Background Dysregulating mutations in PIK3CA, which encodes the catalytic PI3K p110α subunit, are common in breast cancer and other solid tumors. There are limited data available on the role of PI3Kα inhibition in the post-cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) setting. Inavolisib is a PI3Kα-selective inhibitor and degrader of mutated PI3Kα that has demonstrated encouraging preliminary antitumor activity in patients with PIK3CA-mutated HR+ breast cancer as a single agent, and in combination with antiestrogen therapy. An open-label, phase I/Ib dose-escalation study of inavolisib alone and in combination with endocrine and targeted therapies is ongoing (NCT03006172; GO39374). Data for inavolisib in combination with fulvestrant in female pts with PIK3CA-mutated, HR+/HER2- breast cancer (Arm D) are presented. Methods Safety (NCI-CTCAE v4), pharmacokinetics (PK), and preliminary antitumor activity (assessed every 2 cycles via RECIST v1.1; clinical benefit rate [CBR]: stable disease for ≥24 weeks, partial response [PR], or complete response; progression-free survival [PFS]) of 9 mg inavolisib administered orally once daily in combination with 500 mg intramuscular fulvestrant on Day 1 (and Day 15 of Cycle 1) of 28-day cycles were assessed until intolerable toxicity or disease progression. Early dynamics of PIK3CA-mutation allele frequency were assessed from circulating tumor (ct)DNA samples. Results At clinical cutoff (April 5, 2021), 55 pts were enrolled in Arm D and enrollment was ongoing. Thirty-seven pts (67%) had received ≥2 prior lines of therapy for metastatic breast cancer, 19 (35%) had received chemotherapy in the metastatic setting, 26 (47%) had received prior fulvestrant, and 53 (96%) had received a prior CDK4/6i. Median inavolisib treatment duration was 5.3 months (range 0.2-31.9); cumulative dose intensity was 98%. Thirty-two pts (58%) had dose modifications (interruptions, reductions, and/or discontinuations) due to adverse events (AEs). The most common treatment-related AEs (≥15% of pts) were hyperglycemia (31 pts, 56%), diarrhea (21 pts, 38%), stomatitis (grouped term; 19 pts, 35%), nausea (17 pts, 31%), and dysgeusia (nine pts, 16%). Grade ≥3 treatment-related AEs in ≥2 pts were hyperglycemia (13 pts, 24%) and alanine aminotransferase increased (two pts, 4%). No grade 3 rash was observed. Thirty-eight pts (70%) discontinued treatment: 36, due to radiographic or clinical disease progression; one, due to physician’s decision; and one, due to death (unrelated serious AE of hypertrophic cardiomyopathy). No treatment-related AE resulted in treatment discontinuation. Overall, 12/49 pts with measurable disease achieved a PR (25%; three of the responding pts had received prior fulvestrant; 11, prior CDK4/6i). Nine pts (18%) had a confirmed PR. CBR was 49% (27/55 pts). Preliminary median PFS was 7.1 months (0-29). Analysis of ctDNA from most pts demonstrated decreased PIK3CA-mutation allele frequency during treatment. The PK of inavolisib in combination with fulvestrant was similar to single-agent inavolisib PK. Conclusion Inavolisib in combination with fulvestrant demonstrated a manageable safety profile, encouraging preliminary antitumor activity, similar PK to inavolisib alone, and pharmacodynamic modulation (i.e., decreased PIK3CA-mutation allele frequency in ctDNA), including in patients who previously progressed on a CDK4/6i. Inavolisib continues to be developed in breast cancer and other solid tumors.

Citation Format: Dejan Juric, Phillippe L Bedard, Andrés Cervantes, Valentina Gambardella, Mafalda Oliveira, Cristina Saura, Kevin M Kalinsky, Erika Hamilton, Antoine Italiano, Ian E Krop, Peter Schmid, Nicholas C Turner, Andrea Varga, Stephanie Royer-Joo, Katherine E Hutchinson, Jennifer L Schutzman, Komal L Jhaveri. A phase I/Ib study of inavolisib (GDC-0077) in combination with fulvestrant in patients (pts) with PIK3CA-mutated hormone receptor-positive/HER2-negative (HR+/HER2-) metastatic breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-17-05.