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Background Human epidermal growth factor receptor 2 (HER2)-targeted therapies are successful in patients with HER2-positive malignancies; however, spatial and temporal heterogeneity of HER2 expression may prevent identification of optimal patients for these therapies. Purpose To determine whether imaging with the HER2-targeted PET tracer zirconium 89 (

Background Data on drug-induced liver injury (DILI) and acute liver failure (ALF) in modern phase 1 oncology trials are limited, specifically with respect to the incidence and resolution of DILI and the safety of drug rechallenge. Methods This study reviewed all patients who were recruited to phase 1 oncology trials between 2013 and 2017 at Memorial Sloan Kettering Cancer Center. Clinicopathologic data were extracted to characterize DILI, and attribution was assessed on the basis of data prospectively generated during the studies. Logistic regression models were used to explore factors related to DILI and DILI recurrence after drug rechallenge. Results Among 1670 cases recruited to 85 phase 1 trials, 81 (4.9%) developed DILI. The rate of DILI occurrence was similar for patients in immune-based trials and patients in targeted therapy trials (5.0% vs 4.9%), as was the median time to DILI (5.5 vs 6.5 weeks; P = .48). Two patients (0.12%) met the criteria of Hy's law, although none developed ALF. The DILI resolved in 96% of the patients. Pretreatment factors were not predictive for DILI development. Thirty-six of the 81 patients underwent a drug rechallenge, and 28% of these patients developed DILI recurrence. Peak alanine aminotransferase during the initial DILI was associated with DILI recurrence (odds ratio, 1.04; 95% confidence interval, 1.0-1.09; P = .035). Conclusions In modern phase 1 oncology trials, DILI is uncommon, may occur at any time, and often resolves with supportive measures. Rechallenging after DILI is feasible; however, the high rate of DILI recurrence suggests that clinicians should consider the severity of the DILI episode and treatment alternatives.

Background The tropomyosin receptor kinase (TRK) pathway controls appetite, balance, and pain sensitivity. While these functions are reflected in the on-target adverse events (AEs) observed with TRK inhibition, these AEs remain under-recognized, and pain upon drug withdrawal has not previously been reported. As TRK inhibitors are approved by multiple regulatory agencies for TRK or ROS1 fusion-positive cancers, characterizing these AEs and corresponding management strategies is crucial. Patients and methods Patients with advanced or unresectable solid tumors treated with a TRK inhibitor were retrospectively identified in a search of clinical databases. Among these patients, the frequency, severity, duration, and management outcomes of AEs including weight gain, dizziness or ataxia, and withdrawal pain were characterized. Results Ninety-six patients with 15 unique cancer histologies treated with a TRK inhibitor were identified. Weight gain was observed in 53% [95% confidence interval (CI), 43%–62%] of patients and increased with time on TRK inhibition. Pharmacologic intervention, most commonly with glucagon-like peptide 1 analogs or metformin, appeared to result in stabilization or loss of weight. Dizziness, with or without ataxia, was observed in 41% (95% CI, 31%–51%) of patients with a median time to onset of 2 weeks (range, 3 days to 16 months). TRK inhibitor dose reduction was the most effective intervention for dizziness. Pain upon temporary or permanent TRK inhibitor discontinuation was observed in 35% (95% CI, 24%–46%) of patients; this was more common with longer TRK inhibitor use. TRK inhibitor reinitiation was the most effective intervention for withdrawal pain. Conclusions TRK inhibition-related AEs including weight gain, dizziness, and withdrawal pain occur in a substantial proportion of patients receiving TRK inhibitors. This safety profile is unique relative to other anticancer therapies and warrants careful monitoring. These on-target toxicities are manageable with pharmacologic intervention and dose modification.

Background: LSZ102 is an orally bioavailable selective estrogen receptor degrader (SERD) that inhibits estrogen receptor (ER) gene transcription, induces receptor degradation, and blocks ER-dependent cell growth in preclinical models. This Phase I/Ib, open-label study is evaluating LSZ102 as a single agent and in combination with the CDK4/6 inhibitor ribociclib (LEE011) or the PI3K inhibitor alpelisib (BYL719) in patients (pts) with locally advanced/metastatic ER-positive (ER+) breast cancer (BC). Methods: The primary objective is to characterize the safety and tolerability, and identify a recommended dose and regimen of LSZ102 alone (Arm A) or in combination with ribociclib (Arm B) or alpelisib (Arm C). Secondary objectives include evaluation of preliminary antitumor activity and pharmacokinetics (PK). Eligible pts (aged ≥18 yrs; ECOG PS 0-1) have histologically confirmed ER+ BC that has progressed after endocrine therapy. Results: As of March 14, 2017, dose escalation evaluating 16 pts in Arm A (LSZ102 200 mg [n=4], 400 mg [n=6], and 600 mg [n=6]) had completed (median age 57.5 yrs; 81% ECOG PS 0; 63% received prior fulvestrant). Five pts (median age 59.0 yrs; 80% ECOG PS 0; 60% received prior fulvestrant) had enrolled in the first cohort of Arm B (LSZ102 200 mg QD + ribociclib 300 mg 3 weeks on/1 week off) with evaluation ongoing. Arm C (LSZ102 + alpelisib) had yet to open. As of March 14, 2017, 9/16 (56%) pts in Arm A had discontinued treatment, all due to progressive disease (PD); in Arm B all pts were still receiving treatment. There were no dose-limiting toxicities in either arm at the dose levels evaluated; dose escalation is ongoing. The most common drug-related adverse events (AEs) were diarrhea (Grade [Gr] 1: 7/16; Gr 2: 2/16 pts), nausea (Gr 1: 6/16; Gr 2: 2/16 pts), and vomiting (Gr 1: 3/16 pts) in Arm A, and hot flush, nausea, vaginal discharge (all Gr 1: 2/5 pts), thrombocytopenia (Gr 1: 1/5; Gr 2: 1/5 pts), and neutropenia (Gr 2: 1/5, Gr 3: 1/5 pts) in Arm B. There were no drug-related Gr 3/4 AEs reported in Arm A; in Arm B, Gr 3 neutropenia, leukopenia, and lymphopenia each occurred in 1/5 pts. Preliminary PK assessment showed single-agent LSZ102 exposure increased dose-proportionally from 200 to 600 mg QD. In combination with ribociclib, exposures were consistent with those of the single agent at the same dose. In Arm A, preliminary evidence of antitumor activity was observed. Efficacy data for Arms B and C were not available as of March 14, 2017. One pt, whose tumor harbored an ESR1 D538G mutation, had been treated with multiple prior therapies in the metastatic setting, including letrozole, exemestane, tamoxifen, exemestane + everolimus, and anastrozole, as well as fulvestrant for 120 days prior to PD, and letrozole + palbociclib for 94 days prior to PD. As of March 14, 2017, this pt had been on LSZ102 treatment (400 mg QD) for 167 days, with a best response of stable disease (14% reduction in sum of diameter of target lesions). Conclusions: Oral single-agent LSZ102 appears well-tolerated, with a manageable safety profile. Preliminary data also suggest tolerability when combined with ribociclib. Preliminary evidence of single-agent antitumor activity was seen in heavily pretreated pts with ER+ BC in a post-fulvestrant setting. Citation Format: Juric D, Curigliano G, Cresta S, Yap Y-S, Terret C, Duhoux FP, Takahashi S, Kundamal N, Bhansali S, Liao S, Crystal A, Jhaveri K. Phase I/Ib study of the SERD LSZ102 alone or in combination with ribociclib in ER+ breast cancer [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 P5-21-04.

Somatic mutations of ERBB2 and ERBB3 (which encode HER2 and HER3, respectively) are found in a wide range of cancers. Preclinical modelling suggests that a subset of these mutations lead to constitutive HER2 activation, but most remain biologically uncharacterized. Here we define the biological and therapeutic importance of known oncogenic HER2 and HER3 mutations and variants of unknown biological importance by conducting a multi-histology, genomically selected, 'basket' trial using the pan-HER kinase inhibitor neratinib (SUMMIT; clinicaltrials.gov identifier NCT01953926). Efficacy in HER2-mutant cancers varied as a function of both tumour type and mutant allele to a degree not predicted by preclinical models, with the greatest activity seen in breast, cervical and biliary cancers and with tumours that contain kinase domain missense mutations. This study demonstrates how a molecularly driven clinical trial can be used to refine our biological understanding of both characterized and new genomic alterations with potential broad applicability for advancing the paradigm of genome-driven oncology.

Background: Although ET remains the basis of therapy for ER+, HER2– ABC, treatment resistance frequently occurs. Novel strategies to target the receptor and/or alternative pathways to overcome therapeutic resistance are under investigation. LSZ102 is a novel, orally bioavailable, nonsteroidal SERD. Preclinically, LSZ102 inhibits ER gene transcription, induces receptor degradation, blocks ER-dependent cell growth, and has synergistic activity with the phosphoinositide 3-kinase (PI3K)-alpha inhibitor alpelisib (BYL719). The present study is evaluating the safety and tolerability of LSZ102 plus alpelisib in patients with ER+, HER2– ABC with progression on ET. Trial Design: This phase 1/1b, open-label study is enrolling ˜18-30 patients (men and women of any menopausal status) in Arm C of the dose-escalation part of the study, which investigates the combination of LSZ102 and alpelisib; additional study arms will investigate LSZ102 as a single agent or in combination with ribociclib. Enrollment in Arm C started after identification of a safe and tolerable single-agent dose for LSZ102. Alpelisib dosing began at 200 mg/day and will not be escalated beyond the maximum tolerated dose (MTD) determined in the alpelisib single-agent arm of study CBYL719X2101 (400 mg/day). Dose escalation of alpelisib in combination with LSZ102 is guided by BLRM and integrates Cycle 1 DLT rates, lower grade and later cycle AE, PK, PD and preliminary activity to identify a recommended dose for expansion (RDE). Patients will receive treatment until disease progression, unacceptable toxicity, or withdrawal of consent. For inclusion in the study, patients must have histologically confirmed ER+, HER2– ABC and disease progression after ET for ABC or recurrence on/within 12 months of completion of adjuvant ET. In the escalation part of the study, patients are eligible regardless of PIK3CA status. Premenopausal women must receive concomitant treatment with a gonadotropin-releasing hormone agonist. Eligible patients must have adequate bone marrow and organ function, Eastern Cooperative Oncology Group performance status of 0 or 1, and have completed and recovered from acute toxicities of radiotherapy and/or prior anticancer therapy. Exclusion criteria include symptomatic central nervous system metastases, clinically significant cardiac disease or impaired cardiac function (including a QT interval corrected for heart rate using Fridericia's formula [QTcF] >460 ms in women or >450 ms in men), uncontrolled diabetes mellitus type II (or type I), and prior treatment with a PI3K inhibitor. The primary objectives are characterization of safety and tolerability for the combination and identification of a recommended dose. Secondary objectives include characterization of pharmacokinetic properties and pharmacodynamic effects. Recruitment for Arm C is ongoing. NCT02734615 Citation Format: Curigliano G, Cresta S, Yap Y-S, Juric D, Duhoux FP, Terret C, Takahashi S, Layman RM, Kundamal N, Baldoni D, Liao S, Crystal A, Jhaveri K. Phase 1/1b study of novel oral selective estrogen receptor degrader (SERD) LSZ102 in combination with alpelisib (BYL719) in estrogen receptor-positive (ER+), human epidermal growth factor receptor-2–negative (HER2–) advanced breast cancer (ABC) with progression on endocrine therapy (ET) [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 OT1-03-01.

