Abstract PS11-11: 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)
Authors: Olivera Mafalda , Jhaveri Komal , Juric Dejan , Bedard Philippe L , Cervantes Andrés , Gambardella Valentina , Hamilton Erika , Italiano Antoine , Kalinsky Kevin , Krop Ian E , Schmid Peter , Turner Nicolas , Varga Andrea , Lei Guiyuan , Royer-Joo Stephanie , Thomas Piia , Schutzman Jennifer L , Saura Cristina 
Published: February 2021

Abstract
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.