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DOI: 10.1055/s-0041-1730220
A phase I/Ib study evaluating GDC-0077 (inavolisib) + palbociclib (palbo) + fulvestrant in patients (pts) with PIK3CA-mutant (mut), hormone receptor-positive/HER2-negative metastatic breast cancer (HR+/HER2- mBC)
Background Inavolisib (GDC-0077) is a PI3Kα-selective inhibitor and mutant-PI3Kα-degrader demonstrating antitumor activity in PIK3Camut-BC xenograft-models. Phase-I/Ib-data of inavolisib + palbo + fulvestrant in PIK3CAmut, HR+/HER2-neg-mBC are presented (ongoing study; NCT03006172).
Methods Safety, pharmacokinetics, and preliminary antitumor activity (clinical benefit rate [CBR], partial response [PR]) of 9mg oral daily inavolisib + 125mg palbo 21/28 days + 500mg fulvestrant on day 1 (28-day cycles) were assessed in non-randomized arms E+F. Arm F included obese and/or pre-diabetic pts receiving metformin ≤ 2000 mg daily.
Results 28 pts were enrolled (13/Arm E, 15/Arm F). Median inavolisib treatment-duration was 7.8 months/E and 6.5 months/F. Inavolisib cumulative dose intensity was 98%/88%. Thirteen patients (46%) discontinued treatment: 11, radiographic progression (3/E, 8/F); one, AE/panniculitis; one withdrew. Grade ≥ 3 treatment-related AEs (≥ 2 pts) were neutropenia (62%) and hyperglycemia (23%) (Arm E); hyperglycemia and neutropenia (47% each), and anemia (13%) (Arm F). AEs led to inavolisib dose reduction in 2 (15%/E) and 4 (27%/F) patients. The pharmacokinetics of inavolisib in combination with palbo+fulvestrant were similar to single agent inavolisib. 7/25 pts (28%) with measurable disease had a PR (50%/Arm E; 13%/Arm F). CBR was 62%/E and 60%/F. PIK3CAmut allele frequency by ctDNA analysis decreased during treatment in most patients.
Conclusion This study demonstrated a manageable safety profile when combining 9mg inavolisib with palbo + fulvestrant (standard doses), similar pharmacokinetics to single agent inavolisib, preliminary antitumor activity, and modulation of PIK3CAmut allele frequency in ctDNA. In obese/pre-diabetic patients, hyperglycemia was frequent despite metformin-therapy.
Publication History
Article published online:
01 June 2021
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