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Background: Sacituzumab govitecan (SG) is an antibody-drug conjugate targeting Trop2 with an SN-38 payload recently approved for pretreated patients with locally advanced or metastatic triple-negative breast cancer (TNBC). The XenoSTART Patient-Derived Xenograft (XPDX) breast cancer platform includes over 180 models spanning all subtypes characterized with immunohistochemistry (IHC) including ER, PR, and HER2 protein levels, genomic and transcriptomic sequencing, and in vivo drug sensitivity. To better understand potential benefit of SG in breast cancers other than TNBC and further annotate our platform, Trop2 protein levels were determined in all breast models by IHC. We evaluated tumor growth inhibition by SG in 125 of our XPDX breast models and compared protein expression with agent activity. Methods: 180 breast XPDX models were evaluated for Trop2 expression (AF650, R&D Systems) and 125 were evaluated in vivo against SG; responses were grouped by ER and Trop2 status (+/-). Models were grown subcutaneously in female athymic nude mice and ER+ models supplemented with estradiol. Models were also characterized for PR, HER2, and AR protein expression by IHC and profiled using WES and RNAseq. For in vivo studies, SG was administered by intravenous injection biweekly for two cycles at 1 mg, flat; endpoints included tumor volume and time from treatment initiation with %T/C values and tumor regression reported at study completion; a T/C of ≤ 20% versus control was considered sensitive. Tumor regression (%T/C< 0%) versus Day 0 tumor volume was also reported. Results: 180 breast models were examined by IHC with 75/180 (42%) classified as ER+ and 105/180 (58%) ER-. In ER+ models 38/75 (51%) were Trop2+ and 37/75 (49%) Trop2-, and in ER- models 41/105 (39%) were Trop2+ and 64/105 (61%) Trop2-. In vivo, 20% of ER+/Trop2+ models reported sensitivity to SG, most notably models from patients with acquired resistance to CDK4/6 inhibitors, including STM001 and ST4316B. Interestingly, >70% of ER+/HER2+/Trop2+ models were insensitive to SG, including ST225 and ST340. Of 41 ER-/Trop2+ models, approximately 40% reported some response to SG with 50% of these sensitive to therapy, including ST5954 established from a patient who began treatment with SG following sample collection and is currently in remission. >75% of Trop2- models were insensitive to SG regardless of ER status. Conclusion: We screened 180 models in our XPDX breast cancer platform for Trop2 expression and compared expression with in vivo SG efficacy in 125 models. Analysis is underway to correlate receptor and molecular profiles with SG sensitivity in breast models and we are expanding expression and in vivo testing to additional indications. Citation Format: Alyssa Simonson, Johnnie Flores, Ebony Anderson, Crystal Moreno, George Plasko, Kyriakos P. Papadopoulos, Amita Patnaik, Drew Rasco, Gladys Rodriguez, Amy Lang, Muralidhar Beeram, Luis Rodriguez, Ronald Drengler, Steven Abbate, Hanni Salih, Lon Smith, Maryam Elmi, Brittany DeBerry, Arthur Rosenthal, Tatiana Hernandez, Nehal Lakhani, Manish Sharma, Michael Wick. Correlation of Trop2 expression with in vivo sensitivity to sacituzumab govitecan in a panel of breast XPDX models [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 P3-08-05.

Background: Several CDK4/6 inhibitors have recently been approved in combination with letrozole or fulvestrant in hormone receptor-positive breast cancer. Although this combination therapy has been found effective in some patients, resistance often develops. To aid in developing new therapies for CDK4/6i-resistant breast cancer and better understand potential resistance mechanisms, we established two XenoSTART Patient-Derived Xenograft (XPDX) models representing ER+/HER2- breast cancer from tissue samples collected seventeen months apart from the same patient before and after palbociclib therapy. These models designated ST4887 and ST4887B were developed and characterized for receptor expression, genomic alterations, and in vivo drug sensitivities toward multiple chemotherapies and targeted agents, including CDK4/6i and fulvestrant. Methods: Models ST4887 and ST4887B were established from metastatic samples collected from a Caucasian female with ER+/HER2- metastatic breast cancer; ST4887 was collected at age 38 from a femur mass biopsy following several treatment regimens including paclitaxel/doxorubicin/cyclophosphamide, radiation and tamoxifen. ST4887B was collected at age 39 from a liver biopsy following treatment with palbociclib/letrozole then palbociclib/fulvestrant, and finally ixabepilone/capecitabine. Both were grown subcutaneously in female athymic nude mice supplemented with exogenous estradiol. The resulting models were passaged, and receptor expression confirmed immunohistochemically; genomic analysis, including WES and RNAseq, was performed to further characterize models. For in vivo studies, both models were evaluated using several chemotherapy and targeted agents alone and in combination including cisplatin, docetaxel, CDK4/6i, fulvestrant, letrozole, olaparib, niraparib, and sacituzumab. In vivo study endpoints included tumor volume and time from treatment initiation with %T/C values and tumor regression reported at study completion; a T/C of ≤ 20% versus control was considered sensitive. Tumor regression (%T/C=< 0) versus Day 0 tumor volume was also reported. Results: ST4887 and ST4887B retained comparable receptor expression (ER=3+/HER2=1+) over tested passages with similar histology compared to archival clinical samples. DNA/RNA sequencing identified several conserved variants including a somatic BRCA2 truncation (BRCA2Y2660*); transcriptomic analysis revealed upregulation of several related genes but no notable fusions. In vivo, both models were insensitive to cisplatin or docetaxel, however ST4887 but not ST4887B was sensitive to fulvestrant or CDK4/6i therapies, although abemaciclib demonstrated some activity toward ST4887B. PARP inhibitors were active toward ST4887 and to a lesser extent ST4887B, while sacituzumab did not have a significant effect on either model. Conclusion: We established and characterized two XPDX models from the same patient before and after acquired resistance to the CDK4/6i palbociclib. Both models were found to retain receptor status and drug sensitivities similar to the patient at the time of sample collection. These models can be utilized as a valuable tool in better understanding acquired resistance to palbociclib. Citation Format: Ashwin Varma, Johnnie Flores, Alyssa Simonson, Anna Stackpole, Kyriakos P. Papadopoulos, Amita Patnaik, Drew Rasco, Muralidhar Beeram, Marisa Sandera, Michael Wick. Establishment and characterization of two ER+/HER2- XPDX models developed sequentially before and after acquired resistance to the CDK4/6 inhibitor palbociclib from a patient with 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 P1-13-22.

HER2-targeted therapies have substantially improved outcomes for patients with HER2-positive breast and gastric or gastro-oesophageal junction cancers. Several other cancers exhibit HER2 expression or amplification, suggesting that HER2-targeted agents can have broader therapeutic impact. Zanidatamab is a humanised, bispecific monoclonal antibody directed against two non-overlapping domains of HER2. The aim of this study was to evaluate the safety and anti-tumour activity of zanidatamab across a range of solid tumours with HER2 expression or amplification.This first-in-human, multicentre, phase 1, dose-escalation and expansion trial included patients aged 18 years and older, with a life expectancy of at least 3 months, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and locally advanced or metastatic, HER2-expressing or HER2-amplified solid tumours of any kind who had received all available approved therapies. The primary objectives of part 1 were to identify the maximum tolerated dose, optimal biological dose, or recommended dose of zanidatamab; all patients were included in the primary analyses. Part 1 followed a 3 + 3 dose-escalation design, including different intravenous doses (from 5 mg/kg to 30 mg/kg) and intervals (every 1, 2, or 3 weeks). The primary objective of part 2 was to evaluate the safety and tolerability of zanidatamab monotherapy in solid tumours. This trial is registered with ClinicalTrials.gov (NCT02892123), and parts 1 and 2 of the trial are complete. Part 3 of the study evaluates the use of zanidatamab in combination with chemotherapy and is ongoing.Recruitment took place between Sept 1, 2016, and March 13, 2021. In Part 1 (n=46), no dose-limiting toxicities were detected and the maximum tolerated dose was not reached. The recommended dose for part 2 (n=22 for biliary tract cancer; n=28 for colorectal cancer; and n=36 for other HER2-expressing or HER2-amplified cancers excluding breast or gastro-oesophageal cancers; total n=86) was 20 mg/kg every 2 weeks. The most frequent treatment-related adverse events in part 1 of the study were diarrhoea (24 [52%] of 46 patients; all grade 1-2) and infusion reactions (20 [43%] of 46 patients; all grade 1-2). The most frequent treatment-related adverse events in part 2 of the study were diarrhoea (37 [43%] of 86 patients; all grade 1-2 except for one patient) and infusion reactions (29 [34%] of 86 patients; all grade 1-2). A total of six grade 3 treatment-related adverse events were reported in four (3%) of 132 patients. In part 2, 31 (37%; 95% CI 27·0-48·7) of 83 evaluable patients had a confirmed objective response. There were no treatment-related deaths.These results support that HER2 is an actionable target in various cancer histologies, including biliary tract cancer and colorectal cancer. Evaluation of zanidatamab continues in ongoing studies.Zymeworks.

Supplementary Table 1. Summary of 33 Patients Treated with Abemaciclib in Dose Escalation. Supplementary Table 2. Baseline patient and disease characteristics. Supplementary Table 3. Possibly related treatment-emergent adverse events (>10% all grades) for hormone receptorpositive breast cancer cohort (n=19) receiving combination therapy with abemaciclib plus fulvestrant. Supplementary Table 4. Summary of abemaciclib pharmacokinetic parameters following a single oral administration. Supplementary Table 5. Summary of abemaciclib pharmacokinetic parameters following repeated once-daily (Q24H) or twice-daily (Q12H) oral administration. Supplementary Table 6. Efficacy for NSCLC cohort, overall and by KRAS status. Supplementary Table 7. Efficacy for other tumor-specific cohorts.

Supplementary Tables S1-2, Figure 1. Supplementary Table S1. Matrix view of Part A-2 dose titration and PK sampling scheme. Supplementary Table S2. Efficacy outcomes by investigator review per RECIST v1.1. Supplementary Figure 1. Seventeen patients were tested with IFN-γ ELISPOT assay.

Supplementary Figure 1 Total Nesvacumab (REGN910) and Total Ang2 vs Time (cycle 1) following IV infusion in Patients. Supplementary Figure 2 Serum levels of ESM1, SDF-1, PLGF-1 and sVCAM-1 following Nesvacumab (REGN910) treatment. Supplementary Figure 3 Correlative analysis of baseline serum Ang2, ESM-1, SDF-1 ,PIGF and cVCAM-1 and treatment duration. Supplementary Figure 4 Correlative analysis of baseline Ang2 in tumor vessels and treatment duration/response. Supplementary Figure 5 Ang2 and VEGF-A protein levels in tumor tissue pre and post treatment with Nesvacumab (REGN910). Supplementary Figure 6 Biomarker analysis of archival tumor tissue. Supplementary Figure 7 Microvascular density in tumor tissue pre and post treatment with Nesvacumab (REGN910). Supplementary Figure 8 Tumor cell proliferation in tumor tissue pre and post treatment with Nesvacumab (REGN910). Supplementary Figure 9 TIE-2 protein levels associated with tumor vessels pre and post treatment with Nesvacumab (REGN910)

Table S1:Summary of baseline pathological diagnosis; Table S2:Noncompartmental Pharmacokinetic Summary Following Oral Administration of ralimetinib on Day 1 and on Day 14 (Cycle 1) - Capsule Formulation; Table S3: Noncompartmental Pharmacokinetic Summary Following Oral Administration of ralimetinib on Day 1 and on Day 14 (Cycle 1) - Tablet Formulation

Supplementary Table 1. Summary of the Most Common (>10%) Treatment-Emergent Adverse Events

Purpose: This study evaluated the clinical relevance of the dual-targeting strategy involving PI3K/AKT/mTOR and RAF/MEK/ERK pathways.Experimental Design: We investigated safety, efficacy, and correlations between tumor genetic alterations and clinical benefit in 236 patients with advanced cancers treated with phase I study drugs targeting phosphoinositide 3-kinase (PI3K) and/or mitogen-activated protein kinase (MAPK) pathways in our Phase I Clinical Trials Program.Results: Seventy-six (32.2%) patients received a PI3K pathway inhibitor in combination with a MAPK pathway inhibitor (D), whereas 124 (52.5%) and 36 (15.3%), respectively, received an inhibitor of either the PI3K or MAPK pathways (S). The rates of drug-related grade >III adverse events were 18.1% for (S) and 53.9% for (D; P < 0.001); the rates of dose-limiting toxicities were 9.4% for (S) and 18.4% for (D; P = 0.06). The most frequent grade >III adverse events were transaminase elevations, skin rash, and mucositis. In our comprehensive tumor genomic analysis, of 9 patients who harbored coactivation of both pathways (colorectal cancer, n = 7; melanoma, n = 2), all 5 patients treated with (D) had tumor regression ranging from 2% to 64%.Conclusions: These results suggest that dual inhibition of both pathways may potentially exhibit favorable efficacy compared with inhibition of either pathway, at the expense of greater toxicity. Furthermore, this parallel pathway targeting strategy may be especially important in patients with coexisting PI3K pathway genetic alterations and KRAS or BRAF mutations and suggests that molecular profiling and matching patients with combinations of these targeted drugs will need to be investigated in depth. Clin Cancer Res; 18(8); 2316–25. ©2012 AACR.

