumab emtansine (T-DM1), the confirmed ORR (cORR) with T-DXd was 60.9% and median PFS (mPFS) was 16.4 mo (Modi NEJM 2020). In pts with HER2-low (IHC 2+/ISH−, IHC 1+) advanced BC, cORR was 37.0% and mPFS 11.1 mo in a phase 1 study (Modi J Clin Oncol 2020). Recently, T-DXd was approved for the treatment of adult pts with HER2+, unresectable or MBC who have received ≥ 2 prior anti-HER2-based regimens (US) or had prior chemotherapy and are refractory to or intolerant of standard treatments (Japan). In preclinical models, T-DXd combined with an anti-PD-1 antibody had greater efficacy than either agent alone (Iwata Mol Cancer Ther 2018). We conducted a phase 1b, open-label, multicenter, 2-part study of T-DXd in combination with nivolumab (Nivo) in pts with HER2-expressing (by centrally testing) MBC or advanced urothelial cancer (DS8201-A-U105; NCT03523572); interim results for the BC cohorts are presented. Methods Pts were aged ≥18 y and immune checkpoint inhibitor naive. Pts were enrolled in the United States and Europe. In part 1 (dose escalation), pts received T-DXd 3.2 or 5.4 mg/kg intravenously (IV) every 3 weeks (q3w) and Nivo 360 mg IV q3w to determine the recommended dose for expansion (RDE). In part 2, the RDE was given to 2 MBC cohorts: HER2+ (IHC 3+ or IHC 2+/ISH+) disease that progressed on prior T-DM1 or HER2 low (IHC 1+ or IHC 2+/ISH−) disease that progressed on prior standard treatments. The primary efficacy endpoint is cORR by independent central review (ICR) per RECIST version 1.1 in part 2. Additional endpoints include duration of response (DOR), disease control rate (DCR), PFS, OS, safety, and pharmacokinetics. Results 52 pts with MBC were enrolled. In part 1, 4 pts received T-DXd 3.2 mg/kg (HER2+, n=3; HER2 low, n=1), 3 pts received 5.4 mg/kg (all HER2+). In part 2, 45 pts received the RDE of T-DXd 5.4 mg/kg and Nivo 360 mg (HER2+, n=29; HER2 low, n=16 [13 HR+]); median follow-up time was 7.0 and 6.9 mo, respectively. All pts (n=48) who received RDE were female; median duration of follow-up was 6.9 mo. HER2+ pts had a median age of 55 y and median of 5 prior lines of metastatic/locally advanced therapy. At data cutoff (June 8, 2020), 56.3% of pts remained on treatment (median treatment duration: T-DXd, 6.5 mo; Nivo, 5.2 mo). HER2 low pts had a median age of 47 y, median of 4 prior lines, and 50.0% remained on treatment (median: T-DXd, 6.3 mo; Nivo, 4.9 mo). In pts treated at RDE, the cORR by ICR in the HER2+ cohort was 59.4% (19/32, 18 PR) and for the HER2 low cohort was 37.5% (6/16, all PR). The DCR was 90.6% and 75.0% in the HER2+ and HER2-low cohorts, respectively. Median DOR was not reached in either cohort; median PFS was 8.6 mo (95% CI, 5.4-NE) for the HER2+ cohort and 6.3 mo (95% CI, 2.3-NE) for the HER2 low cohort. Adverse events (AEs) grade ≥3 occurred in 43.8% (18.8% related to T-DXd, 18.8% to Nivo) of pts treated at RDE (n=48); anemia (16.7%) and transaminase increase (6.3%) were most common. Nausea (54.2%), fatigue (45.8%), and alopecia (41.7%) were the most common any-grade AEs. 5 pts (10.4%, all HER2+) had treatment-related interstitial lung disease (ILD) as adjudicated by an independent committee (grade 5, n=1; grade 2, n=4). No other deaths associated with a drug-related AE occurred. Conclusions In pts with HER2-expressing MBC, T-DXd plus Nivo demonstrated antitumor activity consistent with prior studies of T-DXd and had an acceptable safety profile in this interim analysis; whether adding IO therapy to T-DXd benefits pts requires longer follow-up and additional studies. Citation Format: Erika Hamilton, Charles L Shapiro, Daniel Petrylak, Valentina Boni, Miguel Martin, Gianluca Del Conte, Javier Cortes, Laila Agarwal, Hendrik-Tobias Arkenau, Antoinette R. Tan, Philip Debruyne, Anna Minchom, Annemie Rutten, Frances Valdes-Albini, Evan Y Yu, Bincy Augustine, Anthony D'Amelio, Jr., Daniel Barrios, Sara A. Hurvitz. Trastuzumab deruxtecan (T-DXd; DS-8201) with nivolumab in patients with HER2-expressing, advanced breast cancer: A 2-part, phase 1b, multicenter, open-label study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD3-07.