Importance Fibroblast growth factor receptor (FGFR) 1 to 4 inhibitors are approved by the US Food and Drug Administration and suppress the mitogen-activated protein kinase (MAPK) pathway, with a potential for treatment-related retinopathy. To date, implications of FGFR inhibitor–associated ocular toxic effects are poorly described. Therefore, more detailed clinical descriptions of this ocular toxic effect could help explain visual symptoms while receiving drug therapy. Objective To describe the clinical and morphologic characteristics of serous retinal disturbances associated with FGFR inhibitors. Design, Setting, and Participants In this retrospective case series, 146 patients receiving FGFR inhibitors as cancer treatment at a single tertiary referral center were included. This study included 40 eyes of 20 patients with retinopathy by optical coherence tomography (OCT). OCTs were obtained on the remaining patients and the results were judged normal. Patients were recruited from March 2012 to January 2021. Main Outcomes and Measures Characteristics of treatment-emergent choroidal and retinal OCT abnormalities as compared with baseline OCT, associated with visual acuity at presentation and at fluid resolution. Results A total of 20 of 146 patients (13.7%) exhibited FGFR inhibitor–associated retinopathy. Of these 20 patients, 11 (55%) were female, and the median (range) age was 62.6 (42.7-86.0) years. The median (range; mean) time from medication start to initial subretinal fluid detection was 21 (5-125; 32) days. The median (interquartile range [IQR]) baseline logMAR best-corrected visual acuity (BCVA) was 0 (0-0.1). At fluid accumulation, 11 eyes had decreased vision: the median (IQR) subgroup baseline BCVA was 0 (0-0.1); and the median (IQR) BCVA change from baseline to accumulation was −0.1 (−0.2 to −0.1). For 26 eyes (65%) with follow-up, the subretinal fluid resolved without medical intervention or drug interruption in all but 1 patient. At fluid resolution, the median (IQR) BCVA was 0.1 (0-0.1), and the change in median (IQR) BCVA from baseline to fluid resolution was 0 (−0.03 to 0). No patient discontinued drug therapy on account of their retinopathy. Conclusions and Relevance FGFR inhibitors result in subretinal fluid foci similar to other drugs that inhibit the MAPK pathway. In this series, FGFR inhibitors did not cause irreversible loss of vision; the retinopathy was self-limited and did not require medical intervention. These results may explain visual symptoms while taking the drug, although the precise frequency or magnitude of this adverse effect cannot be determined with certainty from this retrospective investigation.

In what we believe to be a first-in-human study, we evaluated the safety and dosimetry of 89Zr-pertuzumab PET/CT for human epidermal growth factor receptor 2 (HER2)–targeted imaging in patients with HER2-positive breast cancer. Methods: Patients with HER2-positive breast cancer and evidence of distant metastases were enrolled in an institutional review board–approved prospective clinical trial. Pertuzumab was conjugated with deferoxamine and radiolabeled with 89Zr. Patients underwent PET/CT with 74 MBq of 89Zr-pertuzumab in a total antibody mass of 20–50 mg of pertuzumab. PET/CT, whole-body probe counts, and blood drawing were performed over 8 d to assess pharmacokinetics, biodistribution, and dosimetry. PET/CT images were evaluated for the ability to visualize HER2-positive metastases. Results: Six patients with HER2-positive metastatic breast cancer were enrolled and administered 89Zr-pertuzumab. No toxicities occurred. Dosimetry estimates from OLINDA demonstrated that the organs receiving the highest doses (mean ± SD) were the liver (1.75 ± 0.21 mGy/MBq), the kidneys (1.27 ± 0.28 mGy/MBq), and the heart wall (1.22 ± 0.16 mGy/MBq), with an average effective dose of 0.54 ± 0.07 mSv/MBq. PET/CT demonstrated optimal imaging 5–8 d after administration. 89Zr-pertuzumab was able to image multiple sites of malignancy and suggested that they were HER2-positive. In 2 patients with both known HER2-positive and HER2-negative primary breast cancers and brain metastases, 89Zr-pertuzumab PET/CT suggested that the brain metastases were HER2-positive. In 1 of the 2 patients, subsequent resection of a brain metastasis proved HER2-positive disease, confirming that the 89Zr-pertuzumab avidity was a true-positive result for HER2-positive malignancy. Conclusion: This first-in-human study demonstrated safety, dosimetry, biodistribution, and successful HER2-targeted imaging with 89Zr-pertuzumab PET/CT. Potential clinical applications include assessment of the HER2 status of lesions that may not be accessible to biopsy and assessment of HER2 heterogeneity.

Background GDC-0077 is a PI3Kα-selective inhibitor and mutant PI3Kα degrader that demonstrates antitumor activity in PIK3CAmut BC xenograft models. A phase I/Ib study of GDC-0077 alone and combined with endocrine therapy ± the CDK4/6 inhibitor (i) palbo is ongoing (NCT03006172). Data from GDC-0077 + palbo + fulvestrant in pts with PIK3CAmut, HR+/HER2- mBC are presented herein. Methods Safety (NCI-CTCAE v4), pharmacokinetics (PK), and preliminary antitumor activity (clinical benefit rate [CBR]: RECIST v1.1 stable disease for ≥ 24 weeks, partial response [PR], or complete response) of 9 mg oral once daily GDC-0077 + 125 mg palbo 21/28 days + 500 mg intramuscular fulvestrant on day 1 (and day 15 of cycle 1) of 28-day cycles were assessed in Arms E and F, until intolerable toxicity or disease progression. In Arm F, pts were obese and/or pre-diabetic (body mass index ≥ 30 kg/m2 and/or HbA1c ≥ 5.7%) and also received metformin up to 2000 mg daily starting at 500 mg in cycle 1 day 1, prior to initiating GDC-0077 at cycle 1 day 15 instead of day 1 as in Arm E. Additional key eligibility criteria included Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1, no prior PI3Ki therapy, no prior CDK4/6i, and ≤ 1 prior chemotherapy for Arm E (no restrictions on prior CDK4/6i or chemotherapy for Arm F). PIK3CAmut allele frequency was assessed in circulating tumor (ct) DNA from serial plasma collections. Results At clinical cutoff (03/20/2020), 28 pts were enrolled (13 in Arm E and 15 in Arm F). Median age was 55 years in Arm E and 65 years in Arm F. ECOG PS was 0 in 8 pts (62%) in Arm E and in 7 pts (47%) in Arm F. Three (23%) and 12 (80%) pts in Arm E and F, respectively, had received ≥ 2 prior lines of therapy for mBC. One pt (8%) in Arm E and 10 pts (67%) in Arm F received prior fulvestrant. Nine pts (60%) received prior CDK4/6i (all Arm F). Median GDC-0077 treatment duration was 7.8 months (range 0.1-13.9) in Arm E and 6.5 months (1.2-11.2) in Arm F. GDC-0077 cumulative dose intensity was 98% in Arm E and 88% in Arm F. Thirteen pts (46%) discontinued treatment: 11, due to radiographic disease progression (3 in Arm E, 8 in Arm F); 1, due to an adverse event (AE; treatment-related grade 2 panniculitis in Arm F); and 1 pt withdrew (Arm F). The most common treatment-related AEs (≥ 4 pts) were stomatitis (grouped term; 92%), neutropenia (85%), diarrhea and hyperglycemia (62% each), fatigue (38%), alopecia, nausea, and thrombocytopenia (31% each) in Arm E; and hyperglycemia (67%), diarrhea and neutropenia (53% each), nausea (47%), stomatitis (grouped term; 47%), anemia, decreased appetite, and blurred vision (27% each) in Arm F. Grade ≥ 3 treatment-related AEs (≥ 2 pts) were neutropenia (62%) and hyperglycemia (23%) in Arm E; and hyperglycemia and neutropenia (47% each), and anemia (13%) in Arm F. AEs led to GDC-0077 dose reduction in 2 pts (15%) in Arm E and 4 pts (27%) in Arm F. The PK of GDC-0077 in combination with palbo + fulvestrant was similar to single agent GDC-0077. Overall, 7/25 pts (28%) with measurable disease had a PR (5/10 [50%] pts in Arm E; 2/15 [13%] pts in Arm F, both received prior fulvestrant), of whom 6 pts (24%; 4 in Arm E; 2 in Arm F) had a confirmed PR. CBR was 61% (17/28 pts: 8 in Arm E; 9 in Arm F). PIK3CAmut allele frequency by ctDNA analysis decreased during treatment in most pts. Conclusion This study demonstrated a manageable safety profile when combining GDC-0077 at its single agent recommended phase II dose of 9 mg with palbo + fulvestrant at standard doses, similar PK to GDC-0077 alone, preliminary anti-tumor activity, and modulation of PIK3CAmut allele frequency in ctDNA. In obese and/or pre-diabetic patients enrolled to Arm F, hyperglycemia was frequent despite initiating metformin prior to GDC-0077. A phase III study of GDC-0077 + palbo + fulvestrant is enrolling currently (NCT04191499). Citation Format: Philippe L Bedard, Komal Jhaveri, Andrés Cervantes, Valentina Gambardella, Erika Hamilton, Antoine Italiano, Kevin Kalinsky, Ian E Krop, Mafalda Oliveira, Cristina Saura, Peter Schmid, Nicolas Turner, Andrea Varga, Katherine E Hutchinson, Guiyuan Lei, Stephanie Royer-Joo, Piia Thomas, Jennifer L Schutzman, Dejan Juric. A phase I/Ib study evaluating GDC-0077 + palbociclib (palbo) + fulvestrant in patients (pts) with PIK3CA-mutant (mut), hormone receptor-positive/HER2-negative metastatic breast cancer (HR+/HER2- mBC) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD1-02.

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 .

TPS1103 Background: Modulating estrogen synthesis and/or ER activity is the mainstay of treatment for pts with ER+ BC. Despite substantial progress, many pts experience relapse during/after adjuvant endocrine therapy. However, even though resistant to aromatase inhibitors (AIs) or tamoxifen, growth and survival of the majority of tumors are thought to remain dependent on ER signaling. Therefore, pts with ER+ BC can still respond to second- or third-line endocrine treatment after progression on prior therapy (Di Leo 2010; Baselga 2012). Therapeutic resistance can arise from mutations in ESR1, which can drive estrogen-independent transcription and proliferation. The highly potent, non-steroidal oral selective ER degrader giredestrant achieves robust ER occupancy and is active regardless of ESR1 mutation status. Phase I data indicate that giredestrant is well tolerated, with encouraging activity as a single agent and in combination with the CDK4/6 inhibitor palbociclib (Lim 2020). Single-agent activity was observed after prior treatment with fulvestrant and/or a CDK4/6 inhibitor (Jhaveri 2019). Methods: persevERA BC (NCT04546009) is a double-blind, placebo-controlled, randomized, multicenter phase III study designed to evaluate the efficacy and safety of first-line giredestrant + palbociclib in pts with ER+/HER2– LA/mBC. Randomization: 1:1 to either giredestrant (30 mg PO) plus letrozole placebo QD or letrozole (2.5 mg PO) plus giredestrant placebo QD on Days 1–28 of each 28-day cycle, with palbociclib (125 mg PO QD) on Days 1–21 of each 28-day cycle. Men and premenopausal women will receive an LHRH agonist. Eligibility: females or males ≥18 years old with measurable disease or evaluable bone disease and no prior treatment for advanced disease. Pts who received prior fulvestrant or who have relapsed within 12 months of completion of (neo)adjuvant therapy with an AI and/or prior therapy with CDK4/6 inhibitor are not eligible; relapse during tamoxifen therapy but > 24 months after the start of tamoxifen therapy is allowed. Stratification: site of disease, disease-free interval since the end of (neo)adjuvant therapy, menopausal status, and geographic region. Primary efficacy endpoint: progression-free survival (determined locally by the investigator per RECIST v1.1). Secondary endpoints include overall survival, objective response rate, duration of response, clinical benefit rate, QoL, and safety. Enrollment is open (first patient in: Oct 9, 2020); target recruitment is 978 pts across all sites in a global enrollment phase. After completion of the global enrollment, additional pts may be enrolled in China. Clinical trial information: NCT04546009 .