Trial Profile

Figure S1. Seventeen patients were tested with IFN-γ ELISPOT assay.

Purpose: p38 MAPK regulates the production of cytokines in the tumor microenvironment and enables cancer cells to survive despite oncogenic stress, radiotherapy, chemotherapy, and targeted therapies. Ralimetinib (LY2228820 dimesylate) is a selective small-molecule inhibitor of p38 MAPK. This phase I study aimed to evaluate the safety and tolerability of ralimetinib, as a single agent and in combination with tamoxifen, when administered orally to patients with advanced cancer.Experimental Design: The study design consisted of a dose-escalation phase performed in a 3+3 design (Part A; n = 54), two dose-confirmation phases [Part B at 420 mg (n = 18) and Part C at 300 mg (n = 8)], and a tumor-specific expansion phase in combination with tamoxifen for women with hormone receptor–positive metastatic breast cancer refractory to aromatase inhibitors (Part D; n = 9). Ralimetinib was administered orally every 12 hours on days 1 to 14 of a 28-day cycle.Results: Eighty-nine patients received ralimetinib at 11 dose levels (10, 20, 40, 65, 90, 120, 160, 200, 300, 420, and 560 mg). Plasma exposure of ralimetinib (Cmax and AUC) increased in a dose-dependent manner. After a single dose, ralimetinib inhibited p38 MAPK–induced phosphorylation of MAPKAP-K2 in peripheral blood mononuclear cells. The most common adverse events, possibly drug-related, included rash, fatigue, nausea, constipation, pruritus, and vomiting. The recommended phase II dose was 300 mg every 12 hours as monotherapy or in combination with tamoxifen. Although no patients achieved a complete response or partial response,19 patients (21.3%) achieved stable disease with a median duration of 3.7 months, with 9 of these patients on study for ≥6 cycles.Conclusions: Ralimetinib demonstrated acceptable safety, tolerability, and pharmacokinetics for patients with advanced cancer. Clin Cancer Res; 22(5); 1095–102. ©2015 AACR.

CCR Translation for This Article from The Clinical Effect of the Dual-Targeting Strategy Involving PI3K/AKT/mTOR and RAS/MEK/ERK Pathways in Patients with Advanced Cancer

Purpose: This phase I study evaluated the safety, maximum tolerated dose, antitumor activity, and pharmacokinetics and pharmacodynamics of pembrolizumab in patients with advanced solid tumors.Experimental Design: In a 3 + 3 dose escalation study, 10 patients received pembrolizumab 1, 3, or 10 mg/kg intravenously every 2 weeks until progression or intolerable toxicity. Seven additional patients received 10 mg/kg every 2 weeks. Thirteen patients participated in a 3-week intrapatient dose escalation (dose range, 0.005–10 mg/kg) followed by 2 or 10 mg/kg every 3 weeks. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.Results: No dose-limiting toxicities were observed. Maximum administered dose was 10 mg/kg every 2 weeks. One patient with melanoma and one with Merkel cell carcinoma experienced complete responses of 57 and 56+ weeks' duration, respectively. Three patients with melanoma experienced partial responses. Fifteen patients with various malignancies experienced stable disease. One patient died of cryptococcal infection 92 days after pembrolizumab discontinuation, following prolonged corticosteroid use for grade 2 gastritis considered drug related. Pembrolizumab exhibited pharmacokinetic characteristics typical of humanized monoclonal antibodies. Maximum serum target engagement was reached with trough levels of doses greater than or equal to 1 mg/kg every 3 weeks. Mechanism-based translational models with a focus on intratumor exposure prediction suggested robust clinical activity would be observed at doses ≥2 mg/kg every 3 weeks.Conclusions: Pembrolizumab was well tolerated and associated with durable antitumor activity in multiple solid tumors. The lowest dose with full potential for antitumor activity was 2 mg/kg every 3 weeks. Clin Cancer Res; 21(19); 4286–93. ©2015 AACR.See related commentary by van Elsas et al., p. 4251

Purpose: Nesvacumab (REGN910) is a fully human immunoglobulin G1 (IgG1) monoclonal antibody that specifically binds and inactivates the Tie2 receptor ligand Ang2 with high affinity, but shows no binding to Ang1. The main objectives of this trial were to determine the safety, tolerability, dose-limiting toxicities (DLT), and recommended phase II dose (RP2D) of nesvacumab.Experimental Design: Nesvacumab was administered intravenously every two weeks with dose escalations from 1 to 20 mg/kg in patients with advanced solid tumors.Results: A total of 47 patients were treated with nesvacumab. No patients in the dose escalation phase experienced DLTs, therefore a maximum tolerated dose (MTD) was not reached. The most common nesvacumab-related adverse events were fatigue (23.4%), peripheral edema (21.3%), decreased appetite, and diarrhea (each 10.6%; all grade ≤ 2). Nesvacumab was characterized by linear kinetics and had a terminal half-life of 6.35 to 9.66 days in a dose-independent manner. Best response by RECIST 1.1 in 43 evaluable patients included 1 partial response (adrenocortical carcinoma) of 24 weeks duration. Two patients with hepatocellular carcinoma had stable disease (SD) > 16 weeks, with tumor regression and >50% decrease in α-fetoprotein. Analyses of putative angiogenesis biomarkers in serum and tumor biopsies were uninformative for treatment duration.Conclusions: Nesvacumab safety profile was acceptable at all dose levels tested. Preliminary antitumor activity was observed in patients with treatment-refractory advanced solid tumors. On the basis of cumulative safety, antitumor activity, pharmacokinetic and pharmacodynamic data, the 20 mg/kg dose was determined to be the RP2D. Clin Cancer Res; 22(6); 1348–55. ©2015 AACR.

Supplementary Data. Study entry criteria specific to patients with HCC

Background: Durably effective therapeutic options remain elusive for metastatic triple negative breast cancer (mTNBC) patients. RSK is a novel target kinase for mTNBC, given its integral role in the MAPK/PDK-1 pathways. PMD-026, uniquely developed for TNBC, is a first-in-class, potent, oral RSK inhibitor that constitutes a promising avenue of treatment for mTNBC. PMD-026 demonstrated a favorable safety profile and initial signs of clinical benefit in metastatic breast cancer patients in Phase I. The current expansion is investigating PMD-026 in mTNBC patients whose disease has progressed on standard therapy. Methods: This open-label study evaluates the safety and efficacy of single agent PMD-026 in mTNBC patients. Target accrual for this study is a minimum of 20 mTNBC patients dosed at 200 mg q 12 hours who have measurable disease. A food effect (FE) sub-study is enrolling a total of 12 patients with a two-arm crossover design. Exploratory biomarker analysis of tumor tissue is being assessed for activated RSK2 levels. Exploratory objectives are to understand TNBC heterogeneity, with a view to identify patients who may benefit from PMD-026 optimally. Results: Based on the trial results thus far from 25 patients, PMD-026 continues to be well-tolerated with no G4 treatment-related adverse events. The noted toxicities include low incidence of elevated ALT/AST, rash, colitis or low-grade nausea. There has been no hair loss, myelosuppression or peripheral neuropathy. Given that TNBC is such a heterogeneous disease, we sought to identify subsets of patients with extensive prior therapy (≥ 5 lines) who may benefit from PMD-026 as a monotherapy. Based on ongoing analyses in the Phase I and Ib, patients diagnosed with TNBC at their initial diagnosis (de novo TNBC) stayed on study 3-4 times longer than patients who were initially treated for HR+ or HER2+ breast cancer but lost HR or HER2 expression to become TNBC (secondary TNBC). In addition, de novo TNBC patients treated at the recommended phase II dose (RP2D) of 200 mg BID with an H score for RSK2 ≥ 180 had a median progression free survival (PFS) of 3.3 months (n=3). In contrast, patients with an H score < 180 had a median PFS of 0 months (n=3). Furthermore, the PFS of 3.3 months on PMD-026 is longer than the PFS of 1.7 months in a similar population of TNBC patients on chemotherapy, where the average number of prior treatments was 3a. . Conclusions: Updated safety, clinical activity, PK, and biomarker analyses will be presented. Clinical trial information: NCT04115306.aBardia et al, N Engl J Med 2021; 384:1529-154 Citation Format: Muralidhar Beeram, Judy S. Wang, Lida A. Mina, Pavani Chalasani, Rebecca A. Shatsky, Robert Wesolowski, Sara A. Hurvitz, Meghna S. Trivedi, Hyo S. Han, Amita Patnaik, My-my Huynh, Aarthi Jayanthan, Mary Rose Pambid, Lambert Yue, Gerrit Los, Sandra E. Dunn, Andrew Dorr. First-in-human expansion study of oral PMD-026 in metastatic triple negative breast cancer patients [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 P5-17-12.

Complex, coordinated, and collaborative care of patients with head and neck cancer can be challenging yet amazingly rewarding and successful. The high symptom burden across multiple functional domains in patients with head and neck cancer, even in early stages of disease, mandates a multidisciplinary team approach that harnesses the combined contributions of physicians and ancillary providers to drive greater patient-centered care, addressing factors that heavily influence morbidity, mortality, and quality of life. Well-organized community-based multidisciplinary teams fulfill this unmet need and benefit patients with conveniently located comprehensive services that are typically found in large academic centers. Equivalent, if not superior, outcomes can be achieved in a unified community-based multidisciplinary team with shared patient-centered and outcomes-based goals. However, implementing true multidisciplinary team care in today’s complex health care environment is fraught with challenges and pitfalls. So how have some community-based practices managed to create safe and efficient programs with successful outcomes? The purpose of this review is to discuss barriers to reaching this success and emphasize practical solutions to such challenges.