Background Tucatinib (TUC) is a highly selective oral tyrosine kinase inhibitor of HER2 with minimal inhibition of EGFR. It was recently approved by the FDA for patients (pts) with HER2+ metastatic breast cancer (MBC), including pts with brain metastases (BM) whose cancers have progressed on at least 1 prior anti-HER2 regimen in the metastatic setting. In the HER2CLIMB (NCT02614794) pivotal trial, pts with HER2+ MBC previously treated with trastuzumab (T), pertuzumab, and trastuzumab emtansine (T-DM1) were randomized to receive TUC or placebo in combination with T and capecitabine (C). The addition of TUC resulted in clinically meaningful and statistically significant improvements in overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) in HER2+ MBC pts. Primary methods and outcomes have been reported previously (Murthy, NEJM 2019). Here we present an exploratory analysis describing the outcomes in the HER2CLIMB trial based on hormone receptor (HR) status. Methods Pts were randomized 2:1 to receive TUC or placebo in combination with T and C. All pts had a baseline brain MRI and randomization was stratified by presence of BM, ECOG status, and geographic region. All pts with HER2+ MBC who were positive for either or both estrogen receptor and progesterone receptor (> 1%) were assigned to the HR “positive” subgroup. Pts not meeting the above criteria were assigned to the HR “negative” subgroup. For the exploratory HR+/HR- efficacy analysis presented here, PFS per RECIST 1.1 by blinded independent central review was evaluated in the first 480 pts enrolled. OS, PFS in pts with baseline BM, and confirmed ORR in pts with measurable disease were evaluated in the total study population. P values presented for PFS are nominal. Results Overall, 612 pts were enrolled to HER2CLIMB; 370 pts (60%) had HR+ and 242 (40%) had HR- tumors. Baseline demographics and disease characteristics in HR+/HR- subgroups were generally balanced between treatment arms. In the HR+ group, there was a 42% reduction in the risk of progression or death in the TUC arm (hazard ratio: 0.58; 95% CI: 0.42, 0.80; P=0.0008); median (95% CI) PFS was 7.6 mo (7.4, 9.5) in the TUC arm vs 5.6 mo (4.3, 7.4) in the control arm. In the HR- group, there was a 46% reduction in the risk of progression or death in the TUC arm (hazard ratio: 0.54; 95% CI: 0.34, 0.86; P=0.008); median (95% CI) PFS was 8.1 mo (7.0, 11.6) in the TUC arm vs 4.2 mo (3.1, 8.6) in the control arm. In the total population, median OS was 21.7 mo vs 18.2 mo in HR+ in the TUC arm vs control arm, respectively; median OS in HR- was 31.1 mo in the TUC arm vs 14.1 mo in the control arm. In pts with BM in the HR+ group (n=166 [45%]), there was a 52% reduction in the risk of progression or death (hazard ratio: 0.48; 95% CI: 0.31, 0.75; P=0.0008); median (95% CI) PFS was 7.5 mo (5.6, 9.5) in the TUC arm vs 5.1 mo (4.1, 5.7) in the control arm, and median OS was 18.1 mo vs 12.8 mo, respectively. In pts with BM in the HR- group (n=125 [52%]), there was a 50% reduction in the risk of progression or death (hazard ratio: 0.50; 95% CI: 0.27, 0.95; P=0.03); median (95% CI) PFS was 7.8 mo (6.1, 11.6) in the TUC arm vs 5.4 mo (2.9, 8.6) in the control arm, and median OS was 18.5 mo vs 11.5 mo, respectively. In the total population, ORR was numerically higher in the TUC arm vs the control arm regardless of HR status (HR+: 37.4% [95% CI: 30.8, 44.5] vs 27.1% [95% CI: 19.0, 36.6], respectively and HR-: 45.3% [95% CI: 36.7, 54.0] vs 15.6% [95% CI: 7.8, 26.9], respectively). Conclusions Among pts with HER2+ MBC previously treated with T, pertuzumab, and T-DM1, the addition of TUC to T and C showed clinically meaningful improvements of PFS, OS, and ORR independent of HR status. Furthermore, pts with HR+ and HR- MBC with BM derived similar benefit from the addition of TUC to T and C. Citation Format: Erika Hamilton, Mattea Reinisch, Sherene Loi, Alicia Okines, Paula R. Pohlmann, Eva Harder Brix, Hugues Bourgeois, Belinda Yeo, Cheryl Aylesworth, Melody Cobleigh, Anthony Goncalves, Rebecca Moroose, Katherine H.R. Tkaczuk, Michaela Tsai, Christine Simmons, Michael Andersson, Hatem Soliman, Michelina Cairo, Lisa A. Carey, David Cameron, Jorge Ramos, Wentao Feng, Mafalda Oliveira. Tucatinib vs placebo in combination with trastuzumab and capecitabine for patients with locally advanced unresectable or HER2-positive metastatic breast cancer (HER2CLIMB): Outcomes by hormone receptor status [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD3-08.