2548 Background: Fascin inhibitors block tumor metastasis and increase antigen uptake in intra-tumoral dendritic cells. Filopodia, finger-like protrusions on cell surfaces, are necessary for migration of metastatic tumor cells and intra-tumoral dendritic cells. Fascin is the primary actin cross-linker in filopodia and elevated levels correlate with increased risk of metastasis, disease progression and mortality. NP-G2-044 is a novel small molecule that inhibits function of fascin. Pre-clinical data demonstrate drug-associated reductions in tumor growth and metastasis, enhanced immune response and survival in treated animals, and drug-drug synergism when combined with anti-PD-1 antibodies. Methods: This multicenter phase 1A clinical trial was designed to evaluate safety and tolerability of NP-G2-044 and to identify the drug’s recommended phase 2 dose (RP2D) using a 3+3 dose escalation design. NP-G2-044 was administered to patients (pts.) with treatment-refractory solid tumor malignancies as a single oral daily dose for 6-week cycles that included 4 weeks on (daily dosing) and 2 weeks off (rest). Results: A total of 23 pts. were enrolled in 7 dose cohorts ranging from 200-2100 mg. QD. Overall, NP-G2-044 appeared well-absorbed and distributed with Tmax of ̃4 hrs and T1/2 of 20-24 hrs. Across all cohorts, no DLTs, drug-related SAEs or patient deaths were observed. Based on PK and safety findings, 1600 mg. daily was selected as the provisional RP2D. While no formal RECIST-based objective responses were observed, consistent with the drug’s non-cytotoxic mechanism of action, preliminary signals of anti-tumor and anti-metastatic activity were observed. These include dose proportional increases in duration of treatment, progression-free-survival, and metastasis-free interval, in particular for 4/4 late-stage ovarian cancer patients (table). Comparison of time on treatment (TOT) for ovarian cancer patients. Conclusions: In this first-in-human clinical trial, the novel fascin inhibitor, NP-G2-044, appeared safe and well tolerated. Signals of single-drug anti-tumor and anti-metastatic activity were observed. A phase 2A clinical trial with a particular focus on Ovarian Cancer will seek to elucidate signals of RP2D activity in both monotherapy and the combination of NP-G2-044 with anti-PD-(L)1 immune checkpoint inhibitors. Clinical trial information: NCT03199586. [Table: see text]

577 Background: Modulation of ER activity and/or estrogen synthesis is the mainstay therapeutic strategy in ER+ BC treatment. Giredestrant is a highly potent, nonsteroidal oral selective ER degrader (SERD) that achieves robust ER occupancy and is effective regardless of ESR1 mutation status. The first short-term preoperative WOO study (NCT03916744) of giredestrant in ER+/HER2– operable BC was designed for dose selection, while providing an early readout of PD as measured by traditional immunohistochemistry (IHC) and transcriptional profiling by assessing treatment effects in paired tumor tissue pre/posttreatment. We present an interim analysis. Methods: Pts were assigned to 14 days’ preoperative treatment with 10, 30, or 100 mg PO giredestrant QD. Pts had newly diagnosed, stage I–III operable, ER+/HER2– untreated BC ≥1.5 cm in diameter (by ultrasound). Modulation of ER signaling and cell proliferation were assessed using paired formalin-fixed paraffin-embedded tumor specimens collected before and after ̃14 days of study treatment. ER, progesterone receptor (PR), and Ki67 protein levels were analyzed by IHC. Change from baseline in tumor cell proliferation by Ki67 was the primary endpoint. Gene expression analysis was performed using the Illumina TruSeq RNA Access method. Results: From Jul 26, 2019 to Oct 15, 2020, 46/75 biomarker-evaluable pts were enrolled across three dose cohorts (10 mg: n = 15; 30 mg: n = 18; 100 mg: n = 13). Pt demographics and tumor characteristics were similar across cohorts. Baseline PAM50 analysis classified tumors as Luminal A (77%) or B (23%). Giredestrant treatment resulted in robust and indistinguishable PD and biologic activity at all doses. Geometric mean posttreatment proportional reduction of Ki67 was 79% (95% CI: 69–89; 10 mg: 80%; 30 mg: 76%; 100 mg: 80%), and 51% of tumors exhibited complete cell cycle arrest, defined as Ki67 ≤2.7%. Mean posttreatment proportional reductions of ER and PR H-scores were 71% (95% CI: 67–75) and 60% (95% CI: 51–70), respectively. An analysis of a predefined, experimentally derived set of 38 ER target genes (the ‘ER activity signature’), was completed for 42 paired tumor specimens. Forty-one of 42 pts (98%) showed a posttreatment reduction in ER activity with a mean proportional decrease of 79% (95% CI: 70–88). A wide range of baseline ER activity was observed with no correlation to baseline ER or PR H-score, or Ki67. There were no discontinuations due to adverse events (AEs). A single grade 3 serious AE was reported in each cohort (all assessed as unrelated to giredestrant). No grade 4 or 5 AEs were reported. Conclusions: Giredestrant was well tolerated in the preoperative setting in ER+/HER2– operable BC, and PDs were consistent with the 30 mg dose achieving maximal ER inhibition. Clinical trial information: NCT03916744.

TPS1096 Background: HER2-targeted therapies have improved survival in patients (pts) with HER2+ advanced/metastatic breast cancer (mBC) but challenges remain, including resistance to current HER2-targeted therapies. Also, additional treatment options are needed in pts with brain metastases (BM). In the phase 2 DESTINY-Breast01 trial, T-DXd demonstrated efficacy, with an objective response rate (ORR) of 61.4% and median progression-free survival (mPFS) of 19.4 mo in pts with previously treated HER2+ advanced/mBC (Modi SABCS 2020); data from an earlier cutoff of this trial supported approval of T-DXd in the US, Europe, and Japan. In a subgroup analysis of 24 pts with stable BM, T-DXd showed preliminary efficacy, with mPFS of 18.1 mo (Jerusalem ESMO Breast Cancer 2020). Here, we describe a phase 1b/2 trial evaluating the safety and preliminary antitumor activity of T-DXd monotherapy and combinations in pts with HER2+ advanced/mBC, including pts with stable and active BM. Methods: DESTINY-Breast07 (NCT04538742) is a global, multicenter, open-label, phase 1b/2 trial designed to evaluate the safety, tolerability, and preliminary antitumor activity of T-DXd monotherapy and combinations in pts with HER2+ advanced/mBC. This study consists of a T-DXd monotherapy module (module 0) and 5 combination modules of T-DXd plus (1) durvalumab, (2) pertuzumab, (3) paclitaxel, (4) durvalumab + paclitaxel, or (5) tucatinib, all in pts with no or stable BM. Two additional modules consisting of (6) T-DXd + tucatinib and (7) T-DXd monotherapy will include pts with untreated BM not requiring local therapy or previously treated BM that have progressed since local therapy (active BM). The need for chronic steroids or local therapy to manage BM symptoms is exclusionary. Modules 2 to 5 will each consist of 2 parts: dose finding (part 1) and dose expansion (part 2). Modules 0, 1, 6, and 7 will include part 2 only. Part 1 of individual modules will enroll pts who have had disease progression while receiving ≥1 prior line of therapy in the metastatic setting. In part 2, pts who have received no prior therapy (modules 0 to 5) or ≤1 prior therapy (modules 6 to 7) for metastatic disease will be randomized to receive a T-DXd combination regimen or monotherapy. The primary endpoints are determination of the recommended phase 2 doses (part 1 only) and safety and tolerability of T-DXd and combinations (parts 1 and 2). Secondary endpoints include ORR, PFS, PFS2, duration of response (DoR), and overall survival (all assessed in part 2 only) and pharmacokinetics and immunogenicity (parts 1 and 2). To assess central nervous system (CNS) activity, exploratory endpoints were added, including CNS-ORR, CNS-DoR, and CNS-PFS (by RECIST version 1.1 and RANO-BM criteria) as well as cognitive and symptom assessment using CANTAB, MDASI-BT, and NANO. Clinical trial information: NCT04538742 .

1017 Background: Targeting ER activity and/or E synthesis is a mainstay of ER+ BC treatment, but many pts relapse during/after adjuvant endocrine therapy (ET) or develop resistance via ESR1 mutations that drive E-independent transcription and proliferation. Most tumors remain ER signaling-dependent and pts may respond to second-/third-line ET after disease progression (PD) on prior therapies (Di Leo 2010; Baselga 2012). Giredestrant, a highly potent, nonsteroidal oral selective ER degrader, achieves robust ER occupancy, is active despite ESR1 mutations, and was well tolerated ± palbociclib with encouraging antitumor activity in the nonrandomized, open-label, dose-escalation and -expansion, phase Ia/b GO39932 study (NCT03332797; Jhaveri 2019; Lim 2020). We present updated interim data from the dose-escalation and -expansion single-agent giredestrant cohorts. Methods: Pts had ≤2 prior therapies in the LA/mBC setting with disease recurrence/PD while being treated with adjuvant ET for ≥24 mo and/or ET in the LA/mBC setting, and derived a clinical benefit (CB) from therapy (tumor response/stable disease [SD] ≥6 mo). Pts received 10, 30, 90/100, or 250 mg PO giredestrant QD on D1–28 of each 28-day cycle. Pts were postmenopausal (medical menopause on LHRH agonists was allowed with ≥100 mg giredestrant). Results: Clinical cutoff: Jul 31, 2020; median prior therapy lines in the LA/mBC setting: 1; mean dose intensity: 98%. Safety/activity: see the table below. No adverse events (AEs) led to study drug withdrawal. No dose-limiting toxicities (DLTs) occurred; maximum tolerated dose was not reached. Most common AEs in 107 pts: fatigue (22; 21%), arthralgia (18; 17%), and nausea (17; 16%); largely grade 1/2. Related grade 3 AEs were infrequent (5; 5%); none were grade 4/5 per investigator assessment (grade 5 duodenal perforation occurred with 90/100 mg after stopping giredestrant due to PD). 8 (7%) had bradycardia (none with 10 mg or the 30 mg phase 3 dose; all grade 1 except one grade 2 at 250 mg; no treatment interruptions/dose reductions were required). Objective responses and CB were observed at all doses. Conclusions: Single-agent giredestrant was well tolerated at all doses, with no DLTs. AEs were generally low grade and in keeping with expected AEs for ETs. Clinical activity was observed at all doses. Updated data, including biomarker and correlative data, will be presented. Clinical trial information: NCT03332797 .[Table: see text]

Background: The combination of taxanes with trastuzumab (H) and pertuzumab (P) for first line treatment of HER2-positive metastatic breast cancer (MBC) is associated with improved progression-free survival (PFS) and overall survival (OS). Treatment per physician's choice with anti-HER2 therapy after second line therapy is associated with a median PFS of 3 months. While continued use of H in therapeutic combinations after progression on H-based therapy is common, the efficacy of continuing HP-based treatment after progression on P-based therapy is unknown. Methods: This is a single arm phase II trial of gemcitabine (G) with HP. Eligible patients had HER2-positive (IHC 3+ or FISH ≥ 2.0) MBC with prior HP-based treatment and ≤ 3 prior chemotherapies. Patients received G (1200 mg/m2) on days 1 and 8 of a q 3 week (w) cycle, and H (8 mg/kg load → 6 mg/kg) and P (840 mg load → 420 mg) q3w. The primary endpoint is PFS at 3 months. Secondary endpoints include OS, safety and tolerability. An exploratory endpoint is to compare PFS by RECIST criteria versus 18-F FDG-PET response criteria. Using a Simon optimal 2-stage design, 21 patients were enrolled in stage 1. The successful 3-month PFS rate for stage 1 was set at 57% to allow accrual to stage 2 for a total of 45 patients. The study therapy will be considered successful if at least 27/45 (60%) patients are progression free at 3 months. Results: As of June 9, 2016, 28 patients are enrolled; 21 are evaluable at 3 months and 7 have not had 3-month evaluation. At 3 months, 16/21 (76%) are progression free; 5 patients have progressed. The 3 month-PFS results for evaluable patients will be updated. There are no cardiac or febrile neutropenic events to date. Initially, 5 of 22 (23%) patients required G dose reduction (4 due to grade 3 neutropenia and 1 due to grade 3 vomiting) and the study was amended to lower initial G dose to 1000 mg/m2. Conclusions: The preliminary 3 month-PFS is 76% (95% CI 55% to 89%) in evaluable patients, and updated data will be presented. These findings suggest clinical benefit when P is continued beyond progression. Citation Format: Iyengar NM, Smyth L, Lake D, Gucalp A, Singh JC, Traina TA, DeFusco P, Dickler MN, Fornier MN, Goldfarb S, Jhaveri K, Modi S, Troso-Sandoval T, Argolo D, Jack K, Ulaner G, Jochelson M, Baselga J, Norton L, Hudis CA, Dang CT. Phase II study of gemcitabine, trastuzumab, and pertuzumab for HER2-Positive metastatic breast cancer after prior pertuzumab-based therapy [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 P4-21-34.