Background: Imlunestrant is a novel, orally bioavailable selective estrogen receptor degrader (SERD) with pure antagonistic properties that result in sustained inhibition of estrogen receptor (ER)-dependent gene transcription and cell growth. Preclinically, imlunestrant has favorable efficacy and pharmacokinetic (PK) properties, including antitumor activity in ESR1-mutant models, along with enhanced efficacy when combined with abemaciclib. In dose escalation (Phase 1a) and dose expansion (Phase 1b) in the EMBER study, imlunestrant monotherapy was well tolerated with favorable safety, PK and encouraging antitumor activity in heavily pre-treated ER+, HER2- advanced breast cancer (aBC) patients (Jhaveri, ASCO 2022); imlunestrant recommended phase 2 dose (RP2D) was determined as 400mg QD. Here, we present the phase 1b dose expansion of imlunestrant with abemaciclib ± aromatase inhibitor (AI) in EMBER (NCT04188548). Methods: Phase 1b enrolled patients with ER-positive (ER+), HER2-negative (HER2-) aBC [shown prior endocrine therapy (ET) sensitivity or untreated de novo aBC; ≤1 prior therapies for aBC but must not have received a prior CDK4/6 inhibitor]. Patients were randomized, based on menopausal status and presence of visceral metastases, to receive imlunestrant + abemaciclib OR imlunestrant + abemaciclib + AI. Men and premenopausal women received a concomitant GnRH agonist. Serial plasma samples were obtained for PK and ctDNA analysis. Key endpoints included safety and tolerability, PK, objective response rate (ORR) per RECIST v1.1 (ORR: complete response [CR] or partial response [PR]) in patients with measurable disease), and clinical benefit rate (CBR: CR or PR, or stable disease ≥24 weeks) in patients enrolled ≥24 weeks prior to data cut. Results: As of 26 May 2022, 85 patients have received imlunestrant [n=80 at 400 mg (RP2D); n=5 at 800 mg] in combination with abemaciclib (150mg twice daily) ± AI. Forty-eight (56%) patients had visceral disease and 9% had at least 1 ESR1 mutation detected in ctDNA at baseline. Patients were predominantly (75%) ET pre-treated, 51% with an AI; and 8% and 5%, respectively, had received prior chemotherapy or fulvestrant, for aBC. The most common treatment-emergent adverse events were diarrhea (87%), nausea (58%), fatigue (45%), neutropenia (39%) and abdominal pain (34%). The majority of treatment-related AEs (TRAEs) were Grade 1 or 2, with Grade ≥3 TRAEs occurring in 36% of patients. Most common TRAEs at RP2D (400mg) were diarrhea (81%), nausea (45%), fatigue (33%) and neutropenia (35%). No patient discontinued treatment due to an AE. Dose reductions were required of both imlunestrant and abemaciclib in 6 (7%) patients and of either imlunestrant in 3 (4%) or abemaciclib in 22 (26%) patients. Preliminary efficacy is presented in Table 1. Conclusion: Imlunestrant in combination with abemaciclib ± AI showed acceptable safety and tolerability, comparable to the MONARCH 2 trial of fulvestrant + abemaciclib, along with evidence of clinical activity in ER+, HER2- aBC patients. These data suggest no additive toxicity of imlunestrant when administered in combination with abemaciclib, along with comparable clinical benefit to that observed in MONARCH 2. Further data will be presented at the meeting. The phase 3, EMBER-3 study is ongoing; evaluating imlunestrant, investigator’s choice ET, and imlunestrant + abemaciclib in ET pre-treated ER+, HER2- aBC patients (NCT04975308). Table 1. Preliminary efficacy in combination therapies in EMBER Citation Format: Komal Jhaveri, Hwei-Chung Wang, Cynthia Ma, Elgene Lim, Jessica J. Tao, Luis Manso, Jean-Yves Pierga, Ritesh Parajuli, Yolanda Jerez Gilarranz, Yen-Shen Lu, Muralidhar Beeram, Tim Larson, Ajay Dhakal, Roohi Ismail-Khan, Claudia Karacsonyi, Shanshan Cao, Cynthia Osborne, Shawn T. Estrem, Bastien Nguyen, Yujia Li, Eunice Yuen. PD13-12 Imlunestrant, an oral selective estrogen receptor degrader, in combination with abemaciclib with or without an aromatase inhibitor, in estrogen receptor-positive advanced breast cancer: Results from the phase 1a/b EMBER 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 PD13-12.

Background: Breast cancer (BC) is the most common malignancy in women and metastatic triple negative breast cancer (mTNBC) remains one of the most difficult to treat cancers with few targeted treatment options. RSK is recognized as a critical signaling component in the MAPK/PDK-1 pathways, is an important driver for BC and a signature of poor prognosis. PMD-026 is the first RSK inhibitor to enter clinical trials and is being developed alongside an immunohistochemistry (IHC) companion diagnostic to select patients with increased activated RSK2 in tumor tissue. A Phase 1/1b trial of PMD-026 in patients with metastatic breast cancer (mBC) or metastatic triple negative breast cancer (mTNBC) established safety at a dose of 200 mg Q12h. Efficacy signals in patients with heavily pretreated mBC/mTNBC are explored in this analysis along with evaluation of the effect of food (FE) on systemic exposure to treatment. Methods: PMD-026 was administered to 41 patients as a single agent in this phase 1/1b open-label study, with 30 patients evaluable for efficacy. Exploratory objectives were to identify subgroups of patients who may optimally benefit from PMD-026. Subgroup analysis of patients included 1) comparing BC patients who received ≤5 vs >5 prior therapies; 2) comparing TNBC patients (de novo vs secondary subtypes)1, and 3) comparing patients with low RSK2 H-scores (< 180) vs high (≥180). In addition, PMD 026 PK was evaluated at the 200 mg Q12h dose and a FE sub-study enrolled 12 patients administered a single 200 mg dose. Results: PMD-026 monotherapy was generally well-tolerated in the 41 mBC patients who were enrolled and treated. Kaplan-Meier PFS analysis of 30 evaluable BC patients who were dosed with PMD-026 showed that patients with less prior therapy (≤5) did significantly better (HR, 0.19; 95% CI [0.06–0.52], p=0.0014) than those with > 5 prior therapies. Subgroup analysis of PFS in those with TNBC demonstrated that de novo TNBC (n=17) had longer time on treatment with PMD-026 compared with secondary TNBC (n=9) (HR, 0.31; 95% CI [0.10-0.99], p=0.0476). In those with de novo TNBC with ≤5 prior therapies, a high RSK2 H-score was associated with significantly longer PFS at the RP2D (4.2 vs 1.3 months, HR, 0.17; 95% CI [0.03-0.80], p=0.0254) than patients with a low RSK2 H-score. In patients with CDK4/6 resistant HR+ BC (n=3), PFS was 5.2 (RSK2 high) vs 1.3 months (RSK2 low). Stable disease was observed in 53% (9/17) of patients with de novo TNBC and in 67% (6/9) of de novo TNBC patients with high RSK2. Tumor necrosis or target lesion reduction (< 30%) was observed in 17% of patients (5/30), all of whom had high RSK2 expression. In the FE sub-study, increased interpatient variability in PMD-026 Cmax and Tmax but not AUC, was observed when administered with food, favored dosing in a fasted state, which is consistent with the pH dependent solubility of PMD-026. Notably, all FE patients (12/12) achieved the target concentration of 1µM (IC90 in preclinical studies) within 4 hours when PMD-026 was taken without food. At the RP2D, PMD-026 taken without food showed relatively consistent exposure among patients over 24 hr timeframe. Conclusions: These findings demonstrate that in patients treated with PMD-026 who had received < 5 prior treatment regimens, had de novo TNBC or CDK4/6 refractory HR+ disease and had high RSK2 scores had longer PFS. Overall, PMD-026 is a well-tolerated, orally available RSK2 inhibitor that will be evaluated further for efficacy in TNBC and CDK4/6i refractory HR+ mBC, in a trial that will prospectively enroll patients based on RSK2 activation as defined by the RSK2 IHC H-scores. Clinical trial information: NCT04115306. 1 Patients diagnosed and treated for TNBC from their initial diagnosis (de novo TNBC) vs patients previously treated for hormone receptor positive (HR+) or human epidermal growth factor 2 receptor positive (HER2+) BC, but became HR or HER2 negative (secondary TNBC) Citation Format: Judy S. Wang, Muralidhar Beeram, Pavani Chalasani, Lida Mina, Rebecca A. Shatsky, Sara Hurvitz, Meghna S. Trivedi, Robert Wesolowski, Hyo S. Han, Amita Patnaik, Shakeela Bahadur, My-my Huynh, Aarthi Jayanthan, Gerrit Los, Sandra E. Dunn, Andrew Dorr. High levels of RSK2 in breast cancer patients is associated with longer PFS in patients treated with PMD-026, a first in class RSK inhibitor [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 P4-01-16.

BackgroundCyclin-dependent kinases (CDK) 4 and 6 regulate G1 to S cell cycle progression and are often altered in cancers. Abemaciclib is a selective inhibitor of CDK4 and CDK6 approved for administration on a continuous dosing schedule as monotherapy or as combination therapy with an aromatase inhibitor or fulvestrant in patients with advanced or metastatic breast cancer. This Phase 1b study evaluated the safety and tolerability, pharmacokinetics, and antitumor activity of abemaciclib in combination with endocrine therapy for metastatic breast cancer (MBC), including aromatase inhibitors (letrozole, anastrozole, or exemestane) or tamoxifen.Patients and MethodsWomen ≥18 years old with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) MBC were eligible for enrollment. Eligibility included measurable disease or non-measurable but evaluable bone disease by Response Evaluation Criteria in Solid Tumours (RECIST) v1.1, Eastern Cooperative Oncology Group performance status 0–1, and no prior chemotherapy for metastatic disease. Adverse events were graded by the National Cancer Institute Common Terminology Criteria for Adverse Events v4.0 and tumor response were assessed by RECIST v1.1.ResultsSixty-seven patients were enrolled and received abemaciclib 200 mg every 12 hours in combination with letrozole (Part A, n=20), anastrozole (Part B, n=16), tamoxifen (Part C, n=16), or exemestane (Part D, n=15). The most common treatment-emergent adverse events (TEAE) were diarrhea, fatigue, nausea, and abdominal pain. Grade 4 TEAEs were reported in five patients (one each with hyperglycemia, hypertension, neutropenia, procedural hemorrhage, and sepsis). There was no effect of abemaciclib or endocrine therapy on the pharmacokinetics of any combination study drug. Across all treated patients, the median progression-free survival was 25.4 months (95% confidence interval: 18.0, 35.8). The objective response rate was 38.9% in 36 patients with measurable disease.ConclusionsAbemaciclib in combination with multiple endocrine therapy options exhibited manageable safety and promising antitumor activity in patients with HR+, HER2- MBC.Clinical Trial Registrationhttps://clinicaltrials.gov/, identifier NCT02057133

Summary Background Isocitrate dehydrogenase-1 (IDH1) is mutated in up to 25% of cholangiocarcinomas, especially intrahepatic cholangiocarcinoma. Ivosidenib is an oral, targeted inhibitor of mutant IDH1 (mIDH1) approved in the USA for the treatment of mIDH1 acute myeloid leukaemia in newly diagnosed patients ineligible for intensive chemotherapy and patients with relapsed or refractory disease. Ivosidenib is under clinical evaluation in a phase 1 study that aims to assess its safety and tolerability in patients with mIDH1 solid tumours. Here we report data for the mIDH1-cholangiocarcinoma cohort. Methods We did a phase 1 dose-escalation and expansion study of ivosidenib monotherapy in mIDH1 solid tumours at 12 clinical sites in the USA and one in France. The primary outcomes were safety, tolerability, maximum tolerated dose, and recommended phase 2 dose. Eligible patients had a documented mIDH1 tumour based on local testing, an Eastern Cooperative Oncology Group performance status of 0 or 1, one or more previous lines of therapy, and evaluable disease by Response Evaluation Criteria in Solid Tumors version 1.1. During dose escalation, ivosidenib was administered orally at 200–1200 mg daily in 28-day cycles in a standard 3 + 3 design; during expansion, patients received the selected dose on the basis of pharmacodynamic, pharmacokinetic, safety, and activity data from dose escalation. Safety and clinical activity analyses were reported for all patients with mIDH1-cholangiocarcinoma who were enrolled and received at least one dose of study treatment. Enrolment is complete, and the study is ongoing. This trial is registered at ClinicalTrials.gov, number NCT02073994. Findings Between March 14, 2014 and May 12, 2017, 73 patients with mIDH1-cholangiocarcinoma were enrolled and received ivosidenib. No dose-limiting toxicities were reported and maximum tolerated dose was not reached; 500 mg daily was selected for expansion. Common (≥20%) adverse events, regardless of cause, were fatigue (31 [42%]; two [3%] grade ≥3), nausea (25 [34%]; one [1%] grade ≥3), diarrhoea (23 [32%]), abdominal pain (20 [27%]; two [3%] grade ≥3), decreased appetite (20 [27%]; one [1%] grade ≥3), and vomiting (17 [23%]). Common grade 3 or worse adverse events were ascites (four [5%]) and anaemia (three [4%]); the only treatment-related grade 3 or worse adverse event in more than one patient was fatigue (two [3%]). Two (3%) patients had serious adverse events leading to on-treatment death (Clostridioides difficile infection and procedural haemorrhage); neither was assessed by the investigator as related to treatment. 46 (63%) patients had adverse events deemed related to ivosidenib, of which four (5%) were grade 3 or higher (two [3%] for fatigue; one [1%] each for decreased blood phosphorus and increased blood alkaline phosphatase). One serious adverse event was considered possibly related to treatment (grade 2 supraventricular extrasystoles). Four (5%; 95% CI 1·5–13·4) patients had a partial response. Median progression-free survival was 3·8 months (95% CI 3·6–7·3), 6-month progression-free survival was 40·1% (28·4–51·6), and 12-month progression-free survival was 21·8% (12·3–33·0). Median overall survival was 13·8 months (95% CI 11·1–29·3); however, data were censored for 48 patients (66%). Interpretation Ivosidenib might offer a well tolerated option for patients with mIDH1-cholangiocarcinoma. An ongoing, global phase 3 study is evaluating ivosidenib versus placebo in patients with previously treated nonresectable or metastatic mIDH1-cholangiocarcinoma. Funding Agios Pharmaceuticals, Inc.

