Abstract CT109: A phase I/Ib study evaluating GDC-0077 plus fulvestrant in patients with PIK3CA-mutant, hormone receptor-positive/HER2-negative breast cancer
Authors: Kalinsky Kevin , Juric Dejan , Bedard Philippe L. , Oliveira Mafalda , Cervantes Andres , Hamilton Erika , Krop Ian E. , Turner Nick , Schmid Peter , Varga Andrea , Italiano Antoine , Veitch Zachary , Saura Cristina , Gambardella Valentina , Cheeti Sravanthi , Kotani Naoki , Lei Guiyuan , Hutchinson Katherine E. , Royer-Joo Stephanie , Vaze Anjali , Schutzman Jennifer L. , Jhaveri Komal 
Published: September 2020

Abstract
Background: PIK3CA encodes the PI3K p110α subunit, and dysregulating mutations are widely seen in breast cancer (BC) and other solid tumors. GDC-0077 (G) is a potent p110α-selective inhibitor that degrades mutant p110α and demonstrates antitumor activity in PIK3CA-mutant BC xenograft models, either as a single agent, or combined with anti-estrogen therapy. From an ongoing, open-label, phase I/Ib dose-escalation study of G alone and combined with endocrine + targeted therapies (NCT03006172), we present data of G + fulvestrant (F) in postmenopausal patients (pts) with PIK3CA-mutant, hormone receptor-positive/HER2-negative BC, including a food-effect assessment on the pharmacokinetics (PK) of G. Methods: Safety (NCI-CTCAE v4), 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 G + 500 mg intramuscular F on Day 1 (and Day 15 of Cycle 1) of 28-day cycles were assessed until intolerable toxicity/disease progression. The effect of a standard high-fat meal on the PK of G was evaluated after a single dose and at steady state. Relevant signaling and pharmacodynamic (PD) biomarkers were assessed using circulating tumor (ct) DNA samples. Results: At clinical cutoff (Jul 19, 2019), 20 pts were enrolled in the food-effect portion of the G + F arm. Fifteen (75%) had received ≥2 prior lines of therapy for metastatic BC. Median G treatment duration was 5.9 months (range 1.7-17.8); cumulative dose intensity, 98%. Adverse events (AEs) led to dose reduction in 3 pts (15%). The most common treatment-related (TR) AEs (≥4 pts, 20%) were hyperglycemia (11, 55%), diarrhea (10, 50%), stomatitis (grouped term; 9, 45%), nausea (8, 40%), decreased appetite (7, 35%), dysgeusia, fatigue, and muscle spasms (4 each, 20%). Grade ≥3 TRAEs were hyperglycemia, nausea, lymphopenia, hyperamylasemia, and hyperlipasemia (1 each, 5%). The PK of G in combination with F was similar to single-agent PK. Comparable G exposures (Cmax and AUC0-24) were observed following administration in fasted or fed states. Seventeen pts (85%) discontinued treatment, all due to radiographic/clinical disease progression. Overall, 5/14 pts with measurable disease had a PR (36%; 2 received prior F; 4, prior CDK4/6i), of whom 2 pts (14%) had a confirmed PR. CBR was 60% (12/20 pts). Most pts showed decreased ctDNA PIK3CA-mutant allele frequency during treatment. Conclusion: G + F demonstrated a manageable safety profile, similar PK to G alone, preliminary antitumor activity, and PD modulation of PIK3CA-mutant allele frequency in ctDNA. The presence of food did not significantly impact the rate or extent of G absorption following single or multiple doses. Additional pts are being enrolled in the G + F arm to further inform the safety and efficacy of this combination.
Citation Format: Kevin Kalinsky, Dejan Juric, Philippe L. Bedard, Mafalda Oliveira, Andres Cervantes, Erika Hamilton, Ian E. Krop, Nick Turner, Peter Schmid, Andrea Varga, Antoine Italiano, Zachary Veitch, Cristina Saura, Valentina Gambardella, Sravanthi Cheeti, Naoki Kotani, Guiyuan Lei, Katherine E. Hutchinson, Stephanie Royer-Joo, Anjali Vaze, Jennifer L. Schutzman, Komal Jhaveri. A phase I/Ib study evaluating GDC-0077 plus fulvestrant in patients with PIK3CA-mutant, hormone receptor-positive/HER2-negative breast cancer [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 CT109.