Background AZD9496 is a potent orally bioavailable ER antagonist and degrader that has shown antitumor efficacy in a range of preclinical xenograft models including ESR1wild-type tamoxifen-resistant and long term estrogen deprived models and an ESR1 mutant model. Methods This is a phase I, open label global multicenter study in women with ER+ HER2–ve BC either metastatic or locoregionally recurrent, not amenable to treatment with curative intent. Patients are post-menopausal, or pre-menopausal women receiving LHRH agonist therapy, with disease progression after ≥6 months endocrine therapy for ER+ BC (no limit on number of prior endocrine therapies; ≤2 prior chemotherapies in advanced setting). The primary objective is to determine the safety and tolerability of AZD9496. Cohorts of 3-6 patients received daily oral therapy and dose limiting toxicities (DLTs) occurring in cycle 1 (28 days) were assessed. Patients are dosed until MTD (defined as ≤1/6 patients with a DLT) or maximum feasible dose (MFD) is reached. Key secondary objectives include determination of single and multiple dose pharmacokinetics (PK), and preliminary antitumor efficacy. ER target modulation by protein and gene expression is evaluated in circulating tumor cells and paired tumor biopsies. In addition to the dose escalation phase, expansion cohort(s) in patients with or without ESR1 mutations can be enrolled to examine the safety, tolerability, PK and biological activity of AZD9496 further. Results Preliminary data as of 30th April 2016: 45 patients (median age 62 (range 41-83); 38 post-menopausal, 7 pre/perimenopausal; visceral metastases 76%, prior fulvestrant 25/45) received AZD9496 in 7 dose escalation cohorts: 20mg QD n=4, 40mg BID n=6, 80mg BID n=5, 150mg BID n=6, 250mg BID n=6, 400mg BID n=6, 600mg BID n=6 and also a 250mg BID expansion cohort n=6. The majority of adverse events (AEs) were grade 1 or 2; the most common treatment-related AEs (≥10%) have been diarrhoea (33%), fatigue (27%), nausea (22%), upper abdominal pain (13%) and increased liver function tests (13%). Six patients had treatment-related grade 3 AEs, 5 of which were manageable with dose interruption +/- dose reduction. Specifically, three had DLTs: grade 3 increased AST/ALT/GGT-150mg BID, serious adverse reaction (SAR) leading to withdrawal; grade 3 diarrhoea and grade 3 increased AST/ALT/GGT-400mg BID, SAR, manageable with dose reductions; grade 3 diarrhoea 600mg BID, manageable with dose reduction. The MTD/MFD has not been reached. Following the first dose up to 400mg the AZD9496 exposure increased in reasonable proportion to increasing dose. At 600mg a more than dose-proportional increase in exposure was observed. Evidence of reduced ER and Ki67 has been observed in on-study biopsies at 150mg BID and above. 10 subjects received treatment for >3-6- Conclusions AZD9496 has a tolerable safety profile, evidence of PD biomarker modulation and prolonged stabilisation of disease in women with heavily pre-treated ER+ve ABC. Citation Format: Hamilton E, Patel M, Armstrong A, Baird R, Jhaveri K, Hoch M, Morgan S, Dowdall T, Schiavon G, Klinowska T, Weir H, Bujac S, Nash T, Im S-A. A phase I study of AZD9496, a novel oral, selective estrogen receptor degrader (SERD) in women with estrogen receptor positive, HER-2 negative advanced breast cancer (ABC) [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 P6-12-03.

BACKGROUND: Lucitanib is a potent, oral antiangiogenic tyrosine kinase inhibitor of Vascular Endothelial Growth Factor Receptors 1-3 (VEGFR1-3), Platelet-Derived Growth Factor Receptors alpha and beta (PDGFRα/β), and Fibroblast Growth Factor Receptors 1-3 (FGFR1-3). FGF aberrancies (amplification of FGFR1,or 11q[amplicon containing FGF ligands 3, 4, and 19]), are genomic alterations observed in over 20% of breast cancer pts and promote cancer proliferation and survival. METHODS: MBC pts who had received at least 1 metastatic line of therapy were randomized 1:1 to 10 or 15 mg QD of lucitanib. Stratification was based on local assessment of FGF aberrancy; pts with both FGFR1 and 11q-amplified tumors were stratified as FGFR1 amplified. Central confirmation of FGFR1 or 11q amplification was done using Abbott FISH probes (FGFR1 or 11q copy number ≥ 6 and a ratio of FGFR1 or 11q to centromere ≥ 2). Investigator-assessed progression-free survival (PFS) was the primary endpoint. Secondary endpoints included objective response rate (ORR) per RECIST 1.1, disease control rate (DCR), duration of response (DR), and incidence of treatment-emergent adverse events (TEAE). RESULTS: Enrollment completed in 3/2016; 178 pts that received at least 1 dose of lucitanib are included in this analysis (baseline characteristics in Table 1). Due to grade 3 hypertension in the 15 mg group (46% vs 37% in 10 mg group), enrollment to the 15 mg group was halted. Overall, most pts (97%) experienced at least 1 TEAE, with the most frequently (≥ 30%) occurring events being hypertension (73%), fatigue (48%), nausea (43%), hypothyroidism (40%), and headache (33%). Grade ≥ 3 TEAEs occurred in 66% of pts, with hypertension as the most frequent event (40%) followed by proteinuria and hyponatremia (both 6%). AEs were manageable with dose interruption or reduction, with approximately 8% of pts ending treatment due to an AE. Current median PFS is 3.5 mos (95% CI 2.8-4.6; range 0.62-12.95) and 2.6 mos (95% CI 1.8-2.9; range 0.82-18.87) respectively for the 10 mg and 15 mg treatment groups. No differences in clinical activity were observed by treatment group, FGF aberrancy, hormone receptor or HER2 status. Of the 168 evaluable pts, confirmed ORR was 3%; overall DCR was 27% (32% for pts in the 10 mg group compared to 20% for the 15 mg group); overall mean (standard deviation) DR of 3.3 (1.8) mos. Baseline Characteristics 10 mg QD15 mg QD N=109N=69Age (years)Median5653Range27-8227-80SexFemale109 (100%)67 (97%)Male02 (3%)ECOG PSmissing5 (5%)2 (3%)051 (47%)30 (43%)153 (49%)37 (54%)Number of prior anticancer therapies in the metastatic setting> 332 (29%)21 (30%)3-648 (44%)32 (46%)> 629 (27%)16 (23%)Endocrine/HER2 statusmissing7 (6%)1 (1%)ER+ or PR+74 (68%)50 (73%)HER2+12 (11%)7 (10%)TNBC16 (15%)11 (16%)FGFR aberrancyFGFR1 amplified54 (49%)29 (42%)11q amplified31 (28%)24 (35%)FGFR1 and 11q amplified13 (12%)9 (13%)FGFR1 and 11q non-amplified11 (10%)7 (10%) CONCLUSION: At 10 mg QD, lucitanib has modest activity with manageable toxicity in this heavily pretreated pt population. Future clinical development for lucitanib may focus on alternative biomarkers to identify sensitive tumors and rational combinations with other anti-cancer drugs. Citation Format: Mayer IA, Arteaga CL, Nanda R, Miller KD, Jhaveri K, Brufsky AM, Rugo H, Yardley DA, Vahdat LT, Sadeghi S, Audeh MW, Rolfe L, Litten J, Knox A, Raponi M, Tankersley C, Isaacson J, Wride K, Morganstern DE, Vogel C, Connolly RM, Gradishar WJ, Patel R, Pusztai L, Abu-Khalaf M. A phase 2 open-label study of lucitanib in patients (pts) with FGF aberrant metastatic breast cancer (MBC) [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 P6-11-03.

Purpose Diffusion-weighted imaging (DWI) and 18F-fluorodeoxyglucose–positron emission tomography (18F-FDG–PET) independently correlate with malignancy in breast cancer, but the relationship between their structural and metabolic metrics is not completely understood. This study spatially correlates diffusion, perfusion, and glucose avidity in breast cancer with simultaneous PET/MR imaging and compares correlations with clinical prognostics. Methods In this Health Insurance Portability and Accountability Act-compliant prospective study, with written informed consent and approval of the institutional review board and using simultaneously acquired FDG-PET and DWI, tissue diffusion (Dt), and perfusion fraction (fp) from intravoxel incoherent motion (IVIM) analysis were registered to FDG-PET within 14 locally advanced breast cancers. Lesions were analyzed using 2D histograms and correlation coefficients between Dt, fp, and standardized uptake value (SUV). Correlations were compared with prognostics from biopsy, metastatic burden from whole-body PET, and treatment history. Results SUV||Dt correlation coefficient significantly distinguished treated (0.11 ± 0.24) from nontreated (−0.33 ± 0.26) patients (P = 0.005). SUV||fp correlations were on average negative for the whole cohort (−0.17 ± 0.13). Conclusion Simultaneously acquired and registered FDG-PET/DWI allowed quantifiable descriptions of breast cancer microenvironments that may provide a framework for monitoring and predicting response to treatment. Magn Reson Med, 2016. © 2016 International Society for Magnetic Resonance in Medicine

Purpose To compare fluorine 18 ((18)F) fluorodeoxyglucose (FDG) combined positron emission tomography (PET) and magnetic resonance (MR) imaging with (18)F FDG combined PET and computed tomography (CT) in terms of organ-specific metastatic lesion detection and radiation dose in patients with breast cancer. Materials and Methods From July 2012 to October 2013, this institutional review board-approved HIPAA-compliant prospective study included 51 patients with breast cancer (50 women; mean age, 56 years; range, 32-76 years; one man; aged 70 years) who completed PET/MR imaging with diffusion-weighted and contrast material-enhanced sequences after unenhanced PET/CT. Written informed consent for study participation was obtained. Two independent readers for each modality recorded site and number of lesions. Imaging and clinical follow-up, with consensus in two cases, served as the reference standard. Results There were 242 distant metastatic lesions in 30 patients, 18 breast cancers in 17 patients, and 19 positive axillary nodes in eight patients. On a per-patient basis, PET/MR imaging with diffusion-weighted and contrast-enhanced sequences depicted distant (30 of 30 [100%] for readers 1 and 2) and axillary (eight of eight [100%] for reader 1, seven of eight [88%] for reader 2) metastatic disease at rates similar to those of unenhanced PET/CT (distant metastatic disease: 28 of 29 [96%] for readers 3 and 4, P = .50; axillary metastatic disease: seven of eight [88%] for readers 3 and 4, P > .99) and outperformed PET/CT in the detection of breast cancer (17 of 17 [100%] for readers 1 and 2 vs 11 of 17 [65%] for reader 3 and 10 of 17 [59%] for reader 4; P < .001). PET/MR imaging showed increased sensitivity for liver (40 of 40 [100%] for reader 1 and 32 of 40 [80%] for reader 2 vs 30 of 40 [75%] for reader 3 and 28 of 40 [70%] for reader 4; P < .001) and bone (105 of 107 [98%] for reader 1 and 102 of 107 [95%] for reader 2 vs 106 of 107 [99%] for reader 3 and 93 of 107 [87%] for reader 4; P = .012) metastases and revealed brain metastases in five of 51 (10%) patients. PET/CT trended toward increased sensitivity for lung metastases (20 of 23 [87%] for reader 1 and 17 of 23 [74%] for reader 2 vs 23 of 23 [100%] for reader 3 and 22 of 23 [96%] for reader 4; P = .065). Dose reduction averaged 50% (P < .001). Conclusion In patients with breast cancer, PET/MR imaging may yield better sensitivity for liver and possibly bone metastases but not for pulmonary metastases, as compared with that attained with PET/CT, at about half the radiation dose. (©) RSNA, 2016 Online supplemental material is available for this article.

Background The National Cancer Institute—Molecular Analysis for Therapy Choice (NCI-MATCH) is a national precision medicine study incorporating centralized genomic testing to direct refractory cancer patients to molecularly targeted treatment subprotocols. This treatment subprotocol was designed to screen for potential signals of efficacy of ado-trastuzumab emtansine (T-DM1) in HER2-amplified histologies other than breast and gastroesophageal tumors. Methods Eligible patients had HER2 amplification at a copy number (CN) >7 based on targeted next-generation sequencing (NGS) with a custom Oncomine AmpliSeq™ (ThermoFisher Scientific) panel. Patients with prior trastuzumab, pertuzumab or T-DM1 treatment were excluded. Patients received T-DM1 at 3.6 mg/kg i.v. every 3 weeks until toxicity or disease progression. Tumor assessments occurred every three cycles. The primary end point was centrally assessed objective response rate (ORR). Exploratory end points included correlating response with HER2 CN by NGS. The impact of co-occurring genomic alterations and PTEN loss by immunohistochemistry were also assessed. Results Thirty-eight patients were enrolled and 36 included in efficacy analysis. Median prior therapies in the metastatic setting was 3 (range 0–9; unknown in one patient). Median HER2 CN was 17 (range 7–139). Partial responses were observed in two (5.6%) patients: one mucoepidermoid carcinoma of parotid gland and one parotid gland squamous cell cancer. Seventeen patients (47%) had stable disease including 8/10 (80%) with ovarian and uterine carcinomas, with median duration of 4.6 months. The 6-month progression-free survival rate was 23.6% [90% confidence interval 14.2% to 39.2%]. Common toxicities included fatigue, anemia, fever and thrombocytopenia with no new safety signals. There was a trend for tumor shrinkage with higher levels of gene CN as determined by the NGS assay. Conclusion T-DM1 was well tolerated. While this subprotocol did not meet the primary end point for ORR in this heavily pre-treated diverse patient population, clinical activity was seen in salivary gland tumors warranting further study in this tumor type in dedicated trials.