This abstract was withdrawn by the authors. Citation Format: Hamilton EP, Barve M, Bardia A, Beeram M, Edenfield WJ, Noonan A, Tolcher A, Bendell J, Mosher R, Xu J, Hailman E, Burris III H, Soliman HH. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-17-35.

1021 Background: Imlunestrant is a novel, orally bioavailable SERD with pure antagonistic properties that result in sustained inhibition of ER-dependent gene transcription and cell growth. In dose escalation, imlunestrant showed favorable safety, pharmacokinetics (PK) and preliminary efficacy in patients with ER+, HER2- aBC and ER+ EEC (Phase 1a EMBER, Jhaveri 2021). Here we present updated data from the dose escalation (Phase 1a) and dose expansion (Phase 1b) of imlunestrant monotherapy in EMBER (NCT04188548). Methods: Phase 1a/1b enrolled patients with ER+ aBC (prior ET sensitivity; ≤3 prior therapies for aBC in Phase 1a following protocol amendment and ≤2 in Phase 1b) and ER+ EEC (prior platinum therapy; no prior fulvestrant or aromatase inhibitor). Premenopausal women received a concomitant GnRH agonist. Serial plasma samples were obtained for PK and ctDNA analysis. Key endpoints included recommended phase 2 dose (RP2D) determination, safety and tolerability, PK, objective response rate per RECIST v1.1 (ORR: complete response [CR] or partial response [PR]) in patients with measurable disease and ≥1 post-baseline tumor assessment or discontinued prior to tumor assessment, and clinical benefit rate (CBR: CR or PR, or stable disease ≥24 weeks) in patients enrolled ≥24 weeks prior to data cut. Results: As of January 14, 2022, 138 patients (n = 114 aBC, n = 24 EEC) received imlunestrant monotherapy at doses ranging from 200-1200 mg QD. Median age was 62.0 years (range 32-95). Median number of prior therapies for aBC and EEC was 2 (range 0-8) and 1 (0-5), respectively. aBC patients had received a prior ET (94.7%), CDK4/6 inhibitor (92.1%), fulvestrant (50.9%) and chemotherapy (26.3%). No dose-limiting toxicities were observed. Most treatment-emergent adverse events (TEAEs) were grade 1. At the RP2D (400 mg QD, n= 69), the most common all grade TEAE’s were nausea (33.3%), fatigue (27.5%), and diarrhea (23.2%). Across all doses, the incidence of treatment-related grade 3 AEs was low (3.6%). No patient discontinued due to a TEAE. In evaluable aBC patients, ORR was 8.0% (6/75) and CBR was 40.4% (42/104). In evaluable EEC patients, ORR was 5.0% (1/20 had a PR- ongoing pending confirmation) and CBR was 47.1% (8/17). Clinical benefit was observed regardless of baseline ESR1 mutation status as determined by ctDNA sequencing. Additional biomarker analyses will be presented at the meeting. Conclusions: Imlunestrant continues to demonstrate a favorable side effect profile, with no cardiac or opthalmic safety signals, and has continued evidence of clinical activity in heavily pre-treated ER+ aBC and EEC patients. Clinical trial information: NCT04188548.

Background New strategies are needed to improve outcomes in human epidermal growth factor receptor 2 (HER2)-expressing cancers. SBT6050 is a novel therapeutic comprising a specific small molecule toll-like receptor (TLR) 8 agonist conjugated to a HER2-directed monoclonal antibody. TLR8 is highly expressed in myeloid cells that are prevalent in human tumors, including dendritic cells (DCs) and macrophages, and modulates their pro-inflammatory activity. SBT6050 is designed to activate human myeloid cells only in the presence of moderate-to-high HER2 expression (immunohistochemistry [IHC] 2+ or 3+) and binds to the same epitope as pertuzumab. In preclinical studies, SBT6050 potently induces a broad spectrum of antitumor immune mechanisms, including proinflammatory cytokine and chemokine production, inflammasome activation, and indirect activation of T and natural killer (NK) cells. TLR8 agonism has emerged as a promising approach to overcome resistance to immune checkpoint inhibitors in tumors lacking T-cell infiltrates, as these cancers are often replete with myeloid cells. Using an SBT6050 mouse surrogate in vivo, curative single-agent efficacy was observed in multiple murine tumor models, including a model deficient in T, B, and NK cells. In preclinical toxicology studies in nonhuman primates, SBT6050 was well tolerated, supporting a first-in-human starting dose that is predicted to be pharmacologically active, with a short escalation to projected clinically active doses. Preclinical studies also support combinations with checkpoint inhibitors and with trastuzumab to further enhance antitumor activity. Methods SBT6050-101 is an ongoing phase 1/1b, first-in-human, open-label, multicenter study. Eligible subjects are adults with histologically confirmed, HER2-expressing (IHC 2+ or 3+), locally advanced (unresectable) and/or metastatic cancer. Subjects must have measurable disease per the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and have previously received all therapies known to confer clinical benefit. SBT6050 is given subcutaneously every 2 weeks and treatment may continue for up to 2 years or until disease progression, unacceptable toxicity, or other reason for discontinuation. The trial objectives are to evaluate the safety and tolerability of SBT6050 and to identify the maximum tolerated dose and recommended phase 2 dose (RP2D). The study has 2 parts: Part 1, consisting of a dose escalation using a standard 3+3 design, and Part 2, consisting of 5 parallel expansion cohorts based on tumor type and HER2 expression level and treated with SBT6050 at the RP2D. Pharmacokinetics, immunogenicity, and antitumor activity will be evaluated and pharmacodynamic markers of myeloid cell activation will be assessed in peripheral blood and on-treatment tumor biopsies. Results N/A Conclusions N/A Trial Registration NCT04460456 Ethics Approval The study was approved by MD Anderson Cancer Center Institutional Review Board, approval number 2020-0326 MOD001.

The phase I study characterized the safety, pharmacokinetics, anti-tumor activity, and recommended phase II dose/schedule of LY3164530 in patients with advanced or metastatic cancer. Patients received LY3164530 on days 1 and 15 (Schedule 1: 300, 600, 1000, and 1250 mg) or Days 1, 8, 15, and 22 (Schedule 2: 500 and 600 mg) of each 28 days cycle. Dose escalation used a modified toxicity probability interval model. Dose escalation defined a maximum tolerated dose (MTD) of 1000 mg on Schedule 1 and 500 mg on Schedule 2. Treatment-emergent adverse events related to study treatment were consistent with epidermal growth factor receptor (EGFR) inhibition and included maculopapular rash/dermatitis acneiform (83%, Grade 3/4 17%), hypomagnesemia (55%, Grade 3/4 7%), paronychia (35%), fatigue (28%, Grade 3/4 3%), skin fissures (24%), and hypokalemia (21%, Grade 3/4 7%). Partial response was achieved in three patients on Schedule 2 with colorectal cancer (n = 2) or squamous cell cancer. Overall response rate (ORR) was 10.3%, disease control rate (ORR + stable disease [SD]) was 51.7 and 17.2% of patients had SD ≥ 4 months. The in vivo stability of the bispecific antibody was confirmed. Schedule 2 provided greater and more consistent inhibition of mesenchymal-epithelial transition (MET)/EGFR throughout the dosing interval than Schedule 1. Although this study defined the LY3164530 MTD and pharmacokinetics on both schedules, significant toxicities associated with EGFR inhibition and lack of a potential predictive biomarker limit future development. Nonetheless, the results provide insight into the development of bispecific antibody therapy.

Background: ZW25, a novel IgG1-like bispecific antibody, targets the same domains of HER2 as trastuzumab (T) and pertuzumab (P). In preclinical studies, ZW25 demonstrated increased tumor cell binding density and internalization relative to T and activity in T-resistant cell lines as well as models of HER2-low to high cancers. Initial dose escalation data demonstrated that once-weekly ZW25 was well tolerated at all doses evaluated and associated with single-agent anti-tumor activity in pts with heavily pre-treated (tx) HER2-expressing cancers. Methods: 3+3 dose escalation of ZW25 given weekly (QW; 5, 10 or 15 mg/kg) or biweekly (Q2W; 20 mg/kg) in 4-week cycles. Eligibility included HER2 IHC 1, 2 or 3+ or FISH+ BC, progression after T, P and T-DM1, and measurable or non-measureable disease per RECIST 1.1. Active brain metastases were excluded. Baseline brain MRI was performed in QW cohorts only if pts had prior history (hx) of CNS mets, and in all Q2W pts regardless of hx. Assessments included AEs, LVEF, immunogenicity, PK and tumor response every 2 cycles. Results: 8 pts with HER2-high BC were tx with ZW25 QW at 5 (n=2), 10 (n=2) or 15 mg/kg (n=4); 20 mg/kg Q2W is enrolling. 5/8 pts were HR+; 7 had measurable disease, 6 visceral disease, and 3 stable CNS disease. Median years since initial dx was 6 (range 5-16). Prior tx included T and T-DM1 (n=8); P (n= 6), and lapatinib (n=5). Median number of prior HER2-targeted regimens for metastatic disease was 6 (range 3-7) and non-hormonal HER2 regimens was 5 (range 3-7). ZW25 was well tolerated with no DLTs or decreases in cardiac function. Most common related AEs (all Gr 1 or 2) were diarrhea (n=4), infusion reaction (IR) (n=4) and vomiting (n=3). All IRs occurred only with 1st dose. There were no treatment-related SAEs. Related Gr 3 AEs (hypophosphatemia, fatigue and arthralgia) were reported in 1 pt (10 mg/kg). At data cut-off, pts had received 2-10 cycles of treatment, with 3 pts active. Best overall response was 2 PR (10 mg/kg), 3 SD (1 at 5 mg/kg, 2 at 15 mg/kg), and 3 PD (1 at 5 mg/kg, 2 at 15 mg/kg) for a disease control rate of 63%. Decreases in target lesions were seen in 6/7 patients with at least one tumor re-staging. One pt with SD (5 mg/kg; active on study) had an 8% decrease after C2, and 29% decrease after C8. One PR pt with prior hx of brain mets had a 33% decrease after C2 and 44% decrease after C4, although was found to have new leptomeningeal disease (LMD) at that time. Two additional pts with systemic SD (15 mg/kg; no prior hx of CNS mets) were also considered to have PD due to symptomatic brain mets. One of these pts remains on study after receiving stereotactic radiotherapy. Conclusions: ZW25 was associated with single-agent anti-tumor activity and systemic disease control in HER2-high BC pts after a median of 6 prior HER2-targeted regimens for metastatic disease. Systemic disease control was maintained despite PD due to brain mets or LMD. The presence of CNS disease in an unscreened population is consistent with the biology of late-stage HER2-high BC. The activity and tolerability of ZW25 support further evaluation as a single agent and in combination including with CNS-directed therapies in early and late lines of treatment for HER2-expressing BC. Citation Format: Hamilton E, Meric-Bernstam F, Infante J, Murthy R, Patnaik A, Piha-Paul SA, Tolcher A, Hausman D, Royer N, Beeram M. Phase 1 dose escalation with ZW25, a HER2-targeted bispecific antibody, in patients (pts) with HER2-high breast cancer (BC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-20-06.

