Ipatasertib plus paclitaxel for PIK3CA/AKT1/PTEN-altered hormone receptor-positive HER2-negative advanced breast cancer: primary results from cohort B of the IPATunity130 randomized phase 3 trial

Abstract

Purpose: PI3K/AKT pathway alterations are frequent in hormone receptor-positive (HR+) breast cancers. IPATunity130 Cohort B investigated ipatasertib-paclitaxel in PI3K pathway-mutant HR+ unresectable locally advanced/metastatic breast cancer (aBC).

Methods: Cohort B of the randomized, double-blind, placebo-controlled, phase 3 IPATunity130 trial enrolled patients with HR+ HER2-negative PIK3CA/AKT1/PTEN-altered measurable aBC who were considered inappropriate for endocrine-based therapy (demonstrated insensitivity to endocrine therapy or visceral crisis) and were candidates for taxane monotherapy. Patients with prior chemotherapy for aBC or relapse < 1 year since (neo)adjuvant chemotherapy were ineligible. Patients were randomized 2:1 to ipatasertib (400 mg, days 1-21) or placebo, plus paclitaxel (80 mg/m2, days 1, 8, 15), every 28 days until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed progression-free survival (PFS).

Results: Overall, 146 patients were randomized to ipatasertib-paclitaxel and 76 to placebo-paclitaxel. In both arms, median investigator-assessed PFS was 9.3 months (hazard ratio, 1.00, 95% CI 0.71-1.40) and the objective response rate was 47%. Median paclitaxel duration was 6.9 versus 8.8 months in the ipatasertib-paclitaxel versus placebo-paclitaxel arms, respectively; median ipatasertib/placebo duration was 8.0 versus 9.1 months, respectively. The most common grade ≥ 3 adverse events were diarrhea (12% with ipatasertib-paclitaxel vs 1% with placebo-paclitaxel), neutrophil count decreased (9% vs 7%), neutropenia (8% vs 9%), peripheral neuropathy (7% vs 3%), peripheral sensory neuropathy (3% vs 5%) and hypertension (1% vs 5%).

Conclusion: Adding ipatasertib to paclitaxel did not improve efficacy in PIK3CA/AKT1/PTEN-altered HR+ HER2-negative aBC. The ipatasertib-paclitaxel safety profile was consistent with each agent's known adverse effects. Trial registration NCT03337724.

Keywords: First-line; HER2 negative; Hormone receptor positive; Ipatasertib; PI3K/AKT.

Conflict of interest statement

N Turner has received honoraria for advisory/consultancy from AstraZeneca, Bristol-Myers Squibb, Lilly, Merck Sharpe and Dohme, Novartis, Pfizer, Roche/Genentech, Bicycle Therapeutics, Taiho, Zeno pharmaceuticals, Repare therapeutics; research grant/funding (to institution) from AstraZeneca, BioRad, Pfizer, Roche/Genentech, Clovis, Merck Sharpe and Dohme, Guardant Health. RA Dent has received honoraria from Roche, Novartis, Lilly, Pfizer, Eisai, Merck, AstraZeneca; travel/accommodation/expenses from AstraZeneca, Merck, Pfizer, Roche. J O’Shaughnessy has received honoraria for advisory/consultancy from AbbVie Inc., Agendia, Amgen Biotechnology, AstraZeneca, Bristol-Myers Squibb, Celgene Corporation, Eisai, Genentech, Genomic Health, GRAIL, Immunomedics, Heron Therapeutics, Ipsen Biopharmaceuticals, Jounce Therapeutics, Lilly, Merck, Myriad, Novartis, Odonate Therapeutics, Pfizer, Puma Biotechnology, Prime Oncology, Roche, Seattle Genetics, Syndax Pharmaceuticals, Takeda. S-B Kim has served as an advisor/consultant for Novartis, AstraZeneca, Lilly, Enzychem Lifesciences, Dae Hwa Pharmaceutical Co. Ltd, ISU Abxis, Daiichi-Sankyo; research grants/funding (to institution) from Novartis, Sanofi-Aventis, Kyowa-Kirin Inc, DongKook Pharm Co. SJ Isakoff has served as an advisor/consultant for Genentech, AbbVie, Hengrui, Immunomedics, Mylan, Puma, Oncopep Research; research grants/funding (to institution) from Genentech, AbbVie, Oncopep, AstraZeneca, Merck. C Barrios has received honoraria for advisory/consultancy roles from Boehringer Ingelheim, GSK, Novartis, Pfizer, Lilly, Roche/Genentech, Eisai, MSD, AstraZeneca, Bayer; research grants/funding (to institution) from AbbVie, Amgen, Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Celgene, Covance, Lilly, Medivation, Merck Serono, MSD, Novartis, Pfizer, PharmaMar, Roche/Genentech; travel/accommodation/expenses from Boehringer Ingelheim, GSK, Novartis, Pfizer, Lilly, Roche/Genentech, Eisai, MSD, AstraZeneca, Bayer. S Saji has received honoraria from Chugai, Eisai, AstraZeneca, Takeda, Novartis, Kyowa-Kirin, Eli Lilly, MSD, Pfizer; has served as an advisory/consultant for Chugai, Novartis, Kyowa-Kirin; research grants/funding (to institution) from Chugai, Eisai, Takeda, Novartis, Daiichi-Sankyo, Taiho Pharmaceutical. I Bondarenko reports no disclosures. Z Nowecki has received travel/accommodation/expenses from Roche. Q Lian is an employee of GNE/Roche and holds stocks/shares in Roche. S-J Reilly is an employee of Roche Products Ltd and holds shares in Roche. H Hinton is an employee of F. Hoffmann-La Roche Ltd and holds shares in Roche. MJ Wongchenko is an employee of Genentech and holds shares in Roche. B Kovic is an employee of Hoffmann-La Roche Limited. A Mani is an employee of Genentech and holds shares in Roche. M Oliveira has served as an advisor/consultant for GNE, GSK, PUMA Biotechnology, Roche, Seattle Genetics, Novartis; research grants/funding (to institution) from GNE, GSK, PUMA Biotechnology, Roche, Seattle Genetics, Novartis, Philips, AstraZeneca, Immunomedics, Boehringer Ingelheim, Zenith Epigenetics, Cascadian Therapeutics, Sanofi, Celldex, Bayer, Piqur; member of the executive board of the SOLTI Breast Cancer Research Group (non-remunerated).

© 2021. The Author(s).

Figures

Fig. 1

Patient profile

Fig. 2

PFS. a investigator assessed; b IRC assessed. IPAT ipatasertib, NE not evaluable, PAC paclitaxel, PBO placebo

Fig. 3

PFS in subgroups. Data for race ‘multiple’ (two patients in the placebo arm, none in the ipatasertib arm), race ‘unknown’ (one patient in the placebo arm without an event, nine patients in the ipatasertib arm) and number of metastatic sites in patients with mBC ‘0’ (one patient in the placebo arm without an event) are not shown because hazard ratios could not be calculated with events in only one arm. ECOG Eastern Cooperative Oncology Group, eCRF electronic case report form, HR hazard ratio, IPAT ipatasertib, mBC metastatic breast cancer, NE not evaluable, PAC paclitaxel, PBO placebo