HER2 mutations define a subset of metastatic breast cancers with a unique mechanism of oncogenic addiction to HER2 signaling. We explored activity of the irreversible pan-HER kinase inhibitor neratinib, alone or with fulvestrant, in 81 patients with HER2-mutant metastatic breast cancer. Overall response rate was similar with or without estrogen receptor (ER) blockade. By comparison, progression-free survival and duration of response appeared longer in ER+ patients receiving combination therapy, although the study was not designed for direct comparison. Pre-existent concurrent activating HER2 or HER3 alterations were associated with poor treatment outcome. Similarly, acquisition of multiple HER2-activating events, as well as gatekeeper alterations, were observed at disease progression in a high proportion of patients deriving clinical benefit from neratinib. Collectively these data define HER2 mutations as a therapeutic target in breast cancer and suggest that co-existence of additional HER signaling alterations may promote both de novo and acquired resistance to neratinib.

Summary: Standard treatment for estrogen receptor–positive metastatic breast cancer involves antiestrogen therapy used alone or in combination with inhibitors of CDK4/6 or mTOR; this approach works mechanistically by eliciting and reinforcing cell-cycle arrest. In this issue, Lok and colleagues diverge from this paradigm by combining the BCL2 inhibitor venetoclax with tamoxifen in a phase Ib clinical trial, building on preclinical work to demonstrate that targeting apoptosis could represent a promising new strategy in the treatment of breast cancer. See related article by Lok et al., p. 354.

Alterations in protein-protein interaction networks are at the core of malignant transformation but have yet to be translated into appropriate diagnostic tools. We make use of the kinetic selectivity properties of an imaging probe to visualize and measure the epichaperome, a pathologic protein-protein interaction network. We are able to assay and image epichaperome networks in cancer and their engagement by inhibitor in patients’ tumors at single-lesion resolution in real time, and demonstrate that quantitative evaluation at the level of individual tumors can be used to optimize dose and schedule selection. We thus provide preclinical and clinical evidence in the use of this theranostic platform for precision-medicine targeting of the aberrant properties of protein networks.

Activating mutations in

Purpose:Common resistance mechanisms to endocrine therapy (ET) in estrogen receptor (ER)–positive metastatic breast cancers include, among others, ER loss and acquired activating mutations in the ligand-binding domain of the ER gene (ESR1LBDm). ESR1 mutational mediated resistance may be overcome by selective ER degraders (SERD). During the first-in-human study of oral SERD AZD9496, early changes in circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) were explored as potential noninvasive tools, alongside paired tumor biopsies, to assess pharmacodynamics and early efficacy.Experimental Design:CTC were enumerated/phenotyped for ER and Ki67 using CellSearch in serial blood draws. ctDNA was assessed for the most common ESR1LBDm by droplet digital PCR (BioRad).Results:Before starting AZD9496, 11 of 43 (25%) patients had ≥5 CTC/7.5 mL whole blood (WB), none of whom underwent reduction to Conclusions:Elevated CTC at baseline was a strong prognostic factor in this cohort. Early on-treatment changes were observed in CTC-ER+ and ESR1LBDm+ ctDNA, but not in overall CTC number. Integrating multiple biomarkers in prospective trials may improve outcome prediction and ET resistance mechanisms' identification over a single biomarker.

Background In patients (pts) with HER2+ (immunohistochemistry [IHC] 3+ or IHC 2+/in situ hybridization [ISH]+) metastatic breast cancer (mBC), HER2-targeted therapies have greatly improved survival. However, for pts with HER2-low mBC (IHC 1+ or IHC 2+/ISH−), there are no approved HER2-directed therapies. In pts with hormone receptor (HR)+, HER2-low mBC whose disease progresses on standard first-line treatment (endocrine therapy [ET] and CDK4/6 inhibitors), median progression-free survival (PFS) with continued ET alone is ≈ 2 months, and with mTOR or PI3K inhibitors (in PIK3CA-mutant tumors) in the second-line setting, PFS ranges from 3.5 to 7.3 months, respectively (André F, et al. ESMO 2018; Dhakal A, at al. ASCO 2018; Rugo R, et al. ASCO 2020). For ET-refractory pts, chemotherapy (CTX) is the standard of care and has a poor benefit-risk ratio. The treatment landscape for pts with HR−, HER2-low mBC is even more limited, consisting largely of CTX (with or without PD-1/PD-L1 inhibitors in the first-line setting). T-DXd is an antibody-drug conjugate composed of a humanized HER2 antibody attached to a membrane-permeable topoisomerase I inhibitor payload via a cleavable tetrapeptide-based linker at a drug to antibody ratio of ≈ 8. In a recent phase 1b study, pts with heavily pretreated (median, 7.5 prior therapies) HER2-low advanced or metastatic breast cancer treated with T-DXd 5.4 or 6.4 mg/kg had a confirmed objective response rate (ORR) of 37.0% (20/54) by independent central review and a median PFS of 11.1 months, and the safety profile was generally manageable (Modi S, et al. J Clin Oncol. 2020;38:1887-1896). Here, we describe a phase 1b trial evaluating the safety, tolerability, and pharmacokinetics (PK) of T-DXd in combination with other anticancer agents in pts with HER2-low, HR+ or HR− mBC. Study Description DESTINY-Breast08 is a multicenter, open-label, 2-part study evaluating T-DXd combinations in pts with HER2-low mBC. The 5 treatment modules comprise T-DXd in combination with (1) capecitabine, (2) durvalumab + paclitaxel, (3) capivasertib, (4) anastrozole, and (5) fulvestrant. Part 1 (dose finding): Each treatment module will enroll 3 to 12 pts per dose level to determine the recommended phase 2 dose (RP2D) in combination; modules 1 through 3 will enroll irrespective of HR status, whereas modules 4 and 5 will be restricted to only HR+ pts. HR+ pts should have received ≥ 1 prior line of ET and ≥ 1 prior line of CTX; HR− pts should have received ≥ 1 prior line of CTX. Part 2 (dose expansion): Modules 1, 4, and 5 will enroll 20 pts, and modules 2 and 3 will enroll 40 pts using the RP2D determined in part 1 of each module. Patient eligibility per module in part 2 is as follows: Module 1 (HR+ or HR−): HR−, only 1 prior line of CTX for mBC; HR+, only 1 prior line of ET but no prior CTX for mBCModule 2 (HR−): no prior CTX for mBCModule 3 (HR−): only 1 prior line of CTX for mBCModules 4 and 5 (HR+): only 1 prior line of ET but no prior CTX for mBC The primary endpoint in part 1 is safety and tolerability and determination of RP2Ds. In part 2, the primary endpoint is safety and tolerability, and secondary endpoints include ORR, duration of response, and PFS (all by investigator assessment according to RECIST 1.1) as well as overall survival, PK, and immunogenicity. Citation Format: Komal Jhaveri, Erika Hamilton, Sherene Loi, Peter Schmid, Annie Darilay, Chen Gao, Gargi Patel, Magdalena Wrona, Fabrice Andre. Trastuzumab deruxtecan (T-DXd; DS-8201) in combination with other anticancer agents in patients with HER2-low metastatic breast cancer: A phase 1b, open-label, multicenter, dose-finding and dose-expansion study (DESTINY-Breast08) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-03-05.

Background Activating mutations in PIK3CA, encoding the p110α subunit of phosphatidylinositol 3-kinase (PI3K) occur in ~40% of HR+/HER2- BCs. GDC-0077, a PI3Kα-selective inhibitor and mutant PI3Kα degrader, is being developed as an anticancer agent. A phase I/Ib study of GDC-0077 alone and combined with other therapies is ongoing in pts with locally advanced or metastatic PIK3CAmut, HR+/HER2- mBC (NCT03006172). Targeted safety events are presented here. Methods Safety was assessed via NCI-CTCAE v4 for GDC-0077 administered alone (Arm A), with letrozole and palbo (Arm B), with letrozole (Arm C), with fulvestrant (Arm D), or with fulvestrant and palbo (Arm E, plus metformin in Arm F for pts with body mass index ≥ 30 and/or HbA1c ≥ 5.7%), in 28-day cycles until intolerable toxicity or disease progression. GDC-0077 was administered orally daily at 3, 6, 9, or 12 mg; letrozole, at 2.5 mg orally daily; palbo, at 125 mg orally 21/28 days; and fulvestrant, at 500 mg intramuscularly every 4 weeks. Targeted adverse events (AEs) included hyperglycemia, diarrhea, stomatitis (includes stomatitis, mucosal inflammation, mouth ulceration, glossitis, lip ulceration, palatal ulcer, and tongue ulceration), rash (includes rash, maculopapular rash, dermatitis acneiform, erythema, and erythematous rash), neutropenia (includes neutropenia and neutrophil count decreased), thrombocytopenia, and pneumonitis. Results As of clinical data cutoff (03/20/2020), 157 pts were enrolled and treated (Arm A: 20; Arm B: 33; Arm C: 37; Arm D: 39; Arm E: 13; Arm F: 15). Median cumulative dose intensity was 97.2% for GDC-0077, 90.6% for palbo, 99.9% for letrozole, and 100% for fulvestrant. Pneumonitis was reported in 2 pts, both in palbo-containing arms (grade 1 in Arm B; grade 2 in Arm F). Hyperglycemia required antihyperglycemic treatment in 69 pts (44%), and the most frequent agents used were metformin (39%; except Arm F where this was required as part of study treatment), empagliflozin (16%), and sitagliptin (15%). Fifteen pts (10%) required GDC-0077 dose reductions due to hyperglycemia. Stomatitis treatment was administered in 51 pts (32%), with dexamethasone mouthwash used most frequently (22%). Neutropenia and thrombocytopenia were managed with palbo dose reduction in 13 pts (21%) and 1 pt (2%), respectively. Overall, treatment-related AEs led to GDC-0077 discontinuation in 2 pts (1%) (grade 3 hyperglycemia in Arm B; grade 2 panniculitis in Arm F). Conclusion Targeted safety events with GDC-0077 alone and in combination ET ± palbo were manageable and required minimal GDC-0077 dose modifications or discontinuations. No unexpected safety events were reported in combination with palbo. A phase III study of GDC-0077 in combination with palbo and fulvestrant is enrolling currently (NCT04191499). Pts, n (%)Treatment-related AEsTreatment-related grade ≥ 3 AEsAll arms;All arms;N = 157N = 157Hyperglycemia98 (62)36 (23)Stomatitis (grouped terms)69 (44)2 (1)Diarrhea68 (43)0Rash (grouped terms)19 (12)1 (1)Palbo arms (B/E/F);Palbo arms (B/E/F);N = 61N = 61Neutropenia45 (74)36 (59)Stomatitis (grouped terms)41 (66)2 (3)Thrombocytopenia19 (31)4 (7) Citation Format: Mafalda Olivera, Komal Jhaveri, Dejan Juric, Philippe L Bedard, Andrés Cervantes, Valentina Gambardella, Erika Hamilton, Antoine Italiano, Kevin Kalinsky, Ian E Krop, Peter Schmid, Nicolas Turner, Andrea Varga, Guiyuan Lei, Stephanie Royer-Joo, Piia Thomas, Jennifer L Schutzman, Cristina Saura. Targeted safety events from a phase I/Ib study evaluating GDC-0077 alone and in combination with endocrine therapy (ET) ± palbociclib (palbo) in patients (pts) with PIK3CA-mutant (mut), hormone receptor-positive/HER2-negative metastatic breast cancer (HR+/HER2- mBC) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS11-11.