Summary Background The signaling protein p38 mitogen-activated protein kinase (MAPK) regulates the tumor cell microenvironment, modulating cell survival, migration, and invasion. This phase 1 study evaluated the safety of p38 MAPK inhibitor LY3007113 in patients with advanced cancer to establish a recommended phase 2 dose. Methods In part A (dose escalation), LY3007113 was administered orally every 12 h (Q12H) at doses ranging from 20 mg to 200 mg daily on a 28-day cycle until the maximum tolerated dose (MTD) was reached. In part B (dose confirmation), patients received MTD. Safety, pharmacokinetics, pharmacodynamics, and tumor response data were evaluated. Results MTD was 30 mg Q12H. The most frequent treatment-related adverse events (>10%) were tremor, rash, stomatitis, increased blood creatine phosphokinase, and fatigue. Grade ≥ 3 treatment-related adverse events included upper gastrointestinal haemorrhage and increased hepatic enzyme, both occurring at 40 mg Q12H and considered dose-limiting toxicities. LY3007113 exhibited an approximately dose-proportional increase in exposure and time-independent pharmacokinetics after repeated dosing. Maximal inhibition (80%) of primary biomarker MAPK-activated protein kinase 2 in peripheral blood mononuclear cells was not reached, and sustained minimal inhibition (60%) was not maintained for 6 h after dosing to achieve a biologically effective dose (BED). The best overall response in part B was stable disease in 3 of 27 patients. Conclusions The recommended phase 2 dosage of LY3007113 was 30 mg Q12H. Three patients continued treatment after the first radiographic assessment, and the BED was not achieved. Further clinical development of this compound is not planned as toxicity precluded achieving a biologically effective dose.

Introduction: Obesity is associated with poor breast cancer outcomes in postmenopausal women. Our prior retrospective studies have shown that use of nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with reduced recurrence in obese breast cancer patients and a doubling of time to recurrence. Because it was recently determined that CD163+ M2 macrophages were clinically associated with fast proliferation, poor differentiation, estrogen receptor negativity and histological duct type in human primary breast tumors, the mechanism proposed was a decrease in prostaglandin E2 (PGE2) and aromatase locally in the breast with a concomitant decrease in circulating M2-activated tumor associated macrophages (TAMs). Methods: Postmenopausal women of varying body habitus were recruited at the CTRC in San Antonio and underwent randomized assignment to 1 of 3 arms: Aspirin (ASA) at 81mg daily, 1500mg of docosahexaenoic acid (DHA) and 2500mg eicosapentaenoic acid (EPA) given daily, or combined ASA and DHA/EPA. Sera were collected prior to and following 28 days of exposure, and cytokines including prostaglandin E2 were assessed via enzyme ­linked immunosorbent assay (ELISA). 28 circulating cytokines/chemokines were assessed by Luminex array using Millipore Milliplex MAP to look for associations between cytokine array profiles, PGE2 production and macrophage activation. Circulating class M-1 activated and M-2 activated macrophages were enumerated by flow cytometry to assess how PGE2 modulation influences macrophage phenotype and function. Investigators were blinded to randomization until analysis was complete. Results: A total of 122 patients were randomized with 2 drop outs and 115 completing the 28 days of intervention as planned. The median BMI was 31.4, with 12.8% normal (BMI 29.9). Patients had a median age of 63 (47-76), 91% white, and 46.0 % Hispanic. A positive correlation was observed between BMI and baseline PGE2 levels. The most consistent impact on PGE2 was observed with ASA with 81% obtaining a decrease from baseline (median change -28%); by comparison 55.1% (-1%) and 65.6% (-22%) of subjects showed decrease in the DHA/EPA and combined groups respectively. As of today, full cytokine profiling was performed on a subset of 38 patients and revealed a positive correlation with change in PGE2 and cytokines: EGF, Eotaxin, GM-CSF, IL1Ra, IL5, IL8, MIP1b, and TNFa. Conclusion: Aspirin alone most consistently impacted patient circulating PGE2 levels, and will be used in planned studies as an adjunct to adjuvant endocrine therapy in obese hormone receptor positive post-menopausal patients. Full cytokine and macrophage activation status will be reported. Citation Format: Brenner AJ, Lengfelder L, Quach DK, Cavazos DA, Ramirez RJ, Gruslova A, Kist K, Lathrup K, Kaklamani V, Beeram M, deGraffenried LA. Randomized study of COX2 inhibition on systemic inflammation in obese and non-obese subjects [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-09-16.

PURPOSE To evaluate the safety, pharmacokinetics, and pharmacodynamics of Hu5F9-G4 (5F9), a humanized IgG4 antibody that targets CD47 to enable phagocytosis. PATIENTS AND METHODS Adult patients with solid tumors were treated in four cohorts: part A, to determine a priming dose; part B, to determine a weekly maintenance dose; part C, to study a loading dose in week 2; and a tumor biopsy cohort. RESULTS Sixty-two patients were treated: 11 in part A, 14 in B, 22 in C, and 15 in the biopsy cohort. Part A used doses that ranged from 0.1 to 3 mg/kg. On the basis of tolerability and receptor occupancy studies that showed 100% CD47 saturation on RBCs, 1 mg/kg was selected as the priming dose. In subsequent groups, patients were treated with maintenance doses that ranged from 3 to 45 mg/kg, and most toxicities were mild to moderate. These included transient anemia (57% of patients), hemagglutination on peripheral blood smear (36%), fatigue (64%), headaches (50%), fever (45%), chills (45%), hyperbilirubinemia (34%), lymphopenia (34%), infusion-related reactions (34%), and arthralgias (18%). No maximum tolerated dose was reached with maintenance doses up to 45 mg/kg. At doses of 10 mg/kg or more, the CD47 antigen sink was saturated by 5F9, and a 5F9 half-life of approximately 13 days was observed. Strong antibody staining of tumor tissue was observed in a patient at 30 mg/kg. Two patients with ovarian/fallopian tube cancers had partial remissions for 5.2 and 9.2 months. CONCLUSION 5F9 is well tolerated using a priming dose at 1 mg/kg on day 1 followed by maintenance doses of up to 45 mg/kg weekly.

1050 Background: Novel degraders and antagonists of ER are under evaluation in aBC, to overcome both ER mediated resistance and the bioavailability and dosing limitations of fulvestrant, the only approved SERD. ER is also overexpressed in ̃80% of EEC and endocrine therapy (ET) is utilized for these patients (pts). LY3484356, a novel, orally bioavailable SERD with pure antagonistic properties results in sustained inhibition of ER-dependent gene transcription and cell growth. Preclinically, LY3484356 shows favorable efficacy and pharmacokinetic (PK) properties, including antitumor activity in ESR1 mutants. Here we present the initial clinical data from EMBER, an ongoing first-in-human phase 1a/b trial of this novel agent. Methods: Phase 1a evaluated LY3484356 dose escalation (i3+3 design) in women with ER+, HER2- aBC (≤3 prior therapies for aBC following protocol amendment; prior ET sensitivity) and ER+ EEC (prior platinum therapy). Premenopausal women received a concomitant GnRH agonist. Key endpoints included determination of the recommended phase 2 dose, safety and tolerability, PK, and objective response rate and clinical benefit rate per RECIST v1.1. Results: As of the data cut (November 9, 2020), 28 pts (n = 24 aBC, n = 4 EEC) were enrolled at doses ranging from 200-1200 mg QD. Median age was 59 years (range, 35-80). Median number of prior therapies for aBC was 2 (range, 1-8; 6 pts enrolled prior to protocol amendment had received ≥4 prior therapies), including prior fulvestrant (46%), a CDK4/6 inhibitor (83%), and chemotherapy (33%). No dose-limiting toxicities were observed. Treatment-emergent adverse events (TEAEs) were mostly grade 1-2, including nausea (32%), fatigue (25%), and diarrhea (18%). The only grade 3 treatment-related AE was diarrhea (n = 1). TEAEs of bradycardia and QTc prolongation were not observed despite intensive central ECG monitoring. Dose-proportional increases in LY3484356 exposures were observed across all evaluated doses and t1/2 was 25-30 hours. At the starting dose level (200 mg QD), unbound LY3484356 exposures exceeded those achieved with fulvestrant. 16 of 28 pts were efficacy evaluable, with the remaining 12 pts ongoing prior to first scan. Among 16 evaluable pts, 11 (8 aBC, 3 EEC) had stable disease (10 pts ongoing), and 5 had progressive disease. RECIST responses were observed after the data cut and will be detailed at the meeting. Plasma ctDNA analysis indicated decreases in mutant allele frequencies, including mutant ESR1 in 9/12 (75%) evaluable pts across all dose levels. Conclusions: LY3484356 QD dosing shows favorable safety and PK properties, along with preliminary efficacy in pts with heavily pretreated ER+ aBC and EEC. Updated data will be presented at the meeting. Clinical trial information: NCT04188548 .

e13043 Background: P90 ribosomal S6 kinase (RSK) is an actionable molecular target against metastatic triple negative breast cancer (mTNBC). RSK is a major convergence point in the integral TNBC signaling pathways, MAPK and PDK-1. PMD-026 is a first-in-class oral RSK inhibitor with high selectivity. The dose escalation portion of this study established the RP2D of PMD-026 as 200 mg Q12. PMD-026 demonstrated good plasma exposure following oral dosing, with a T1/2 of ̃ 6 h (range 4-8 h), and achieved the targeted preclinical efficacious concentrations using a Q12h dosing schedule. PMD-026 also demonstrated a tolerable safety profile and initial signs of efficacy in patients with metastatic breast cancer. The intensity of RSK2 activation ranged from an H Score of 110-268 based on a CLIA companion immunohistochemistry assay. We present initial data from the expansion cohort. Methods: The primary aim of this single-arm, open-label, first-in-human phase 1/1b study is to evaluate the safety of single agent PMD-026 in patients with mTNBC. Secondary endpoints are clinical activity, pharmacokinetics, and correlative biomarker expression on tumor specimens. Patients are dosed at 200 mg twice daily in 21-day cycles. Eligible patients have measurable disease as per RECIST v1.1 and have had disease progression on or after standard of care treatment. Tumor tissue is assessed to retrospectively correlate RSK2 activity by immunohistochemistry (IHC) with clinical outcomes. Pharmacokinetics are assessed along with a food effect (sub-study with n=12). In addition, a pharmacodynamic marker, YB-1 phosphorylation, is being explored in peripheral blood mononuclear cells before and during treatment. Results: As of February 16, 2021, 7 patients with mTNBC (median age 62 years, range 33-74) have been enrolled in the phase 1b Expansion (median of 7 prior lines of therapy). Notable prior therapies in the phase 1b include sacituzumab govitecan (n=4) and atezolizumab/nab-paclitaxel (n=1). Patients in escalation and expansion treated with the RP2D had median progression free survival of 30 vs 99 days for low vs high RSK2 expression, respectively. This cut-off will be further evaluated in the expansion phase of the study. Conclusions: Updated safety, clinical activity, pharmacokinetic, and biomarker analyses will be presented. Target accrual for phase 1b Expansion is a minimum of 20 patients with mTNBC. Clinical trial information: NCT04115306.