Background: Molecular biomarkers such as the expression status of hormone receptors (HR) and HER2 influence disease diagnosis, prognosis, and treatment decisions in breast cancer patients. Recent advances in genetic sequencing technologies and targeted therapies have revealed additional actionable biomarkers including PIK3CA, ESR1, and BRCA1/2; however, it remains unclear whether physicians in community-based clinics are universally adopting molecular profiling practices. Here, we describe the utility of next generation sequencing (NGS) in the care of breast cancer patients in community-based clinics with a focus on physician behaviors and molecular landscapes. Methods: Sarah Cannon provides clinical research services to medical oncology practices who order NGS panels as part of standard of care. Genospace, Sarah Cannon’s web-based precision medicine platform, links NGS test results with electronic medical records to identify and analyze clinico-genomic data of molecularly-profiled cancer patients. Here, a total of 2,673 NGS reports from 2,313 unique patients dated between January 2014 and December 2019 were analyzed. Hormone statuses were abstracted from physician notes using natural language processing capabilities and manual abstraction. Linear regression modeling was used for statistical analysis. Results: Physician ordering of NGS tests for breast cancer patients increased 6.3-fold from 2014 to 2019. Ordering of plasma-based NGS tests increased from 0.6% (versus 99.4% tissue) in 2014 to 47.0% (versus 53.0% tissue) in 2019. The time from initial diagnosis to NGS results increased from a median of 1008 days in 2015 to 1296 days in 2019 (p < 0.05), while the time from specimen collection to NGS test results (tissue only) decreased from 53 days in 2015 to 28 days in 2019 (p < 0.01). The majority of NGS-tested breast cancer patients were HR+/HER2- (62.6%), followed by HR-/HER2- (21.5%), HR+/HER2+ (8.4%), HR-/HER2+ (4.4%), and HER2 equivocal (3.0%). Plasma-based NGS testing was utilized more commonly in HR+ cancers (43.4% of HR+; 25.3% of HR-). In agreement with published studies, BRCA1 alterations were enriched in HR- cancers (1.7% of HR+; 6.6% of HR-) and BRCA2 alterations were enriched in HR+ cancers (6.4% of HR+; 3.2% of HR-). Amplifications in CCND1 (21.7% of HR+; 2.2% of HR-) and FGFR1 (18.1% of HR+; 6.2% of HR-) were also enriched in HR+ cancers, as were mutations in ESR1 (18.9% of HR+; 1.0% of HR-). PIK3CA mutations occurred most frequently in HR+ cancers (45.0%), but were also present in HR- cancers (20.9%). TP53 mutations were comparatively high in HR- cancers (42.9% of HR+; 94.8% of HR-). Conclusions: The usage of NGS for the care of breast cancer patients is increasing in community settings. Plasma-based NGS tests are ordered more frequently in HR+ cancers, likely as a result of difficult-to-biopsy and poor yield bone-only disease. Despite increased testing frequencies, NGS tests are ordered later-in-care which may be a reflection of earlier diagnosis or the development of more efficacious standard of care therapies in front line settings. The tissue specimens sent for sequencing are collected closer to the test date, indicating improved tissue processing systems and prioritization of fresh specimen collection for NGS testing. Overall, physicians are adopting NGS-testing as part of standard of care for breast cancer patients in the community setting and are discovering actionable mutations. Frequency of detection of molecular biomarkers in NGS-tested breast cancer patientsTissueTissueTissueTissuePlasmaPlasmaPlasmaPlasmaGeneAlterationHR+/HER2-HR-/HER2-HR+/HER2+HR-/HER2+HR+/HER2-HR-/HER2-HR+/HER2+HR-/HER2+ERBB2Amp1.1%0.5%45.4%67.9%0.0%0.8%10.4%45.5%CCND1Amp21.3%1.7%21.8%5.1%7.5%1.7%5.2%0.0%MYCAmp9.3%15.5%18.5%17.9%1.3%5.8%1.3%9.1%FGFR1Amp17.4%6.8%18.5%3.8%6.5%3.3%2.6%0.0%PIK3CAMutation43.8%19.1%49.6%32.1%49.5%25.0%50.6%30.3%ESR1Mutation19.4%1.2%13.4%0.0%41.7%4.2%31.2%0.0%BRCA1Mutation1.9%7.2%0.8%3.8%5.1%5.0%2.6%9.1%BRCA2Mutation6.7%3.6%5.9%1.3%8.8%5.8%14.3%3.0%ERBB2Mutation3.4%1.4%11.8%6.4%9.5%1.7%15.6%12.1%TP53Mutation42.2%94.7%51.3%93.6%65.8%96.7%68.8%93.9%PTENMutation8.8%10.6%2.5%3.8%12.6%10.8%7.8%6.1%PALB2Mutation1.6%1.2%0.8%0.0%0.2%0.0%0.0%0.0%MTORMutation0.7%0.2%0.8%0.0%2.7%0.0%0.0%0.0%ARID1AMutation9.0%4.8%12.6%2.6%11.0%11.7%7.8%3.0%KRASMutation3.2%3.1%0.8%2.6%6.5%8.3%5.2%6.1%AKT1Mutation6.5%3.4%2.5%1.3%7.5%6.7%1.3%0.0%n=856n=414n=119n=78n=602n=120n=77n=33 