Background HR+/HER2- BC is the most common BC subtype, and adjuvant endocrine therapies (ET) are an integral part of its management; however, ~30% of patients still relapse. Development of ET resistance remains a challenge in HR+/HER2- BC; aberrant phosphoinositide 3-kinase (PI3K) signaling contributes to ET resistance and PIK3CA mutations occur in ~40% of HR+/HER2- BCs. Current research has led to the development of new targeted therapies, including CDK4/6 inhibitors and PI3K inhibitors (alpelisib). Preclinical models have demonstrated synergy between CDK4/6 inhibitors and PI3K inhibitors, with PI3K inhibitors blocking CDK4/6 inhibitor resistance development. GDC-0077 is a potent, selective PI3Kα inhibitor and a mutant p110α-degrader with anti-tumor activity alone and in combination with ET + P in PIK3CA-mutant preclinical models. An ongoing phase I trial showed that GDC-0077 + P + F could be combined at maximum doses. INAVO120 is a phase III, randomized, double-blind, pbo-controlled study that will assess efficacy and safety of GDC-0077/pbo + P + F in patients with PIK3CA-mutant/HR+/HER2- LA/MBC (NCT04191499). Trial design Patients are randomized 1:1 to GDC-0077 (9 mg orally; once daily [QD] continuously on a 28-day cycle) + P (125 mg orally; QD, days 1-21 of each 28-day cycle) + F (500 mg intramuscularly every 28 days with a loading dose in Cycle 1) or pbo + P + F. Circulating tumor DNA or tumor tissue must be positive for a PIK3CA mutation. Eligibility Patients whose disease progressed during/within 12 months of adjuvant ET completion, and who have not received prior systemic therapy for LA/MBC. Aims The primary endpoint is investigator-assessed progression-free survival (PFS) using Response Evaluation Criteria in Solid Tumors v1.1. Secondary endpoints include objective response rate (ORR); best overall response (BoR); duration of response (DoR); clinical benefit rate (CBR); overall survival (OS); safety; patient-reported outcomes; and pharmacokinetics. Statistical methods Patients are stratified by visceral disease, primary vs secondary resistance, and geographic region. For the primary PFS analysis, the treatment arms will be compared using a two-sided stratified log-rank test. The treatment effect will be quantified via a hazard ratio, computed from a stratified Cox proportional-hazards regression, including a 95% confidence interval. Median PFS will be estimated using Kaplan-Meier methodology. Accrual Target enrollment is 400 patients at ~210 sites globally. The study is open for enrollment and, as of 06/04/2020, eight patients have been enrolled. Contact information For more information or to refer a patient, email global.rochegenentechtrials@roche.com or call 1-888-662-6728 (USA only). Originally submitted to the ESMO 2020 Virtual Meeting. Citation Format: Nicolas Turner, Komal Jhaveri, Kevin Kalinsky, Sibylle Loibl, Sherene Loi, Seock-Ah Im, Cristina Saura, Peter Schmid, Jennifer L Schutzman, Thomas J Stout, Guiyuan Lei, Katherine E Hutchinson, Eirini Thanopoulou, Dejan Juric. Phase III study of GDC-0077 or placebo (pbo) with palbociclib (P) + fulvestrant (F) in patients with PIK3CA-mutant/hormone receptor-positive/HER2-negative locally advanced or metastatic breast cancer (HR+/HER2- LA/MBC) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-36-01.

Background HER2-targeted therapies have substantially improved survival in patients with HER2-positive (immunohistochemistry [IHC] 3+ or IHC2+/in situ hybridization-positive) advanced or metastatic breast cancer. Despite significant advancements, patients ultimately develop resistance to standard-of-care HER2-targeted therapies. Therefore, a need remains for regimens that prolong disease control and survival in these patients. T-DXd is a HER2-targeted antibody-drug conjugate containing a linker selectively cleaved in tumor cells and a topoisomerase I inhibitor payload with high cell-membrane permeability. T-DXd has been approved by the FDA for use in adult patients with unresectable or metastatic HER2-positive breast cancer who have received ≥ 2 prior anti-HER2-based regimens in the metastatic setting and by Japan’s Ministry of Health, Labour and Welfare for use in patients with HER2-positive unresectable or recurrent breast cancer after prior chemotherapy (use limited to patients refractory to or intolerant of standard treatments). Results from the phase 2 DESTINY-Breast01 trial demonstrated an objective response rate (ORR) of 60.9% per independent central review and a median progression-free survival (PFS) of 16.4 months in a heavily pretreated population (median of 6 prior lines of therapy) of patients with HER2-positive advanced or metastatic breast cancer treated with T-DXd (Modi S, et al. N Engl J Med. 2020;382:610-621). Here, we describe a phase 1b/2 trial evaluating the safety and preliminary antitumor activity of T-DXd combinations in patients with HER2-positive advanced or metastatic breast cancer. Study Description DESTINY-Breast07 is a global, multicenter, open-label, phase 1b/2 dose-finding and dose-expansion trial designed to evaluate the safety, tolerability, and preliminary antitumor activity of T-DXd in combination with other therapies in patients with HER2-positive advanced or metastatic breast cancer. Patients will be enrolled globally at ≈ 110 sites in ≈ 10 countries. The study will initially consist of 4 combination modules, each with 2 parts: dose finding (part 1) and dose expansion (part 2), and a T-DXd monotherapy module (part 2 only). The 4 combination modules will enroll patients for treatment with (1) T-DXd + durvalumab, (2) T-DXd + pertuzumab, (3) T-DXd + paclitaxel, or (4) T-DXd + durvalumab + paclitaxel. New combination treatment modules may be added via protocol amendment. Part 1 of each combination module will enroll patients who have had disease progression on ≥ 1 prior line of therapy in the metastatic setting. In part 2, patients who have received no prior therapy for metastatic disease will be randomized to receive a combination regimen or T-DXd monotherapy. Antitumor activity will be evaluated based on investigator assessment according to RECIST 1.1. The primary endpoint is to assess the safety and tolerability of T-DXd combinations and determine the recommended phase 2 doses. Secondary endpoints include ORR, PFS, duration of response, overall survival, pharmacokinetics, and immunogenicity. Citation Format: Fabrice Andre, Erika Hamilton, Sherene Loi, Peter Schmid, Tinghui Yu, Shiyao Lu, Sarice Boston, Celina D'Cruz, Pia Herbolsheimer, Komal Jhaveri. Trastuzumab deruxtecan (T-DXd; DS-8201) combinations in patients with HER2-positive advanced or metastatic breast cancer: A phase 1b/2 open-label, multicenter, dose-finding and dose-expansion study (DESTINY-Breast07) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-03-04.

PIK3CA mutations represent the most frequent oncogenic driver lesion found across all human cancers. Given that single PIK3CA mutations are a predictive biomarker for response to PI3K inhibition, and that these clinical benefits are small, we hypothesized that additional genomic factors may cooperate with single PIK3CA mutations in oncogenesis and response to PI3K inhibitors. We analyzed several large pan-cancer datasets and have discovered a phenomenon of dual PIK3CA mutations in 15% of all PIK3CA-mutant cancers, including breast cancer. Dual PIK3CA mutations are clonal, are found in both primary untreated and metastatic tumors, and are enriched at conserved amino acid positions. We have proved that the majority of dual PIK3CA mutations—including the most frequent dual PIK3CA mutant combinations in breast cancer—are in cis compound mutations (i.e., on the same allele, resulting in a protein molecule with two mutations) in patient samples and cell lines, as shown through multiple sequencing techniques including long-range single-molecule real-time sequencing (SMRT-seq). Compound PIK3CA mutations increase PI3K pathway signaling and growth proliferation in nontransformed cells and cancer cells in vitro and in vivo. Biochemical experiments using recombinant PI3K complexes reveal a mechanism where compound mutants increase PI3K complex thermal instability, resulting in increased kinase activity and liposome binding as compared to single mutants. Compound PIK3CA mutations render cells more sensitive to the PI3Kα inhibitors BYL719 and GDC-0077 than single PIK3CA mutations. These data translate to the clinic, where patients with dual PIK3CA-mutant metastatic breast cancer exhibit more durable responses to PI3K inhibition versus patients with single PIK3CA-mutant breast tumors. Our data support a novel mutational dose-response model for oncogene activation, where compound mutations amplify PI3K signaling and growth to a greater degree than single mutants, resulting in increased sensitivity to PI3Kα inhibitor targeted therapy. These findings also have therapeutic relevance, where compound PIK3CA mutations may be a superior predictive biomarker for response to PI3Kα inhibitors than single PIK3CA mutations, across PIK3CA-mutant cancers. Citation Format: Neil Vasan, Jared Johnson, Hong Shao, Pedram Razavi, Alexander Gorelick, Erik Ladewig, Alesia Antoine, Hardik Shah, Eneda Toska, Guotai Xu, Abiha Kazmi, Barry Taylor, Komal Jhaveri, Maura Dickler, Elisa de Stanchina, Eduard Reznik, Raul Rabadan, Melissa Smith, Robert Sebra, Lewis Cantley, Maurizio Scaltriti, Jose Baselga. Compound PIK3CA mutations support a mutational dose-response model for oncogene activation and response to PI3K inhibitor targeted therapy in breast cancer [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr A21.

Introduction Heat shock protein (HSP) 90, a viable target for cancer treatment, mediates the maturation and stabilization of client oncoproteins. HSP90 inhibitors (HSP90i) are potentially active in a variety of tumors, but therapeutic benefit is confirmed in only a small subset. We explored potential biomarkers across multiple studies of HSP90i in advanced solid tumors. Patients and Methods Archived tumor specimens from patients treated with HSP90i in 7 different phase I/II trials at Memorial Sloan Kettering Cancer Center were identified. Tumor tissue was tested using immunohistochemistry; estrogen, progesterone, and androgen receptors ≥ 1% positive and Results Adequate tissue was available for 51 of 158 patients (32%), including 10 different solid tumors. Of these, 71% (36 of 51) and 51% (26 of 51) patients met the criteria to assess CB by best ORR or by the "8-week scan" assessment, respectively. Breast was the most frequent tumor. The mean duration of HSP90i therapy was 55 days (range, 16-411 days). There were 16 responses (4 partial response; 12 stable disease); 13 of 16 responses strongly correlated with HER2-positive status ( P = .001). Conclusion Our findings suggest HER2 as a sensitive client and perhaps the only effective biomarker for sensitivity to these HSP90i.

Background: Resistance to endocrine therapies in HR-positive breast cancer is a significant challenge. The steroidal aromatase inhibitor (AI) exemestane (EXE) has demonstrated short-term efficacy in metastatic HR-positive HER2-negative breast cancer (mHR+BC) that has progressed during treatment with a non-steroidal AI. Combination strategies have not shown a survival benefit. Immunotherapy represents a promising approach as it may increase durability of responses. Low dose cyclophosphamide (CTX) has demonstrated efficacy in combination with neoadjuvant letrozole in HR+BC, conceivably by enhancing anti-tumor immune responses. Here we investigated whether EXE combined with immunomodulatory CTX could provide durable responses in heavily pretreated patients and assessed immunological profiles (NCT01963481). Methods: Phase II trial of EXE (25mg PO daily) with CTX (50 mg PO daily) enrolled postmenopausal women (n=23) with mHR+BC who had progressed on prior endocrine therapy (including nonsteroidal AI, tamoxifen, and/or fulvestrant); prior chemotherapy was allowed. The primary endpoint was PFS (per RECIST 1.1) at 3 months; secondary endpoints were response rate, tolerability, and immune correlates. Detailed functional immune profiling of peripheral T cell subsets were performed by flow cytometry at baseline, 1, 3, 6, 9 & 12 months, with healthy donors available as controls. Results: All 23 patients have been enrolled, and 21 are evaluable for response. Median age was 54 (range 31-77), median prior lines of endocrine therapy was 2 (1-3) and chemotherapy was 1 (0-5). The majority (15/23) had visceral organ involvement. Combination treatment was well tolerated with one grade 3 urinary tract infection but no grade 4 or 5 toxicity. An objective response was observed in 19% of patients (4/21, 1 CR and 3 PR) and an additional 33% (7/21) had SD, resulting in a 3-month-PFS of 48.5% (95% CI, 30.5-77.1). Responses were durable in all patients, lasting =/> 9 months and included patients with liver metastases. Comparison of peripheral immune cell subsets of patients (n=16) at baseline to age/sex-matched healthy controls demonstrated an increased proportion of CD4+ memory T cells with central memory phenotype (CD45RO+CD27+, p Conclusion: EXE and CTX had a favorable safety profile with evidence of clinical activity in patients with heavily pretreated mHR+BC, including durable responses in liver and bone. Correlative studies are ongoing to identify potential biomarkers of response or resistance to therapy. Citation Format: Kwa M, Novik Y, Oratz R, Jhaveri K, Wu J, Gu P, Meyers M, Muggia F, Bonakdar M, Abidoglu C, Kozhaya L, Li X, Joseph B, Iwano A, Friedman K, Goldberg JD, Unutmaz D, Adams S. Phase II trial of exemestane with immunomodulatory oral cyclophosphamide in metastatic hormone receptor (HR)-positive breast cancer: Prolonged progression-free survival (PFS) in patients with distinct T regulatory cell (Treg) profile. [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 P2-11-11.