164 Background: For patients with human epidermal growth factor receptor 2 (HER2)-overexpressing GEA, trastuzumab in combination with chemotherapy is the only approved HER2-targeted therapy, and they have limited treatment options after progression. Zanidatamab, a HER2-targeted bispecific antibody, has shown durable anti-tumor activity with good tolerability in a range of HER2-expressing cancers. Methods: In this 3-part Phase 1 study (NCT02892123), zanidatamab (10 mg/kg QW, 20 mg/kg Q2W, or 30 mg/kg Q3W) is administered as a single agent (Parts 1 & 2; QW or Q2W) or in combination with chemotherapy (Part 3; Q2W or Q3W). Eligibility criteria includes GEA with HER2 expression as assessed by immunohistochemistry (IHC) 3+ or IHC 2+, progression after standard of care therapy, and measurable disease per RECIST 1.1 (Part 2 requirement only). Results: In Parts 1 and 2, 36 GEA patients have been treated with zanidatamab (QW [n = 5]; Q2W [n = 31]). In Part 3, 26 GEA patients have been treated (zanidatamab Q2W + (paclitaxel [n = 11] or capecitabine [n = 6]); zanidatamab Q3W + capecitabine [n = 9]). Conclusions: Zanidatamab, both as a single agent and in combination with chemotherapy, is well tolerated with promising and durable anti-tumor activity in heavily pretreated GEA patients (including prior HER2-targeted therapy). These data support further investigation of zanidatamab as a novel therapeutic for patients with HER2-expressing GEA. Clinical trial information: NCT02892123. [Table: see text]

This phase I study evaluated the safety, tolerability, and pharmacokinetics of copanlisib, an intravenously administered pan-phosphatidylinositol 3-kinase inhibitor in patients with advanced solid tumors or non-Hodgkin's lymphoma. Copanlisib was well tolerated with a manageable safety profile, with anti-tumor activity in both advanced solid tumors and hematological malignancies., Background To evaluate the safety, tolerability, pharmacokinetics, and maximum tolerated dose (MTD) of copanlisib, a phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors or non-Hodgkin's lymphoma (NHL). Patients and methods Phase I dose-escalation study including patients with advanced solid tumors or NHL, and a cohort of patients with type 2 diabetes mellitus. Patients received three weekly intravenous infusions of copanlisib per 28-day cycle over the dose range 0.1–1.2 mg/kg. Plasma copanlisib levels were analyzed for pharmacokinetics. Biomarker analysis included PIK3CA, KRAS, BRAF, and PTEN mutational status and PTEN immunohistochemistry. Whole-body [18F]-fluorodeoxyglucose positron emission tomography (18FDG-PET) was carried out at baseline and following the first dose to assess early pharmacodynamic effects. Plasma glucose and insulin levels were evaluated serially. Results Fifty-seven patients received treatment. The MTD was 0.8 mg/kg copanlisib. The most frequent treatment-related adverse events were nausea and transient hyperglycemia. Copanlisib exposure was dose-proportional with no accumulation; peak exposure positively correlated with transient hyperglycemia post-infusion. Sixteen of 20 patients treated at the MTD had reduced 18FDG-PET uptake; 7 (33%) had a reduction >25%. One patient achieved a complete response (CR; endometrial carcinoma exhibiting both PIK3CA and PTEN mutations and complete PTEN loss) and two had a partial response (PR; both metastatic breast cancer). Among the nine NHL patients, all six with follicular lymphoma (FL) responded (one CR and five PRs) and one patient with diffuse large B-cell lymphoma had a PR by investigator assessment; two patients with FL who achieved CR (per post hoc independent radiologic review) were on treatment >3 years. Conclusion Copanlisib, dosed intermittently on days 1, 8, and 15 of a 28-day cycle, was well tolerated and the MTD was determined to be 0.8 mg/kg. Copanlisib exhibited dose-proportional pharmacokinetics and promising anti-tumor activity, particularly in patients with NHL. ClinicalTrials.gov NCT00962611; https://clinicaltrials.gov/ct2/show/NCT00962611.

Purpose: Nesvacumab (REGN910) is a fully human immunoglobulin G1 (IgG1) monoclonal antibody that specifically binds and inactivates the Tie2 receptor ligand Ang2 with high affinity, but shows no binding to Ang1. The main objectives of this trial were to determine the safety, tolerability, dose-limiting toxicities (DLT), and recommended phase II dose (RP2D) of nesvacumab. Experimental Design: Nesvacumab was administered intravenously every two weeks with dose escalations from 1 to 20 mg/kg in patients with advanced solid tumors. Results: A total of 47 patients were treated with nesvacumab. No patients in the dose escalation phase experienced DLTs, therefore a maximum tolerated dose (MTD) was not reached. The most common nesvacumab-related adverse events were fatigue (23.4%), peripheral edema (21.3%), decreased appetite, and diarrhea (each 10.6%; all grade ≤ 2). Nesvacumab was characterized by linear kinetics and had a terminal half-life of 6.35 to 9.66 days in a dose-independent manner. Best response by RECIST 1.1 in 43 evaluable patients included 1 partial response (adrenocortical carcinoma) of 24 weeks duration. Two patients with hepatocellular carcinoma had stable disease (SD) > 16 weeks, with tumor regression and >50% decrease in α-fetoprotein. Analyses of putative angiogenesis biomarkers in serum and tumor biopsies were uninformative for treatment duration. Conclusions: Nesvacumab safety profile was acceptable at all dose levels tested. Preliminary antitumor activity was observed in patients with treatment-refractory advanced solid tumors. On the basis of cumulative safety, antitumor activity, pharmacokinetic and pharmacodynamic data, the 20 mg/kg dose was determined to be the RP2D. Clin Cancer Res; 22(6); 1348–55. ©2015 AACR.

Purpose: p38 MAPK regulates the production of cytokines in the tumor microenvironment and enables cancer cells to survive despite oncogenic stress, radiotherapy, chemotherapy, and targeted therapies. Ralimetinib (LY2228820 dimesylate) is a selective small-molecule inhibitor of p38 MAPK. This phase I study aimed to evaluate the safety and tolerability of ralimetinib, as a single agent and in combination with tamoxifen, when administered orally to patients with advanced cancer. Experimental Design: The study design consisted of a dose-escalation phase performed in a 3+3 design (Part A; n = 54), two dose-confirmation phases [Part B at 420 mg (n = 18) and Part C at 300 mg (n = 8)], and a tumor-specific expansion phase in combination with tamoxifen for women with hormone receptor–positive metastatic breast cancer refractory to aromatase inhibitors (Part D; n = 9). Ralimetinib was administered orally every 12 hours on days 1 to 14 of a 28-day cycle. Results: Eighty-nine patients received ralimetinib at 11 dose levels (10, 20, 40, 65, 90, 120, 160, 200, 300, 420, and 560 mg). Plasma exposure of ralimetinib (Cmax and AUC) increased in a dose-dependent manner. After a single dose, ralimetinib inhibited p38 MAPK–induced phosphorylation of MAPKAP-K2 in peripheral blood mononuclear cells. The most common adverse events, possibly drug-related, included rash, fatigue, nausea, constipation, pruritus, and vomiting. The recommended phase II dose was 300 mg every 12 hours as monotherapy or in combination with tamoxifen. Although no patients achieved a complete response or partial response,19 patients (21.3%) achieved stable disease with a median duration of 3.7 months, with 9 of these patients on study for ≥6 cycles. Conclusions: Ralimetinib demonstrated acceptable safety, tolerability, and pharmacokinetics for patients with advanced cancer. Clin Cancer Res; 22(5); 1095–102. ©2015 AACR.

Background: Abemaciclib, a small molecule inhibitor of CDK4 and CDK6, induces G1 cell cycle arrest in Rb-proficient human cancers.1 The clinical safety profile of abemaciclib enables continuous oral dosing to achieve sustained target inhibition, resulting in single-agent antitumor activity against multiple human cancers. The drug also reaches relevant concentrations in the central nervous system and, in patients taking the drug orally, can be detected in the cerebrospinal fluid.2 For women with previously treated hormone receptor positive (HR+) metastatic breast cancer (MBC), abemaciclib as a single agent achieved a six-month clinical benefit rate of 61.1% and an objective response rate of 33.3%.3 Clinical trials investigating abemaciclib combined with fulvestrant4 or aromatase inhibitors5 have led to randomized Phase 3 studies for women with HR+ breast cancer.6,7 Methods: This Phase 1b study (NCT02057133) with multiple cohorts evaluates safety and tolerability of abemaciclib combined with endocrine or HER2-targeted therapies for MBC. Secondary objectives include pharmacokinetics (PK) and antitumor activity of abemaciclib when given in combination with other therapies. Cohorts were opened to enrollment sequentially. Patients with HR+ HER2 negative MBC received abemaciclib orally every 12 hours (Q12H) in combination with the following standard therapies daily until progression: letrozole (Part A), anastrozole (Part B), tamoxifen (Part C), exemestane (Part D), or exemestane plus everolimus (Part E). Patients with HER2 positive MBC received abemaciclib orally Q12H in combination with trastuzumab every 21 days until progression (Part F). Adverse events (AEs) were graded by NCI CTCAE v4.0 and tumor response was assessed radiographically using RECIST v1.1. Results: Abemaciclib has been combined with multiple targeted therapies for the treatment of women with MBC. We previously reported safety and early efficacy results for the combinations of abemaciclib with letrozole, anastrozole, tamoxifen, exemestane, and exemestane plus everolimus.5 Due to limited follow-up at that time, the efficacy results were not mature. Safety, PK, and efficacy results with approximately 6 months of additional follow-up will be reported across all parts of the study. The most common treatment-emergent AEs include effects on the gastrointestinal and hematopoietic systems. Consistent with previously reported results for both single-agent abemaciclib and the combination of abemaciclib with fulvestrant, tumor responses have been observed among women receiving abemaciclib in combination with targeted therapies for MBC. Conclusions: This study for women with MBC demonstrates the potential for abemaciclib to be combined with therapies targeting specific signaling pathways. References: 1Gelbert et al. Invest New Drugs. 2014;32(5):825-37. 2Shapiro et al. J Clin Oncol 31, 2013 (suppl; abstr 2500). 3Tolaney et al. SABCS 2014: Abstract 763. 4Patnaik et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 534). 5Tolaney et al. J Clin Oncol 33, 2015 (suppl; abstr 522). 6Llombart et al. SABCS 2014: OT1-1-07 (MONARCH 2, NCT02107703). 7Goetz et al. J Clin Oncol 33, 2015 (suppl; abstr TPS624) (MONARCH 3, NCT02246621). Citation Format: Goetz MP, Beeram M, Beck T, Conlin AK, Dees EC, Dickler MN, Helsten TL, Conkling PR, Edenfield WJ, Richards DA, Turner PK, Cai N, Chan EM, Pant S, Becerra CH, Kalinsky K, Puhalla SL, Rexer BN, Burris HA, Tolaney SM. Abemaciclib, an inhibitor of CDK4 and CDK6, combined with endocrine and HER2-targeted therapies for women with metastatic breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-13-25.