Citation Format: Emma Sturgill, Amanda Misch, Rebecca Lachs, Carissa Jones, Dan Schlauch, Suzanne Jones, Mythili Shastry, Denise Yardley, Howard Burris, David Spigel, Erika Hamilton, Andrew McKenzie. Physician adoption and molecular landscape of next-generation sequencing in breast cancer patients from community-based clinics [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS18-34.

Background: Targeting the estrogen receptor (ER) has proven to be one of the most successful strategies in treating HR+ (ER+ and PR+) and HER2- breast cancer. Selective estrogen receptor degraders (SERD) can be used as single agents or in combination with CDK4/6 inhibitors such as palbociclib. Fulvestrant is currently the only approved agent in its class and is limited by poor oral bioavailability necessitating monthly intramuscular injections. D-0502 is an orally bioavailable SERD with potent activity in various HR+ and HER2- breast cancer cell lines and xenograft models. Its combination with palbociclib in both MCF-7 xenograft models and ESR-1 mutated (Y537S) patient derived breast cancer xenograft models resulted in further tumor growth inhibition or regression. Drug metabolism and pharmacokinetic studies both in vitro and in vivo demonstrated that D-0502 exhibits favorable PK profiles suitable for clinical development. Methods: A first-in-human phase 1 study was conducted to evaluate D-0502 in women with advanced or metastatic HR+, HER2- breast cancer (MBC) (NCT03471663). The primary objective is to characterize the safety and tolerability of D-0502 and D-0502 in combination with palbociclib, to identify an MTD and/or RP2D. The secondary objectives are to evaluate the PK properties and the preliminary anti-tumor activities. Patients received D-0502 orally once daily in 28-day cycles. The study has completed dose escalation (phase 1a), and dose expansion and combination studies (phase 1b) are ongoing. In phase Ia, patients were enrolled and evaluated using conventional 3+3 dose-escalation to identify the MTD of D-0502 as a single agent. The phase 1b was divided into 2 stages. In Stage 1, D-0502 was evaluated with palbociclib at a dose below the MTD first before escalating to the MTD. Stage 1 also included patients in China treated at a dose below and at the MTD as single agent as well as in combination with palbociclib. Stage 2 will further evaluate the MTD for both single agent and combination of D-0502 with palbociclib. Results: At the time of this abstract submission, phase 1a dose escalation is completed, R2PD has been identified, and no DLTs were observed. PK analysis of D-0502 indicates a dose proportional increase in exposure as the dose increases, and the exposure has exceeded the potential therapeutic exposure level based on preclinical studies. The Phase Ib Stage 1 portion has also completed enrollment and the study is currently enrolling patients into phase Ib Stage 2. D-0502 as a single agent or in combination has been well tolerated with radiological tumor response and clinical benefit response (CBR) observed. Safety, PK and preliminary efficacy data will be reported at the meeting presentation. Conclusion: A first-in-human phase 1 study of D-0502 has been initiated in women with advanced or metastatic HR-positive and HER2-negative breast cancer. D-0502 has been well tolerated and achieved significant exposure and preliminary clinical activity in patients. Further results will be presented at the meeting. Citation Format: Cynthia Osborne, Donald A Richards, Sharon T Wilks, Sami Diab, Dejan Juric, Kate Lathrop, Andrea Silber, William Edenfield, Amardeep Aulakh, Ben Cho, Binghe Xu, Tao Sun, Quchang Ouyang, Yanxia Shi, Kathryn Stazzone, Zhe Shi, Ling Zhang, Yaolin Wang, Erika P Hamilton. A phase 1 study of D-0502, an orally bioavailable SERD, for advanced or metastatic HR-positive and HER2-negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS11-26.

