Abstract PD1-02: A phase I/Ib study evaluating GDC-0077 + palbociclib (palbo) + fulvestrant in patients (pts) with <i>PIK3CA</i>-mutant (mut), hormone receptor-positive/HER2-negative metastatic breast cancer (HR+/HER2- mBC)

Abstract 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.

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