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.

Interessenkonflikt

P. Schmid: Consulting Fees (e.g. advisory boards); Author; P, AZ, N, R, MSD, BI, Puma. Consulting Fees (e.g. advisory boards); Spouse/Partner; G, R. Contracted Research; Author; R, G, Oncogenex, K. Jhaveri: Consulting Fees (e.g. advisory boards); Author; Novartis (N), Pfizer (P), Genentech (G), Lilly, AstraZeneca (AZ), Bristol-Myers-Squibb (BMS), ADC Therapeutics (ADC), Taiho, Jounce Therapeutics, AbbVie.; Author; P, G, N, Lilly, AZ, Immunomedics, Puma, Novita, ADC, Zymeworks, Debio, Clovis.; Author; Yes. D. Juric: Consulting Fees (e.g. advisory boards); Author; N, G, EMD Serono, Eisai, Ipsen, Syros, Vibliome, Relay, MapKure, Petra, Silverback Therapeutics (ST). Contracted Research; Author; N, G, Eisai, EMD Serono, P, Syros, Takeda, Amgen, InventisBio, Dizal, Celgene, Infinity. A. Varga: Contracted Research; Author; AZ, BMS, Boehringer Ingelheim (BI), Janssen Cilag, MSD, N, P, F. Hoffmann-La Roche Ltd (R), Sanofi. Other; Author; BI, AZ. N. Turner: Consulting Fees (e.g. advisory boards); Author; AZ, BMS, Lilly, MSD, N, P, R/G, Bicycle Therapeutics (BT), Taiho, Zeno, Repare (RT). Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g. speakers´ bureaus); Author; AZ, BS, Lilly, MSD, N, P, R/G, BT, Taiho, Zeno, RT. Contracted Research; Author; AZ, BioRad, P, R/G, Clovis, MSD, Guardant. C. Saura: Contracted Research (NOTE: Pls must provide disclosure in this category); Author; AZ, Daiichi Sankyo, Lilly, G, Immunomedics, Macrogenics, MSD España S.A., N, P, Puma, R, Synthon, Zenith. Other; Author; AZ, Celgene, Daiichi Sankyo, R, Genomic Health, MSD España S.A., N, Odonate, P, Philips, Pierre Fabre, prIME, Puma, Synthon, Sanofi Aventis. M. Oliveira: Consulting Fees (e.g. advisory boards); Author; R/G, Glaxo-Smith-Kline (GSK), Seattle Genetics (SG), AZ, Puma. Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g. speakers´ bureaus); Author; R, SG, N. Contracted Research; Author; AZ, Philips, G, R, N, Immunomedics, SG, GSK, BI, Puma, Zenith. Other; Author; R, Pierre-Fabre, N, GP, Grünenthal, Eisai. I.E. Krop: Consulting Fees (e.g. advisory boards); Author; G/R, Daiichi/Sankyo, Macrogenenics, Context, Taiho, MSD, N, BMS, Celltrion. Contracted Research; Author; G/R, P, Daiichi-Sankyo. K. Kalinsky: Salary; Spouse/Partner; N, Array Biopharma, P (previous); GRAIL (current). Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g. speakers´ bureaus); Author; Lilly. Contracted Research; Author; Immunomedics, N, Incyte, G/R, Lilly, P, Calithera, Acetylon, SG, Amgen, Zentalis, CytomX. Other; Author; Lilly, AZ. A. Italiano: Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g. speakers´ bureaus); Author; Bayer, R, Springworks, AZ, Epizyme. Contracted Research; Author; Bayer, MSD, Pharmamar, AZ, R. E. Hamilton: Consulting Fees (e.g. advisory boards); Author; P, G/R, Lilly, Puma, Daiichi Sankyo, Mersana, BI, AZ, N, ST, Black Diamond, NanoString. Contracted Research; Author; SG, Puma, AZ, Hutchinson MediPharma, OncoMed, MedImmune, StemCentrx, G/R, Curis, Verastem, Zymeworks, Syndax, Lycera, Rgenix, N, Mersana, Millenium, TapImmune, Lilly, BerGenBio, Medivation, P, Tesaro, BI, Eisai, H3, Radius, Acerta, Takeda, Macrogenics, AbbVie, Immunomedics, FujiFilm, Effector, Merus, Nucana, Regeneron, Leap, Taiho, EMD Serono, Daiichi Sankyo, ArQule, Syros, Clovis, Cytomx, InventisBio, Deciphera, Unum, Sermonix, Sutro, Aravive, Zenith Epigenetics, Arvinas, Torque, Harpoon, Fochon, Black Diamond, Orinove, Molecular Templates, ST, Compugen, G1, Karyopharm, Torque. V. Gambardella: Contracted Research; Author; R, G. A. Cervantes: Contracted Research (NOTE: Pls must provide disclosure in this category); Author; R, G. P.L. Bedard: Consulting Fees (e.g. advisory boards); Author; R, Sanofi, BMS. Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g. speakers´ bureaus); Author; Sanofi, R. Contracted Research; Author; AZ, BMS, G/R, GSK, MSD, Lilly, Nektar, N, P, PTC, Sanofi, SG, Servier, SignalChem, Zymeworks. Other; Author; Breast International Group, Canadian Clinical Trials Group Cancer Research Institute/Canadian Clinical Trials Group Joint Scientific Leadership Committee, AACR Project Genie Melanie´s Way, JNCI Cancer Spectrum, The Oncologist. R. S. Royer-Joo: Salary; Author; G/R. Ownership Interest (stock, stock options, or other ownership interest excluding diversified mutual funds); Author; R. J.L. Schutzman: Salary; Author; G. Ownership Interest (stock, stock options, or other ownership interest excluding diversified mutual funds); Author; R. K.E. Hutchinson: Salary; Author; G. Ownership Interest (stock, stock options, or other ownership interest excluding diversified mutual funds); Author; R. Other; Author; G. Lei: employee of Roche P. Thomas: employee of Genentech

Publication History

Article published online:
01 June 2021