Background Mutations in p110α, encoded by PIK3CA, are present in ~40% of HR+/HER2- BCs. GDC-0077, a PI3Kα-selective inhibitor and mutant PI3Kα degrader, elicits antitumor activity in PIK3CAmut preclinical models as a single agent and when combined with endocrine therapy (ET). New evidence suggests BCs harboring multiple PIK3CAmut exhibit increased signaling through the PI3K/AKT pathway and are more sensitive to PI3Kα inhibitors compared with BCs with a single PIK3CAmut. We report a preliminary analysis of PIK3CAmut status with clinical outcomes from an ongoing study of GDC-0077 alone or with ET (letrozole/fulvestrant) ± palbociclib (palbo) in pts with PIK3CAmut HR+/HER2- mBC (NCT03006172). Methods Detectable PIK3CAmut from local tumor tissue/blood-based assay or tumor tissue by cobas PIK3CA assay were required to enroll. Plasma-derived circulating tumor (ct) DNA was collected at baseline (BL), cycle 1 day 15 (C1D15), and C2D1 (in the cohort where GDC-0077 starts at C1D15) to detect PIK3CAmut. Paired tumor samples were analyzed for Ki67 and pAKT/pS6 expression by immunohistochemistry. Single vs multiple PIK3CAmut was correlated with the percentage of pharmacodynamic (PD) inhibition of Ki67/pAKT/pS6 expression; with the PIK3CAmut allele frequency ratio between BL and C1D15 or C2D1 (MAFr15); with best overall response (BOR, RECIST v1.1); and with time on treatment (TOT) in days. Statistical analyses: Kruskal-Wallis and Mann-Whitney-Wilcoxon for group and pairwise comparisons, respectively, and two-sample proportion testing for categorical comparisons. Results Data cutoff was 03/20/2020. PIK3CAmut were detected in 87/103 (84.5%) pts with BL ctDNA available for sequencing. Multiple PIK3CAmut were detected in 21/87 (24.1%) BL ctDNA samples: 9 from pts treated with single-agent GDC-0077; 8 from pts treated with GDC-0077 + letrozole/fulvestrant; and 4 from pts treated with GDC-0077 + letrozole/fulvestrant + palbo. The median number of lines of prior therapy for metastatic disease was not different between pts with multiple (3.0 lines) vs single (2.5 lines) PIK3CAmut detected at BL (p = 0.205). Median percentage inhibition of Ki67/pAKT/pS6 expression was greater in pts with multiple (-65.8, -70.3, -66.8%, respectively) vs single (-42.1, -34.1, -29.5%) PIK3CAmut detected at BL (p = 0.095, 0.002, 0.056). Median MAFr15 was lower in pts with multiple (MAFr15 0.01) vs single PIK3CAmut (MAFr15 0.15) detected at BL (p = 0.004). Of 73 pts with both BL ctDNA-detected PIK3CAmut and BOR data, 16/16 (100%) with multiple PIK3CAmut experienced BOR of partial response (PR) or stable disease (SD) while 42/57 (73.7%) with single PIK3CAmut experienced BOR of PR or SD (p = 0.051). No pts with multiple PIK3CAmut detected experienced a BOR of progressive disease. Median TOT was greater in pts with multiple PIK3CAmut (196 days) vs single PIK3CAmut (140.5 days) detected at BL, but this was not significant (p = 0.1804). Conclusions The fraction of pts in which multiple PIK3CAmut were identified from BL ctDNA in this HR+/HER2- mBC dataset (24.1%) was slightly higher than reported elsewhere. This may be due to the method of detection (blood vs tissue) and/or the definition of multiple PIK3CAmut used. Pts in which multiple PIK3CAmut were detected by ctDNA exhibited greater depth of PD biomarker inhibition in tumors and experienced PR/SD more often compared with pts in which only one PIK3CAmut was detected. However, no significant associations were observed with the number of prior lines of therapy for metastatic disease or TOT. The dataset is currently too small to assess the impact of different treatment regimens in this study but will be re-evaluated as the data mature. Citation Format: Komal Jhaveri, Dejan Juric, Andrea Varga, Nicolas Turner, Peter Schmid, Cristina Saura, Mafalda Oliveira, Ian E Krop, Kevin Kalinsky, Antoine Italiano, Erika Hamilton, Valentina Gambardella, Andrés Cervantes, Philippe L Bedard, Bonnie P Liu, Jessica W Chen, Junko Aimi, Stephanie Royer-Joo, Jennifer L Schutzman, Katherine E Hutchinson. Preliminary correlative analysis of clinical outcomes with PIK3CA mutation (mut) status from a phase I/Ib study of GDC-0077 in patients (pts) with hormone receptor-positive/HER2-negative metastatic breast cancer (HR+/HER2- mBC) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS5-12.