Introduction: Targeted therapies in HER2+ MBC significantly improve outcomes but efficacy is limited by therapeutic resistance. HSP90 is a molecular chaperone involved in the stability and function of multiple signaling onco-proteins. HER2 is an acutely sensitive HSP90 client and HSP90 inhibition can overcome trastuzumab resistance. Our group reported objective responses with 17-AAG plus trastuzumab in HER2+ MBC. Ganetespib, a synthetic, second generation HSP90 inhibitor has increased potency and tolerability compared with earlier agents. We reported anti-tumor activity in metastatic HER2+ and triple negative breast cancer with single agent ganetespib. Preclinically, HSP90 inhibition has synergistic anti-tumor activity with taxanes and trastuzumab. This study will define the MTD and RP2D of ganetespib plus paclitaxel and trastuzumab in HER2+ MBC. Methods: In this 3+3 phase I dose escalation study, patients with trastuzumab-resistant HER2+ MBC receive weekly trastuzumab and paclitaxel (80mg/m2) with ganetespib on day 1, 8, 15 of a 28 day cycle. HR+ positive patients are required to have at least one prior line of endocrine therapy. DLT of ganetespib monotherapy is diarrhea and therefore patients receive prophylactic anti-motility agents. Based on prior experience with ganetespib plus docetaxel in NSCLC, only 3 dose levels of ganetespib were explored: 100mg/m2, 150mg/m2 and a 3rd cohort of 125mg/m2, if needed. Secondary endpoints include evaluation of effects of ganetespib on the pharmacokinetics (PK) of paclitaxel and preliminary efficacy assessment. Results: The dosing cohorts (100 mg/m2 (n=3) and 150 mg/m2 (n=6)) have been completed without any DLTs. Median age was 46 years (range 29-65), median prior lines of chemotherapy and anti-HER2 therapy were 3 (range 2-6) and 3 (range 2-4) respectively, including prior pertuzumab in 9/9 and T-DM1 in 8/9 patients. There were no grade 3/4 adverse events (AEs) related to ganetespib. Most common AEs related to ganetespib were diarrhea, fatigue, anemia and rash. Paclitaxel PK data available from 6/9 patients are not appreciably different from those reported in literature. Overall response rate was 25% (2/8 had PR in 150 mg/m2 cohort; 1 patient was not evaluable), SD in 63% (5/8), and clinical benefit rate (CR+PR+SD>24 weeks) was 50% (4/8). 3 patients remain on study. Conclusion: The RP2D of ganetespib is 150mg/m2 in combination with paclitaxel and trastuzumab. The combination was safe and well tolerated. Updated PFS and PK data will be presented. Despite prior taxanes, pertuzumab and T-DM1, clinical activity of this triplet regimen in this heavily pre-treated cohort is very promising and together with our prior experience with 17-AAG plus trastuzumab and single agent ganetespib warrants further study in HER2+ MBC. A phase 2 trial is being planned in trastuzumab-refractory HER2+ MBC who have progressed on prior pertuzumab and T-DM1. Additionally, the protocol is amended to assess the safety of ganetespib in combination with paclitaxel, trastuzumab and pertuzumab in the first-line setting. Citation Format: Jhaveri K, Teplinsky E, Chandarlapaty S, Solit D, Cadoo K, Speyer J, D'Andrea G, Adams S, Patil S, Haque S, Friedman K, Neville D, Esteva F, Hudis C, Modi S. A phase I trial of ganetespib (heat shock protein 90 inhibitor) in combination with paclitaxel and trastuzumab in patients with human epidermal growth factor receptor-2 positive (HER2+) metastatic breast cancer (MBC). [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 P4-14-21.

PIK3CA is the most frequently mutated oncogene across all human cancers, and codes for p110α, the catalytic subunit of the PI3K complex. PI3K catalyzes the phosphorylation of the lipid PIP2 to PIP3, which initiates a downstream signaling cascade involving the activation of AKT and mTOR. Hotspot E545K and H1047R mutations constitutively activate PI3K and are oncogenic in multiple cancer histologies including breast cancer, where PIK3CA mutations are present in 40% of tumors and are a target for cancer therapy. Recently, the PI3Kα inhibitor alpelisib has demonstrated improved PFS in patients with ER+ PIK3CA mutant metastatic breast cancer on a phase 3 randomized clinical trial, resulting in its FDA approval. In early clinical trials, we observed a population of patients with displayed prolonged clinical benefit to alpelisib, with double PIK3CA mutant tumors. This prompted us to undertake a comprehensive analysis of the prevalence of multiple PIK3CA mutations and to investigate their potential biological relevance and correlation with sensitivity to PI3Kα inhibitors.We analyzed multiple independent primary and metastatic tumor cohorts and found that 10-15% of all PIK3CA mutant tumors across all cancer histologies contain multiple PIK3CA mutations, the vast majority of which carry exactly two mutations. Double mutations occur at specific amino acid positions by codon enrichment analysis, where the most frequent combinations in breast cancer are comprised of a canonical “major mutant” hotspot (involving either E542, E545, or H1047) combined with a second “minor mutant” site (involving either E453, E726, or M1043). Double PIK3CA mutations are enriched in ER+/HER2- breast cancers and occur at similar frequencies in therapy-naïve primary tumors and metastatic tumors. To study the allelic configuration of double mutations, we leveraged single molecule real time sequencing (SMRT-seq) on fresh breast tumor samples from patients known to carry two PIK3CA mutations in their tumors by NGS. Six tumors representative of the most frequent double mutants in breast cancer were obtained from patients, and were analyzed by SMRT-seq. All contained double mutations in cis. We overexpressed double cis mutants and constituent single mutants in nontransformed and ER+ breast cancer cells. Double PIK3CA mutations in cis increased downstream PI3K pathway signaling and cell/tumor proliferation in vitro and in vivo, when compared to single mutations. In contrast, mutations in trans do not increase cell signaling or growth proliferation more than single mutations.The prevailing model of PI3K activation occurs through the engagement of the p85α regulatory subunit with phosphotyrosines on RTK signaling complexes, which relieves catalytic inhibition. Single oncogenic mutations recapitulate these events by weakening the interactions between p110α and p85α (“disrupters”), or by promoting binding to membrane (“binders”). We purified recombinant full length PI3Kα complexes containing single and double cis p110α mutations to dissect the biochemical mechanisms by which these double PIK3CA mutations in cis modulate kinase activity. We demonstrate that cis mutants have increased kinase activity compared to single mutants and that this activation is due to both increased p85α disruption and increased lipid binding, compared to single mutants.We tested whether cis mutant cells exhibit differential sensitivity to PI3Kα inhibitors. While in the absence of treatment, cis mutant signaling is increased compared to single mutants, treatment with the PI3Kα inhibitors alpelisib or GDC-0077 results in a similar PI3K pathway inhibition in nontransformed and ER+ breast cancer cells. With respect to cell viability, E545K and H1047R major hotspot mutants are more sensitive to alpelisib and GDC-0077 compared to minor mutants and WT. In turn, all cis mutants are synergistically more sensitive to alpelisib and GDC-0077 compared to single major and minor hotspots.We analyzed response data from SANDPIPER, a randomized phase 3 clinical trial that tested the efficacy of the ER degrader fulvestrant with or without the PI3Kα/γ/δ inhibitor taselisib in metastatic ER+ PIK3CA mutant breast cancer. We used ctDNA to detect the presence of PIK3CA mutations. PIK3CA mutant patients on the taselisib arm had an objective response rate (ORR) of 20.3% vs 9.7% compared to the placebo arm, which was statistically significant, confirming that PIK3CA mutation predicts response to PI3Kα inhibition. We then compared responses of patients with single vs multiple mutations. Single mutant patients on the taselisib arm had an ORR of 18.1% vs 10.0% compared to the placebo arm, which was not statistically significant. On the contrary, multiple mutant patients on the taselisib arm achieved an ORR of 30.2% vs 8.7% compared to the placebo arm, which was statistically significant. These findings confirm that breast cancer patients with multiple mutant tumors achieve higher clinical benefit to PI3Kα inhibition compared to single mutant tumors.In this work, we have identified double mutations in cis as a novel, and relatively frequent, genomic alteration in PIK3CA, which translates into a clinically meaningful number of patients who may derive additional benefit from targeted therapy. Our results implicate a model of oncogene addiction to double mutant PIK3CA in breast cancer, with graded levels of activation and inhibition for single vs double mutants. PI3Kα inhibitors are now a standard of care in PIK3CA mutant ER+ metastatic breast cancer and are being explored in other PIK3CA mutant tumor histologies. Our findings provide a rationale for testing whether patients with multiple PIK3CA mutant tumors are exquisitely sensitive to PI3Kα inhibitors. Citation Format: Neil Vasan, Pedram Razavi, Jared L. Johnson, Hong Shao, Hardik Shah, Alesia Antoine, Erik Ladewig, Alexander Gorelick, Ting-Yu Lin, Eneda Toska, Guotai Xu, Abiha Kazmi, Matthew T. Chang, Barry S. Taylor, Maura N. Dickler, Komal Jhaveri, Sarat Chandarlapaty, Raul Rabadan, Ed Reznik, Melissa L. Smith, Robert Sebra, Frauke Schimmoller, Timothy R. Wilson, Lori S. Friedman, Lewis C. Cantley, Maurizio Scaltriti, Jose Baselga. Double PIK3CA mutations in cis increase oncogenicity and sensitivity to PI3Kα inhibitors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr NG16.

1023 Background: GDC-9545 is a potent, orally available, selective estrogen receptor degrader developed for the treatment of ER-positive (ER+) breast cancer alone or combined with CDK4/6 inhibitors. A first-in-human study evaluated 10-250 mg GDC-9545; tolerability, pharmacokinetic (PK), pharmacodynamic (PD), and clinical results support expansion cohorts at ≥30 mg (Jhaveri et al., 2019). Methods: This study evaluated PK, PD, and efficacy of GDC-9545 alone and combined with palbociclib, ± LHRH agonist. Eligible patients (pts) had ER+ (HER2-) metastatic breast cancer (MBC) with ≤ 2 prior therapies in the advanced or metastatic setting. No prior treatment with CDK4/6 inhibitor was allowed in pts receiving palbociclib. Results: Eight-five pts were enrolled in 2 cohorts: GDC-9545 100 mg given once daily ± LHRH agonist (Cohort A), and GDC-9545 100 mg +125 mg palbociclib on a 21 day on/7 day off schedule ± LHRH agonist (Cohort B). Of the 39 pts in Cohort A, adverse events (AE) occurring in ≥10% of pts were fatigue, cough, back pain, pain in extremity, and arthralgia. Related AEs were generally Grade (G) 1-2; there were 3 related G3 AEs of fatigue, transaminase increased, and diarrhea. Two pts had GDC-9545 reduced, one due to G3 diarrhea and another due to G3 transaminitis. Of the 46 pts in Cohort B, AEs in ≥10% of pts were neutropenia, fatigue, bradycardia, diarrhea, constipation, dizziness, nausea, anemia, asthenia, thrombocytopenia, pruritus, and visual impairment. Twenty-six (57%) pts had G≥3 AEs. G≥3 neutropenia was reported in 23 (50%) pts. One pt had palbociclib reduced due to G3 febrile neutropenia. Eleven (13%) of 85 pts had G1 asymptomatic bradycardia considered related to GDC-9545. No pts in either cohort discontinued study treatment due to AEs. PK analysis and clinical data demonstrate no clinically relevant drug-drug interactions between GDC-9545 and palbociclib. Reduced ER, PR, and Ki67 levels, and an ER activity signature, were observed in paired pre- and on-treatment biopsies (n = 12). Eighteen of 33 pts in Cohort A had either confirmed partial responses or were on study 24 weeks (clinical benefit rate 55%). Clinical benefit was observed in pts with prior fulvestrant treatment and with detectable ESR1 mutations at enrollment. Clinical benefit data for both cohorts are anticipated to be mature in April 2020. Conclusions: GDC-9545 was well-tolerated as a single agent and in combination with palbociclib with encouraging PK, PD, and anti-tumor activity in ER+ MBC to support Phase III development. Clinical trial information: NCT03332797 .