TPS1110 Background: Metastatic triple negative breast cancer (mTNBC) has a poor prognosis with limited durable treatment options. RSK (P90 ribosomal S6 kinase) is a signaling protein at the convergence point of PDK-1 and MAPK signaling pathways. RSK1-3 phosphorylates transcription factors, including Y-box binding protein-1 (YB-1), thereby inducing drug resistance and cancer growth genes. Phosphorylated YB-1 is involved in tumor cell survival, proliferation, and drug resistance. In human breast tumor samples, RSK2 protein is expressed across all breast cancer subtypes (TNBC, ER+ and HER2+) and is associated with poor overall survival. Expression of RSK2 is found in approximately 87% of mTNBC tumors and of those tumors approximately 41% have very high expression of RSK2. PMD-026 is a potent, oral, small molecule RSK inhibitor with high selectivity for RSK2. Preclinical in vivo studies have demonstrated activity both as a single agent and in combination with standard of care therapies. Further, a CAP/CLIA certified IHC method has been developed with Roche to determine tumor expression of RSK2. Methods: This single-arm, open-label, first-in-human, phase I/Ib study evaluates the safety and efficacy of single agent PMD-026 in patients with metastatic breast cancer for whom standard therapies are no longer effective. During dose escalation, the study utilizes an accelerated titration design with single patient cohorts until the occurrence of DLT or Grade 2+ toxicity; then reverts to 3+3 design to define the maximally tolerated dose (MTD) and recommended phase II dose (RP2D). The dose expansion portion will enroll approximately 20 patients with mTNBC. Patients are dosed orally once daily in 21-day cycles with measures to adapt the dosing schedule based on the pharmacokinetic (PK) data, as needed. Tumor tissue is required for all enrolled patients; RSK2 expression will be retrospectively correlated with clinical outcomes. The primary objectives are to determine safety and tolerability of PMD-026, determine the MTD, define a RP2D, and assess anti-tumor activity of PMD-026 in patients with TNBC. Secondary objectives are to evaluate PK, time to response, mTNBC subtyping using NanoString, and duration of response of PMD-026. To date, cohorts 1 and 2 have been completed without DLT. Enrollment to cohort 3 began in January 2020. Clinical trial information: NCT04115306 .

3064 Background: CD47 is a transmembrane protein that acts as a “Don’t Eat Me” signal to evade immune recognition. It is overexpressed in multiple cancer subtypes and is associated with poor prognosis. SRF231 is an investigational, fully human, high-affinity CD47-targeting antibody that delivers an activating signal to myeloid cells and displays favorable preclinical characteristics regarding its receptor occupancy/tumor exposure/efficacy relationship. Methods: In a Phase 1 study, SRF231-101 (NCT03512340), patients with advanced solid and hematologic malignancies who had failed standard therapy were enrolled in dose escalation cohorts (accelerated single-patient followed by standard 3+3) to establish the preliminary safety of SRF231 as a monotherapy and identify a dose and schedule suitable for expansion. In addition to collection of safety data, clinical outcomes were evaluated based on Response Evaluation Criteria in Solid Tumors (RECIST v1.1) and SRF231 pharmacokinetic (PK) and pharmacodynamic (receptor occupancy) analyses were performed. Results: As of January 11, 2020, a total of 46 patients were enrolled, 25 in every-3-week intravenous (IV) dosing schedules and 21 in weekly IV dosing schedules. Weekly dosing schedules also explored the use of a 1.0 mg/kg initiation dose. Other than one patient with recurrent follicular lymphoma, all patients had recurrent/refractory solid tumors. The most common treatment emergent adverse events across dosing schedules were low-grade fatigue (43%), headache (35%), and pyrexia (30%). On every-3-week dosing schedules, 2 dose-limiting toxicities (DLTs) were observed: Grade 3 febrile neutropenia and Grade 3 hemolysis, both at a 12.0 mg/kg dose level. On weekly dosing schedules, 3 DLTs were observed: Grade 4 thrombocytopenia (6.0 mg/kg), Grade 4 amylase and lipase increased (4.0 mg/kg with initiation dose), and Grade 3 fatigue (4.0 mg/kg). The maximum tolerated dose was 9.0 mg/kg on an every-3-week and 4.0 mg/kg on a weekly schedule. Receptor occupancy was maintained at > 90% throughout the dosing period with a 4.0 mg/kg weekly dose schedule. Out of 37 patients who were response evaluable by RECIST, there were no complete or partial responders, although prolonged stable disease has been observed. Conclusions: Preliminary data from a Phase 1 study of SRF231, an anti-CD47 antibody, demonstrate that SRF231 may be administered safely and doses of 4.0 mg/kg weekly maintain > 90% receptor occupancy throughout the dosing period. Updated safety data, clinical outcomes, and PK/pharmacodynamic data will be presented. Clinical trial information: NCT03512340 .

Purpose The phase I study characterized the safety, pharmacokinetics, anti-tumor activity, and recommended phase II dose/schedule of LY3164530 in patients with advanced or metastatic cancer. Methods Patients received LY3164530 on days 1 and 15 (Schedule 1: 300, 600, 1000, and 1250 mg) or Days 1, 8, 15, and 22 (Schedule 2: 500 and 600 mg) of each 28 days cycle. Dose escalation used a modified toxicity probability interval model. Results Dose escalation defined a maximum tolerated dose (MTD) of 1000 mg on Schedule 1 and 500 mg on Schedule 2. Treatment-emergent adverse events related to study treatment were consistent with epidermal growth factor receptor (EGFR) inhibition and included maculopapular rash/dermatitis acneiform (83%, Grade 3/4 17%), hypomagnesemia (55%, Grade 3/4 7%), paronychia (35%), fatigue (28%, Grade 3/4 3%), skin fissures (24%), and hypokalemia (21%, Grade 3/4 7%). Partial response was achieved in three patients on Schedule 2 with colorectal cancer (n = 2) or squamous cell cancer. Overall response rate (ORR) was 10.3%, disease control rate (ORR + stable disease [SD]) was 51.7 and 17.2% of patients had SD ≥ 4 months. The in vivo stability of the bispecific antibody was confirmed. Schedule 2 provided greater and more consistent inhibition of mesenchymal-epithelial transition (MET)/EGFR throughout the dosing interval than Schedule 1. Conclusions Although this study defined the LY3164530 MTD and pharmacokinetics on both schedules, significant toxicities associated with EGFR inhibition and lack of a potential predictive biomarker limit future development. Nonetheless, the results provide insight into the development of bispecific antibody therapy. Electronic supplementary material The online version of this article (10.1007/s00280-018-3623-7) contains supplementary material, which is available to authorized users.

Purpose: This phase I study evaluated the safety, maximum tolerated dose, antitumor activity, and pharmacokinetics and pharmacodynamics of pembrolizumab in patients with advanced solid tumors. Experimental Design: In a 3 + 3 dose escalation study, 10 patients received pembrolizumab 1, 3, or 10 mg/kg intravenously every 2 weeks until progression or intolerable toxicity. Seven additional patients received 10 mg/kg every 2 weeks. Thirteen patients participated in a 3-week intrapatient dose escalation (dose range, 0.005–10 mg/kg) followed by 2 or 10 mg/kg every 3 weeks. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Results: No dose-limiting toxicities were observed. Maximum administered dose was 10 mg/kg every 2 weeks. One patient with melanoma and one with Merkel cell carcinoma experienced complete responses of 57 and 56+ weeks' duration, respectively. Three patients with melanoma experienced partial responses. Fifteen patients with various malignancies experienced stable disease. One patient died of cryptococcal infection 92 days after pembrolizumab discontinuation, following prolonged corticosteroid use for grade 2 gastritis considered drug related. Pembrolizumab exhibited pharmacokinetic characteristics typical of humanized monoclonal antibodies. Maximum serum target engagement was reached with trough levels of doses greater than or equal to 1 mg/kg every 3 weeks. Mechanism-based translational models with a focus on intratumor exposure prediction suggested robust clinical activity would be observed at doses ≥2 mg/kg every 3 weeks. Conclusions: Pembrolizumab was well tolerated and associated with durable antitumor activity in multiple solid tumors. The lowest dose with full potential for antitumor activity was 2 mg/kg every 3 weeks. Clin Cancer Res; 21(19); 4286–93. ©2015 AACR. See related commentary by van Elsas et al., p. 4251

Background: Abemaciclib, a small molecule inhibitor with selectivity against cyclin-dependent kinases 4 and 6 (CDK4/6), induces G1 arrest in Rb-proficient human breast cancers. In an early phase clinical trial, the safety and antitumor activity of abemaciclib (LY2835219) were evaluated in 2 cohorts of patients with metastatic breast cancer (mBC). One cohort evaluated single-agent abemaciclib in an unselected population of patients with mBC [Part D], while the combination of abemaciclib plus fulvestrant was evaluated in patients with hormone receptor positive (HR+) mBC [Part G]. We previously reported early results for these 2 cohorts of patients with mBC treated with either single-agent abemaciclib or the combination of abemaciclib plus fulvestrant (Patnaik et al, ASCO 2014). In the single-agent cohort, 47 patients with previously treated mBC were enrolled (36 HR+). All patients with >30% tumor reduction had HR+ mBC (13 of 36 patients). In this group of 13 patients with HR+ mBC, 9 patients had confirmed response for an objective response rate of 25%, and 4 patients had unconfirmed response. This study was ongoing with 14 of 36 HR+ mBC patients on treatment at time of analysis (range 238-471 days). Patients continuing on single-agent abemaciclib included 4 patients with unconfirmed response and 6 patients with confirmed response. For the combination of abemaciclib plus fulvestrant, 18 patients with HR+ mBC enrolled and 13 patients (72%) were still on treatment (range 31-143 days) at the time of analysis. Methods: In the single-agent cohort, patients with mBC were treated with abemaciclib at 150 or 200mg orally every 12 hours on a continuous schedule. In the combination cohort, patients with HR+ mBC (n=18) were treated with the combination of abemaciclib plus fulvestrant. Patients received abemaciclib at 200mg orally every 12 hours on a continuous schedule. Patients also received fulvestrant at 500mg intramuscularly every month. NCI CTCAE v4.0 was used to grade adverse events (AEs) and RECIST v1.1 was used to assess tumor response. Results: In the single-agent cohort, patients began enrolling in May 2012 with the last patient enrolled in March 2013. Patients had a median of 7 prior systemic therapies and 81% of patients had ≥2 metastatic sites. In the combination cohort, patients began enrolling in September 2013 with the last patient enrolled in January 2014. Patients in the combination cohort had a median of 4 prior systemic therapies and 67% of patients had ≥2 metastatic sites. An updated analysis will be presented for objective response rate, duration of treatment and clinical benefit rate and will include an additional 6 months of information for both the single-agent and combination cohorts. New analyses will include time to response, duration of response, change in tumor size over time, and characteristics of responders. In addition, safety data will include longer term follow-up through approximately September 2014. Conclusions: Abemaciclib is an oral cell cycle inhibitor that demonstrates single-agent activity against mBC, especially for HR+ disease. Based on its safety and efficacy profile, abemaciclib warrants further clinical investigation in confirmatory studies, both as a single agent and in combination with endocrine therapy. Citation Format: Sara M Tolaney, Lee S Rosen, Muralidhar Beeram, Jonathan W Goldman, Leena Gandhi, Anthony W Tolcher, Kyriakos P Papadopoulos, Drew W Rasco, Scott P Myrand, Palaniappan Kulanthaivel, Joan M Andrews, Martin Frenzel, Damien M Cronier, Edward M Chan, Keith T Flaherty, Patrick Y Wen, Geoffrey I Shapiro, Amita Patnaik. Clinical activity of abemaciclib, an oral cell cycle inhibitor, in metastatic breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-19-13.