RATIONALE: Addition of CDK 4/6 inhibitors to endocrine therapy has become standard for patients (pts) with ER+ and HER2- BC with improvements in overall survival. However, acquired resistance to front-line therapy is inevitable, and response to later-line therapy is poor. H3B-6545 is a selective, orally available, small molecule covalent antagonist of the estrogen receptor (ERα). H3B-6545 binds covalently to a cysteine residue at position 530 of both wild-type and the constitutively active mutant ERα proteins. H3B-6545 demonstrated significant antitumor activity in multiple PDX breast cancer models, including those with mutated ESR1 (the gene encoding ERα). A phase I-II study was conducted to explore the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics, and efficacy of this agent in advanced ER+ and Her2- breast cancer pts (NCT03250676). METHODS: PK samples in phase I were obtained at day 1 and day 15 of cycle 1 (Predose, 0.5, 1, 2, 4, 6, 8, 10, and 24 h post dose) and sparse PK samples were collected in the phase II part of the trial. For pts enrolled in the food effect sub-study of phase II, plasma samples were collected during cycle 1 on day 15 and day 22 (Predose, 0.5, 1, 2, 4, 6, 8, 10, and 24 h post dose). Nonlinear mixed effect model (NONMEM) was applied for development of population PK models to fit H3B-6545 plasma concentration data with NONMEM® version 7.4 software. R was used for data management, visualization and statistical summaries. RESULTS: This phase I-II trial enrolled 47 pts in phase I part and 83 pts in the phase II part at the recommended phase II dose of 450 mg QD as of May 15, 2020. The 1180 plasma concentrations of H3B-6545 from a total of 103 pts at doses of 100-600 mg available as of January 15, 2020 were included in this analysis, with the following characteristics [n or (median, min-max) unit]: race (n=91/5/1/6 for White/Black/Asian/others), age (62.5, 31-81) yrs, body weight (79.5, 49-140) Kg, BMI (26.9, 17.6-45.6) Kg/m2, albumin (40, 29-52) g/dL, ALP (88.5, 39-917) IU/L, ALT (28, 10-193) IU/L, AST (36.5, 13-259) IU/L, bilirubin (8.6, 1.7-25.7) µM and creatinine clearance (112, 49.5-389) mL/min. The median number of prior therapy in the metastatic setting was 3 (range: 1 - 10). Out of 103 patients, 32 pts received treatment with a single high-fat meal to test food effect on PK over a randomized crossover design. H3B-6545 plasma concentrations were best described with a one compartment disposition PK model, plus a combined first- and zero-order parallel absorption and lag time. The estimated apparent clearance (CL/F) and volume of distribution (V/F) were 31 L/h and 422 L, respectively, with a typical terminal half-life of about 10 hours. H3B-6545 was absorbed fast, with a typical tmax of about 4 hours. A moderate to high variability (40-60%) was identified in major PK parameters (CL/F, V/F, bioavailability [F1]). A high-fat meal increased bioavailability by approximately 45% and prolonged tmax, roughly from 4 hours to 6 hours post dose. No significant effect was identified from other covariates: age, body weight, race, albumin, AST, ALP, ALT, bilirubin and creatinine clearance. CONCLUSIONS: H3B-6545 PK profiles in breast cancer patients were well described by a one-compartment disposition model with no significant effect of demographics, liver and renal function. When administered with a high fat meal, H3B-6545 exposure was modestly increased. Citation Format: Oneeb Majid, Jianjun Alan Xiao, Tarek Sahmoud, Sanae Yasuda, Lisa Cantagallo, Erika P Hamilton, Timothy Pluard, Dejan Juric, Antonio Gualberto, Ziad Husseiin. Pharmacokinetics of H3B-6545 in patients with locally advanced or metastatic estrogen receptor-positive HER2 negative breast cancer (ER+ and HER2- BC) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS12-15.