1063 Background: Rash develops in approximately 50% of breast cancer patients receiving alpelisib, often requiring dose modifications. Herein, we describe the characteristics of alpelisib-related dermatologic adverse events (dAEs). Methods: A single center retrospective analysis was conducted via review of electronic medical records. We collected clinical, laboratory and management data relevant to patients treated with alpelisib for advanced breast cancer under four different randomized clinical trials or post approval by regulatory agencies from 6/1/2013 to 7/31/2019. Type and severity of dAEs was recorded using the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0). Results: A total of 102 patients (mean age 56 years, range 27-83) receiving alpelisib from 200 to 350 mg daily, most frequently in combination with endocrine therapy (79, 77.5%) were included. We identified 41 (40.2%) patients with all-grade rash [CTCAE grade 1/2 = 22 (21.6%); CTCAE grade 3 = 19, (18.6%)] distributed primarily along the trunk (18, 78%) and developing, on average, within 12.8 +/- 1.5 days of treatment initiation (n = 38). Mean duration of rash was 7.1 +/- 3.8 days; and no grade 4 dAEs were observed. Of 29 patients with documented morphology of alpelisib-related dAEs, the majority (26, 89.7%) had maculopapular rash. Thirteen (68%) of 19 patients with any-grade rash and report of any associated symptoms had pruritus (7, 36%) or burning pain (6, 32%). All-grade dAEs correlated with an increase in serum eosinophils from 2.7% to 4.4% (p < 0.05), and prophylaxis with non-sedating antihistamines (n = 43) was correlated with a reduction of grade 1/2 rash onset (OR 0.39, p = 0.09). Sixteen (84.2%) of 19 patients with grade 3 dAEs had interruption of alpelisib, followed by management with antihistamines, topical and/or systemic corticosteroids. We did not observe rash recurrence in 12 (75%) of these 16 patients who re-initiated therapy; and the majority (9, 56.3%) were re-challenged without a dose reduction. Conclusions: Pruritus and increased blood eosinophils occur with maculopapular rash within the first two weeks of initiating alpelisib and persists for approximately seven days. To reduce onset of grade 1/2 rash, non-sedating antihistamines (i.e. cetirizine) are recommended during the first eight weeks. While grade 3 rash leads to interruption of alpelisib, dermatologic improvement is evident with systemic corticosteroids; and most patients can resume therapy at a maintained or reduced dose upon re-challenge.

Activating mutations in PIK3CA, the gene coding for the catalytic subunit (p110α) of phosphoinositide-3-kinase (PI3K), are the most frequent oncogenic alterations in estrogen receptor-positive (ER+) breast cancer and are also prevalent in other tumor types. PI3Kα inhibitors including alpelisib have recently been shown to be clinically active in ER+ PIK3CA mutant breast cancer. To characterize determinants of sensitivity to these agents, we undertook a comprehensive analysis of PIK3CA mutant cancer genomes and observed the presence of double PIK3CA mutations in 12-15% of breast cancer and other tumor types. These double PIK3CA mutations are clonal, located in cis on the same allele, and are composed of a single hotspot mutation combined with a recurrent second-site mutation. Double PIK3CA mutations in cis result in increased PI3K activity and downstream signaling together with enhanced cell proliferation and tumor growth compared to single hotspot mutations. The biochemical mechanisms underlying this increased oncogenicity include increased disruption of p110α binding to the inhibitory subunit p85α, which relieves its catalytic inhibition, and increased membrane lipid binding. Finally, these double PIK3CA mutations predict for increased sensitivity to PI3Kα inhibitors compared to single hotspot mutations (e.g. E545K or H1047R) in experimental models and in patients with ER+ PIK3CA mutant metastatic breast cancer from the SANDPIPER randomized phase III clinical trial. These findings implicate double PIK3CA mutations in cis as a novel mechanism of oncogene addiction relative to single hotspot mutations, providing a rationale to develop PI3Kα inhibitors for the therapy of double PIK3CA mutant cancers. Citation Format: Neil Vasan, Pedram Razavi, Jared L Johnson, Hong Shao, Timothy Wilson, Frauke Schimmoller, Hardik Shah, Alesia Antoine, Erik Ladewig, Alexander Gorelick, Ting-Yu Lin, Eneda Toska, Guotai Xu, Abiha Kazmi, Matthew T Chang, Barry S. Taylor, Maura N. Dickler, Komal Jhaveri, Sarat Chandarlapaty, Raul Rabadan, Ed Reznik, Melissa L Smith, Robert Sebra, Lori Friedman, Lewis C Cantley, Maurizio Scaltriti, José Baselga. Double PIK3CA mutations in cis drive oncogene addiction and enhance sensitivity to PI3K alpha inhibitors in breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-03-01.

Background: Modulation of estrogen activity and/or synthesis is a mainstay therapeutic strategy for ER+ breast cancer (BC). However, despite the effectiveness of available endocrine therapies, many patients ultimately relapse or develop resistance to these agents via estrogen-dependent and estrogen-independent mechanisms, including mutations in ESR1 affecting the ER ligand-binding domain, that drive ER-dependent transcription and proliferation in the absence of estrogen. ER antagonists that robustly suppress ER signaling in both ESR1 wild-type and mutant tumors may be of substantial therapeutic benefit. GDC-9545 is a novel, potent, non-steroidal, orally bioavailable, selective ER antagonist/ER degrader (SERD) that induces tumor regression in ER+ BC patient-derived xenograft models. Methods: A phase I dose escalation study with 3+3 design was conducted in postmenopausal women with ER+ (HER2−) advanced or metastatic BC (mBC). Patients were eligible if they had advanced or mBC that had progressed while being treated with adjuvant endocrine therapy for ≥ 24 months and/or endocrine therapy in the advanced or mBC setting for ≥ 6 months. No more than 2 prior treatments for advanced or mBC. Primary objective was to determine the safety, pharmacokinetics (PK) and the recommended Phase 2 dose (RP2D) of GDC-9545. Pharmacodynamic (PD) activity was assessed with [18F]-fluoroestradiol (FES)-PET scans and, when feasible, by performing biomarker analysis of pre- and on-study tumor biopsies. Plasma samples were collected for PK analyses and imaging for response assessment (CT and bone scans) were repeated every 8 weeks. Results: From November 27 2017 to February 1 2019 patients (n = 29) with a median age of 58 years (range 42-75) and a median number of prior therapies for mBC of 2 (range 1-4) were enrolled at 4 total daily dose levels (10, 30, 90 and 250 mg) given once daily (QD) while fasting. Increases in GDC-9545 exposure were approximately dose proportional and t1/2 was ~30 hours. Treatment related adverse events (AEs) were all Grade 1 or 2. The most common treatment-related AEs in ≥10% of patients were fatigue (21%, n=6), nausea (21%, n=6), hot flushes (17%, n=5), diarrhea (17%, n=5), arthralgia (17%, n=5), constipation (10%, n=3) and dyspepsia (10%, n=3). No dose-limiting toxicities, treatment-related serious adverse events (SAEs), Grade ≥ 3 events, or fatal events have been reported. Treatment interruption was required for 3 patients: one patient for a short episode of dyspepsia, vomiting, diarrhea, and dizziness; and two patients due to unrelated SAEs. In 14 patients with FES-PET avid disease at baseline and post-baseline scans, 11 (78%) showed complete or near complete (> 90%) suppression of FES uptake to background levels, including patients with ESR1 mutations. Evidence of reduced ER, PR, and Ki67 IHC values and an ER activity signature was observed in paired pre- and on-treatment biopsies (n = 7). Twelve of 27 patients (10 mg [n=2], 30 mg [4], 90 mg [4], 250 mg [2]) had either confirmed partial responses (n = 3) or were on study ≥ 24 weeks (CBR = 44%), including patients pretreated with CDK4/6i, fulvestrant or harboring baseline ESR1 mutations. The R2PD was 100 mg QD and was selected for dose-expansion in post- and pre/peri-menopausal women with and without palbociclib, which is ongoing. Updated results will be presented. Conclusions: GDC-9545 is well-tolerated to date with PK exposure supporting QD dosing, evidence of robust PD target engagement, and encouraging anti-tumor activity in patients with advanced or ER+ mBC, including patients with ESR1 mutations. Dose expansion cohorts of GDC-9545 with or without palbociclib in post-menopausal and pre/peri-menopausal women with mBC are ongoing. Citation Format: Komal Jhaveri, Eric Paul Winer, Elgene Lim, Jose AlejandroPerez Fidalgo, Meritxell Bellet, Ingrid Alina Mayer, Valentina Boni, Jaymin M Patel, Aditya Bardia, Jose Manuel Garcia, Peter Kabos, Mary Gates, Ya-Chi Chen, Jill Fredrickson, Xiaojing Wang, Lori Sickels Friedman, Jill Spoerke, Steven Gendreau, Ciara Metcalfe, Lichuan Liu, Ching-Wei Chang, Sharareh Monemi, Monica Gonzalez, Ursula McCurry, Sandra Milan, Eric William Humke, Sherene Loi. A first-in-human phase I study to evaluate the oral selective estrogen receptor degrader (SERD), GDC-9545, in postmenopausal women with estrogen receptor-positive (ER+) HER2-negative (HER2-) metastatic breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD7-05.

Filopodia are finger-like plasma membrane protrusions that are formed upon remodeling of the actin cytoskeleton beneath the plasma membrane. Fascin protein is the main actin-bundling protein in filopodia and invadopodia which are fundamental to cell shape and motility events. Human fascin expression is low or absent in normal adult epithelial cells but highly expressed in metastatic tumors and in antigen-presenting dendritic cells within the tumor microenvironment. Elevated levels of fascin are correlated with poor prognosis and short survival due to aggressive phenotypes with increased lymph node and distant metastases. Mouse genetic studies demonstrate that deletion of fascin gene delays tumor development, slows tumor growth, reduces metastatic colonization, and increases overall survival. These mouse genetic studies provide strong evidence for fascin’s role in tumor initiation, tumor progression and tumor metastasis, making it an attractive target for drug development. Chemical libraries were screened to identify small-molecule compounds that specifically inhibit the biochemical function of fascin to bundle actin filaments. The inhibitors were optimized to produce the lead compound, NP-G2-044. Preclinical studies showed that fascin inhibitors increase the overall survival of tumor-bearing mice and reinvigorate anti-tumor immune response in syngeneic mouse models of breast, lung, pancreatic and prostate tumors. Fascin protein levels are increased in conventional dendritic cells (cDCs) in the immunosuppressive tumor microenvironment. The number of intra-tumoral activated cDCs is increased following fascin inhibitor treatment. Moreover, together with anti-PD-1 antibody, fascin inhibition markedly increases the number of Ki67+ proliferating and Granzyme-B+ activated CD8+ killer T-cells in tumor tissue. These data demonstrate that fascin inhibitors simultaneously act on tumor cells to block tumor metastasis and on intratumoral DCs to reinvigorate anti-tumor immune response. We are currently conducting a first-in-human phase 1 trial of NP-G2-044 in patients with advanced or metastatic solid tumor malignancies. Citation Format: Vincent Chung, Frank Tsai, Komal Jhaveri, Yufeng Wang, Daniel D Von Hoff, Edward G Garmey, J. Jillian Zhang, Xin-Yun Huang. NP-G2-044, a novel fascin inhibitor, blocks tumor metastasis and increases antitumor immune response [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C053. doi:10.1158/1535-7163.TARG-19-C053

Purpose: AZD9496 is an oral nonsteroidal, small-molecule inhibitor of estrogen receptor alpha (ERα) and a potent and selective antagonist and degrader of ERα. This first-in-human phase I study determined the safety and tolerability of ascending doses of oral AZD9496 in women with estrogen receptor (ER)+/HER2− advanced breast cancer, characterized its pharmacokinetic (PK) profile, and made preliminary assessment of antitumor activity. Patients and Methods: Forty-five patients received AZD9496 [20 mg once daily (QD) to 600 mg twice daily (BID)] in a dose-escalation, dose-expansion “rolling 6” design. Safety, tolerability, and PK activity in each cohort were reviewed before escalating to the next dose. PK was determined by mass spectrometry. Adverse events (AEs) were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Objective tumor response was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Results: Most common causally related AEs were diarrhea (35.6%), fatigue (31.1%), and nausea (22.2%), and seven patients had grade ≥3 AEs. Three patients experienced a dose-limiting toxicity: one each at 150 mg BID (abnormal hepatic function), 400 mg BID (diarrhea and elevated liver function tests), and 600 mg BID (diarrhea), and all were reversible. The maximum tolerated dose was not reached. Partial response was confirmed in one patient, who also had decreased tumor marker Ca15.3. Four patients had stable disease at 12 months' follow-up. Conclusions: AZD9496 is well tolerated with an acceptable safety profile, showing evidence of prolonged disease stabilization in heavily pretreated patients with ER+/HER2− advanced breast cancer. Clin Cancer Res; 24(15); 3510–8. ©2018 AACR. See related commentary by Jordan, p. 3480

The 'Competing interests' statement of this Article has been updated; please see the accompanying Amendment. The original Article has not been corrected online.