Obesity is associated with a worse breast cancer prognosis and elevated levels of inflammation, including greater cyclooxygenase-2 (COX-2) expression and activity in adipose-infiltrating macrophages. The product of this enzyme, the proinflammatory eicosanoid prostaglandin E2 (PGE2), stimulates adipose tissue aromatase expression and subsequent estrogen production, which could promote breast cancer progression. This study demonstrates that daily use of a nonsteroidal anti-inflammatory drug (NSAID), which inhibits COX-2 activity, is associated with reduced estrogen receptor α (ERα)–positive breast cancer recurrence in obese and overweight women. Retrospective review of data from ERα-positive patients with an average body mass index of >30 revealed that NSAID users had a 52% lower recurrence rate and a 28-month delay in time to recurrence. To examine the mechanisms that may be mediating this effect, we conducted in vitro studies that utilized sera from obese and normal-weight patients with breast cancer. Exposure to sera from obese patients stimulated greater macrophage COX-2 expression and PGE2 production. This was correlated with enhanced preadipocyte aromatase expression following incubation in conditioned media (CM) collected from the obese-patient, sera-exposed macrophages, an effect neutralized by COX-2 inhibition with celecoxib. In addition, CM from macrophage/preadipocyte cocultures exposed to sera from obese patients stimulated greater breast cancer cell ERα activity, proliferation, and migration compared with sera from normal-weight patients, and these differences were eliminated or reduced by the addition of an aromatase inhibitor during CM generation. Prospective studies designed to examine the clinical benefit of NSAID use in obese patients with breast cancer are warranted. Cancer Res; 74(16); 4446–57. ©2014 AACR.

Melanomas are vascular tumors with a high incidence of BRAF mutations driving tumor proliferation. Complete inhibition of vascular endothelial growth factor (VEGF) signaling has potential for enhanced antitumor efficacy.Patients with advanced melanoma and adequate organ function were eligible. Sorafenib was given orally at 200 mg BiD for 5 days every week; bevacizumab was administered 5 mg/kg intravenously every 14 days. The primary objective was to determine clinical biological activity. The secondary objectives were safety, tolerability, and time to progression (TTP). Pharmacodynamic analysis included serum VEGF and soluble VEGF receptor-1 and VEGF receptor-2 performed at baseline, C1D15 and C2D1. The study was terminated during the first stage of a Simon two-stage design, after 14 of planned 21 subjects were enrolled.Of the 14 patients who received treatment, no objective tumor responses were observed. Stable disease (SD) ≥16 weeks was observed in 57 % patients, including three patients with SD lasting ≥1 year. Median TTP was 32 weeks. The most frequently reported drug-related adverse events (AEs) were hand-foot syndrome (57.1 %), fatigue (57.1 %), hypertension (64.3 %), and proteinuria (35.7). Grade 3/4 drug-related AEs were hypertension (14.2 %), hand-foot syndrome, proteinuria, and thrombocytopenia (7 % each). Patients with low VEGF (300 pg/ml) experienced longer TTP than those with high VEGF [median 50 vs. 15 weeks, p = 0.02). A similar pattern was seen for VEGFR1 and VEGFR2, although it did not reach statistical significance.Combined VEGF/VEGFR blockade using bevacizumab with sorafenib shows clinical activity. The linkage between VEGF levels and time to tumor progression needs further exploration.

The human monoclonal antibody MNRP1685A targets the VEGF binding domain of neuropilin-1 (NRP1), a multi-domain receptor necessary for neural development and blood vessel maturation. In nonclinical studies, MNRP1685A prevents vascular maturation by keeping blood vessels in an immature, highly VEGF-dependent state. We explored the safety and tolerability of MNRP1685A in patients with advanced solid tumors. Patients were treated with MNRP1685A given intravenously every 3 weeks using a 3 + 3 dose-escalation design with 7 dose-escalation cohorts. Twenty-four of 35 patients (69 %) experienced drug-related adverse events (AEs) of infusion-related reaction on the day of MNRP1685A administration. With premedication including dexamethasone, infusions were well-tolerated with main symptoms of pruritus and rash. Outside the day of infusion, most common (≥ 2 patients) related AEs were fatigue (17 %), pruritus (9 %), myalgia and thrombocytopenia (both 6 %) (all were Grade 1-2). MNRP1685A-related Grade ≥ 3 AEs consisted of one dose-limiting toxicity of Grade 3 upper gastrointestinal bleeding and one related Grade 3 thrombocytopenia, coinciding with unrelated Grade 3 fungemia and duodenal obstruction. MNRP1685A showed nonlinear PK with more-than-dose proportional increases in exposure, consistent with broad target expression. Transient platelet count reductions (≥ 30 % from predose) were observed in 56 % of evaluable patients. Nine patients were on study for ≥ 4 cycles, one colorectal cancer patient for one year. MNRP1685A was generally well-tolerated. The primary MNRP1685A-related AE was infusion-related reaction, which were attenuated by premedication including dexamethasone. Transient platelet count reductions were frequent but did not impact MNRP1685A dosing.

Background ZW25, a novel IgG1 bispecific antibody, targets HER2 domains ECD2 and ECD4, resulting in multiple differentiated and unique mechanisms of action, including improved receptor internalization and downregulation relative to trastuzumab. Safety, anti-tumor activity, and biomarker data from an ongoing phase 1 trial of ZW25 monotherapy in solid tumors other than breast cancer, are presented here. Methods Eligible patients with HER2 IHC 3+, IHC 2+/FISH+, or IHC 2+/FISH- tumors confirmed by central review of fresh or archival biopsies, who had progressed on all standard therapies, were enrolled. Assessments included tumor evaluations (RECIST 1.1 Q8W), circulating tumor DNA (ctDNA; pre-dose C1 D1, C2 D15, treatment end), and standard safety evaluations. Results A total of 43 patients, including 17, 6, 10, and 10 with gastroesophageal adenocarcinoma (GEA), biliary tract cancers, colorectal cancer, and other cancers, respectively, received single agent ZW25 at 10 mg/kg QW or 20 mg/kg Q2W. The median number of prior therapies was 3 (range 1-6) for all patients. For GEA and non-GEA patients, 88% and 35% respectively received at least one unique prior HER2 therapy. The most common treatment-related adverse events (all Grade 1 or 2) were diarrhea (49%) and infusion related reaction (34%). The objective response rate (all partial response (PR)) for response evaluable patients was 41% (14/34), stable disease (SD) in 38% (13/34), and progressive disease in 21% (7/34). The majority of patients (74%; 25/34) experienced a decrease in the sum of diameters for their target lesions. Compared to FISH, the positive predictive value of HER2 amplification in pre-dose C1D1 ctDNA was 90% (95% CI 79-96%), negative predictive value 45% (25-67%), and diagnostic accuracy 79% (63-90%). Disease control (PR or SD) > 5 months was associated with lower level of copy number adjusted mutational variant allele frequency in pre-treatment ctDNA (Mann Whitney p = 0.0085). Conclusions ZW25 has been well tolerated with promising single agent activity in heavily pre-treated patients. These data support further clinical development of this bispecific antibody in HER2-expressing solid tumors. Clinical trial identification NCT03929666. Legal entity responsible for the study Zymeworks, Inc. Funding Zymeworks, Inc. Disclosure F. Meric-Bernstam: Research grant / Funding (institution): Novartis; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Taiho; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Calithera; Research grant / Funding (institution): Debio; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Aileron; Research grant / Funding (institution): PUMA; Research grant / Funding (institution): CytomX; Research grant / Funding (institution): Zymeworks; Research grant / Funding (institution): Curis; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): eFFECTOR; Research grant / Funding (institution): Abbvie; Research grant / Funding (institution): Guardant Health; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): GlaxoSmithKline; Honoraria (self): Sumitomo Dainippon Pharma; Dialectica; Advisory / Consultancy: Genentech; Inflection; Pieris; Darwin Health; Samsung Bioepis; Aduro; Spectrum; OrigiMed; Debio; Xencor; Jackson Laboratory; Mersana; Seattle Genetics; Zymeworks; Kolon; Parexel International. M. Beeram: Speaker Bureau / Expert testimony, Speaker’s bureau: Genentech. K. Lee: Honoraria (self): BMS; Honoraria (self): Eli Lilly; Research grant / Funding (institution): ALX Oncology; Research grant / Funding (institution): Array BioPharma; Research grant / Funding (institution): AstraZeneca/Medimmune; Research grant / Funding (institution): Five Prime Therapeutics; Research grant / Funding (institution): Green Cross Corp; Research grant / Funding (institution): LSK BioPharma; Research grant / Funding (institution): Macrogenics; Research grant / Funding (institution): Merck KGaA; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Ono Pharmaceutical; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Pharmacyclics; Travel / Accommodation / Expenses: BMS. Y. Kang: Advisory / Consultancy: Ono; Advisory / Consultancy: BMS; Advisory / Consultancy: Daehwa; Advisory / Consultancy: LSKBiopharma; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Macrogenics; Advisory / Consultancy: Zymeworks; Advisory / Consultancy: Blueprint; Advisory / Consultancy: Merck; Advisory / Consultancy: Serono; Advisory / Consultancy: Novartis; Advisory / Consultancy: Astellas; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Novartis. J. Chaves: Shareholder / Stockholder / Stock options: Northwest Medical Specialties, PLLC. C. Vaklavas: Advisory / Consultancy, no compensaton: Genentech; Advisory / Consultancy: Daiichi-Sankyo; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pharmacyclics; Research grant / Funding (institution): Tracon; Research grant / Funding (institution): Innocrin; Research grant / Funding (institution): Zymeworks; Research grant / Funding (institution): H3 Biomedicine. D. Oh: Advisory / Consultancy: Genentech; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Novartis; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Bayer; Advisory / Consultancy: Taiho; Advisory / Consultancy: ASLAN; Advisory / Consultancy: Halozyme; Advisory / Consultancy: Zymeworks; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Array; Research grant / Funding (institution): Eli Lilly. E. Elimova: Full / Part-time employment, spouse is employee in vaccine global division: Meric; Advisory / Consultancy: BMS; Honoraria (self): Zymeworks. C. Ferrario: Honoraria (self): Pfizer; Honoraria (self): Bayer; Honoraria (self): Novartis; Honoraria (self): AstraZeneca; Honoraria (self): Merck; Honoraria (self): Astellas Pharma; Advisory / Consultancy: Genomic Health; Advisory / Consultancy: Merck; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Bayer; Speaker Bureau / Expert testimony, Speaker’s bureau: Novartis; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Astellas Pharma; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Cascadian Therapeutics; Research grant / Funding (institution): Celldex; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Merck; Novartis; Roche/Genentech; Sanofi; Pfizer; Janssen; Zymeworks; Travel / Accommodation / Expenses: Novartis; Roche. A. Fortenberry: Full / Part-time employment: Zymeworks, Inc.; Shareholder / Stockholder / Stock options: Zymeworks, Inc. G. Rowse: Full / Part-time employment: Zymeworks, Inc.; Shareholder / Stockholder / Stock options: Zymeworks, Inc. T. Gray: Full / Part-time employment: Zymeworks, Inc.; Shareholder / Stockholder / Stock options: Zymeworks, Inc. R. Lai: Full / Part-time employment: Zymeworks, Inc.; Shareholder / Stockholder / Stock options: Zymeworks, Inc. E. Hamilton: Research grant / Funding (institution): Zymeworks; Research grant / Funding (institution): Lilly; Advisory / Consultancy, No personal compensation: Lilly; Research grant / Funding (institution): Pfizer; Advisory / Consultancy, No personal compensation: Pfizer; Research grant / Funding (institution): Genentech/Roche; Speaker Bureau / Expert testimony, No personal compensation: Genentech/Roche; Advisory / Consultancy: Flatiron Health; Research grant / Funding (institution): Cascadian Therapeutics; Research grant / Funding (institution): Hutchinson MediPharma; Research grant / Funding (institution): OncoMed; Research grant / Funding (institution): Medimmune; Research grant / Funding (institution): StemCentrx; Research grant / Funding (institution): Abbvie; Research grant / Funding (institution): Curis; Research grant / Funding (institution): Verastem; Research grant / Funding (institution): Zymeworks; Research grant / Funding (institution): Syndax; Research grant / Funding (institution): Lycera; Research grant / Funding (institution): Rgenix; Novartis; Mersana; TapImmune; BerGenBio; Tesaro; Medivation; Kadmon, Boehringer Ingelheim; Eisai; H3 Biomedicine; Radius Health; Acerta; Takeda; Macrogenics; Immunomedics; FujiFilm; Effector. All other authors have declared no conflicts of interest.