Purpose: The IMpassion130 randomized trial in advanced TNBC has demonstrated improved efficacy with the addition of atezo to 1L nab-pac in patients with PD-L1+ tumors. Eganelisib is a first-in-class, novel oral agent targeting tumor-associated myeloid cells through selective inhibition of PI3K-gamma, with the goal of improving the immune response to the approved doublet combination of atezo and nab-pac. We report first results from a completed TNBC safety run-in cohort of a multicenter phase II study. Methods: Eligible patients had measurable unresectable locally advanced or metastatic TNBC, ECOG performance status 0/1, and no prior systemic therapy for advanced disease. A safety run-in was completed to assess the safety of the triplet of oral eganelisib 30 mg daily in combination with nab-pac 100 mg/m2 given on days 1, 8, & 15, and IV atezo 840 mg given on days 1 & 15. After establishing tolerability in the safety run-in (n=6), the expansion phase of the phase II study was initiated to enroll a total of approximately 60 patients (30 PD-L1+ and 30 PD-L1-). Cycles are repeated every 28 days until loss of clinical benefit, unacceptable toxicity, or consent withdrawal. The primary efficacy endpoint is confirmed Complete Response (CR) rate per RECIST v1.1. Secondary endpoints include the overall response rate (ORR) and safety assessment. Tumors are assessed every 8 weeks by CT/MRI scan. Results: We report preliminary efficacy data (as of 6/27/2020) and safety data (as of 6/09/2020) for the completed safety run-in cohort with 6 patients evaluable for safety and 4 evaluable for response defined as having had at least one post-baseline tumor assessment. 1 CR (1/4) and 3 PRs (3/4) were observed with an ORR of 100% (4/4). Responses were seen irrespective of PD-L1 status. The most common all-grade adverse events were decreased white cell count (66.7%), fatigue (50%), diarrhea (33.3%), hyperglycaemia (33.3%), transaminase elevation (16.7%), pyrexia (16.7%), and rash (16.7%). Most common grade ≥3 adverse events occurred in 3 patients (50%) including decreased lymphocytes or neutropenia (33.3%), transaminase elevation (16.7%), fatigue (16.7%), rash (16.7%), and febrile neutropenia (16.7%). Treatment was generally tolerable. Eganelisib 30 mg daily was chosen as the dose for combination with nab-pac and atezo for the expansion phase of the study. Conclusions: The novel triplet regimen of eganelisib, atezo, and nab-pac shows promising antitumor activity (4 responses/4 evaluable patients), irrespective of biomarker status, and has manageable toxicity. The expansion phase of the phase II study is currently enrolling. Updated efficacy, safety and biomarker data will be presented for the safety run-in cohort as well as initial data from the expansion phase of the phase II study. Citation Format: Erika Hamilton, Arielle Lee, Rachel Swart, Gina Newton, Brenda O'Connell, Jennifer Roberts, Halle Zhang, Hatem Soliman. Mario-3 phase II study safety run-in evaluating a novel triplet combination of eganelisib (formerly IPI-549), atezolizumab (atezo), and nab-paclitaxel (nab-pac) as first-line (1L) therapy for locally advanced or metastatic triple-negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS11-32.

Background: AZD9833 is an oral selective estrogen receptor (ER) antagonist and degrader (SERD) in Phase 2 clinical development for the treatment of ER+ HER2− breast cancer. Here we report data from Parts C and D of the ongoing Phase 1 study (SERENA-1) examining AZD9833 in combination with palbociclib, together with updated data from Parts A and B examining AZD9833 monotherapy. Methods: SERENA-1 (NCT03616587) is an ongoing open-label Phase 1 study of AZD9833 in pre- and post-menopausal women with ER+, HER2− advanced breast cancer who have previously received ≥1 endocrine therapy and ≤2 prior chemotherapies. Prior treatment with fulvestrant and/or CDK4/6 inhibitors was permitted. The primary objective is to determine the safety and tolerability of once daily (QD) AZD9833, with dose-limiting toxicities (DLTs) in the first 28 days defining the maximum tolerated dose. Secondary objectives include anti-tumor response (including circulating tumor [ct] DNA response) and pharmacokinetics. Parts A (escalation) and B (expansion) assess AZD9833 as a monotherapy, and Parts C (escalation) and D (expansion) assess AZD9833 in combination with palbociclib. Results: At a data cut-off of March 24 2020, 17 patients had received either 150 mg or 300 mg AZD9833 in combination with palbociclib, given according to its product labeling. Eighty patients had received AZD9833 monotherapy at doses of 25, 75, 150, 300, and 450 mg QD. In patients treated with AZD9833 and palbociclib, treatment-related adverse events (AEs; experienced by ≥10% of patients) included visual disturbances*, bradycardia*, asthenia, anemia, QTcF prolongation, nausea, neutropenia, decreased white blood cell count, and vomiting (*combined terms). All instances of AZD9833-related bradycardia were Grade 1. One DLT was observed in the 150 mg cohort: CTCAE Grade 2 visual disturbances, which began on Cycle 1 Day 8 and resolved by Cycle 1 Day 9 following dose interruption. The patient restarted treatment on Cycle 1 Day 15 at 75 mg and continued this dose until data cut-off. No causally related AEs led to discontinuation of AZD9833. The tolerability of AZD9833 with palbociclib was consistent with the observed tolerability profile of AZD9833 monotherapy, and the known tolerability profile of palbociclib. Pharmacokinetic analysis showed similar AZD9833 exposure for monotherapy and palbociclib combination therapy. Similarly, palbociclib exposure was comparable with simulations using a published population pharmacokinetic model. In Part A, ESR1 hotspot mutations were detected in ctDNA at baseline in 26/56 (46%) patients; 13/26 (50%) of these patients achieved a partial response or stable disease at 24 weeks, including 5/10 (50%) with a Y537S ESR1 mutation. Further, in patients with ESR1 mutations and samples available for longitudinal ctDNA analysis, 17/20 (85%) exhibited a reduction or loss of mutant ESR1 on treatment with AZD9833. Efficacy data to be presented include objective response rate and clinical benefit rate at 24 weeks. Of note, unconfirmed partial responses have been observed in Part C after the data cut-off for this abstract. Conclusions: AZD9833 continues to show an encouraging efficacy and dose-dependent safety profile as a monotherapy or in combination with palbociclib. A Phase 2 study comparing the efficacy and safety of three doses of AZD9833 versus fulvestrant (NCT04214288), and a Phase 2 pre-surgical ‘window of opportunity’ study (EUDRA-CT; 2019-003706-2) are ongoing. Citation Format: Richard Baird, Mafalda Oliveira, Eva Maria Ciruelos Gil, Manish R Patel, Begoña Bermejo de las Heras, Manuel Ruiz-Borrego, Javier García-Corbacho, Anne Armstrong, Udai Banerji, Chris Twelves, Valentina Boni, Jason Incorvati, Peter Kabos, Adam L Cohen, Bruno de Paula, Marta Capelán Rodríguez, Judy S Wang, Christina Hernando, Alejandro Falcón Gonzalez, Ivan Victoria Ruiz, Julia Lai-Kwon, Anosheh Afghani, Christos Vaklavas, Tim Brier, Steven Fox, Bistra Kirova, Teresa Klinowska, Chris Leach, Justin PO Lindemann, Richard Mather, Rhiannon Maudsley, Christopher J Morrow, Nitharsan Sathiyayogan, Andy Sykes, Li Zhang, Erika Hamilton. Updated data from SERENA-1: A Phase 1 dose escalation and expansion study of the next generation oral SERD AZD9833 as a monotherapy and in combination with palbociclib, in women with ER-positive, HER2-negative advanced breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS11-05.