283MO - Ipatasertib (IPAT) + paclitaxel (PAC) for PIK3CA/AKT1/PTEN-altered hormone receptor-positive (HR+) HER2-negative advanced breast cancer (aBC): Primary results from Cohort B of the IPATunity130 randomised phase III trial

Background

PI3K/AKT pathway alterations occur in ∼50% of HR+ breast cancers. In a phase II trial in triple-negative aBC, adding IPAT to PAC improved progression-free survival (PFS), especially in patients (pts) with PIK3CA/AKT1/PTEN-altered tumours [Kim 2017].

Methods

IPATunity130 Cohort B enrolled pts with HR+ HER2– PIK3CA/AKT1/PTEN-altered measurable aBC suitable for chemotherapy (CT). Pts with prior CT for aBC or relapse <1 y since (neo)adjuvant CT were ineligible. Pts were randomised 2:1 to IPAT (400 mg d1–21) + PAC (80 mg/m² d1, 8 & 15) on a 28 d cycle or placebo (PBO) + PAC until progression or unacceptable toxicity, stratified by (neo)adjuvant CT, prior PI3K/mTOR inhibitor and region. The primary endpoint was investigator-assessed PFS.

Results

146 pts were randomised to IPAT + PAC and 76 to PBO + PAC. Prior therapy was balanced between arms, with (neo)adjuvant CT in 55%, endocrine therapy for aBC in 46%, PI3K/mTOR inhibitor in 24% and CDK4/6 inhibitor in 26%. At data cut-off (17/1/20; median follow-up 12.9 mo) 21% of pts remained on therapy. Median investigator-assessed PFS was 9.3 mo in both arms (HR 1.00, 95% CI 0.71–1.40). Median PFS by independent review committee was 9.2 mo with IPAT + PAC vs. 8.5 mo with PBO + PAC (HR 0.79, 95% CI 0.56–1.13). In both arms, objective response rate was 47% and median response duration was 9.2 mo. Overall survival (OS) results are immature (deaths in 25%). Median PAC duration was 6.9 mo with IPAT + PAC vs. 8.8 mo with PBO + PAC; median duration of IPAT was 8.0 mo and PBO was 9.1 mo. IPAT + PAC was associated with more AEs leading to withdrawal of PAC (26% vs. 13%) or IPAT/PBO (11% vs. 4%). IPAT/PBO dose reductions were more common (34% vs. 8%) but PAC dose reductions (26% vs. 24%) and interruptions (53% vs. 51%) and IPAT/PBO interruptions (43% vs. 43%) were similar. No new safety signals were seen. The most common AEs were diarrhoea (85% vs. 37%; grade ≥3: 12% vs. 1%), alopecia (50% vs. 59%) and nausea (41% vs. 20%).

Conclusions

Adding IPAT to PAC did not improve efficacy in PIK3CA/AKT1/PTEN-altered HR+ aBC. The IPAT + PAC safety profile was consistent with known AEs of each agent. OS follow-up is ongoing.

Clinical trial identification

NCT03337724.

Editorial acknowledgement

Jennifer Kelly (Medi-Kelsey Ltd), funded by F. Hoffmann-La Roche.

Legal entity responsible for the study

F. Hoffmann-La Roche.

Funding

F. Hoffmann-La Roche.

Disclosure

N. Turner: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Honoraria (self), Advisory/Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy: Lilly; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Merck Sharpe and Dohme; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Roche/Genentech; Honoraria (self), Advisory/Consultancy: Bicycle Therapeutics; Honoraria (self), Advisory/Consultancy: Taiho; Honoraria (self), Advisory/Consultancy: Zeno Pharmaceuticals; Honoraria (self), Advisory/Consultancy: Repare Therapeutics; Research grant/Funding (institution): BioRad; Research grant/Funding (institution): Clovis; Research grant/Funding (institution): Guardant Health. R. Dent: Honoraria (self), Travel/Accommodation/Expenses: Roche; Honoraria (self): Novartis; Honoraria (self): Lilly; Honoraria (self), Travel/Accommodation/Expenses: Pfizer; Honoraria (self): Eisai; Honoraria (self), Travel/Accommodation/Expenses: Merck; Honoraria (self), Travel/Accommodation/Expenses: AstraZeneca. J. O'Shaughnessy: Honoraria (self), Advisory/Consultancy: AbbVie Inc; Honoraria (self), Advisory/Consultancy: Agendia; Honoraria (self), Advisory/Consultancy: Amgen Biotechnology; Honoraria (self), Advisory/Consultancy: AstraZeneca; Honoraria (self), Advisory/Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy: Celgene Corporation; Honoraria (self), Advisory/Consultancy: Eisai; Honoraria (self), Advisory/Consultancy: Genentech; Honoraria (self), Advisory/Consultancy: Genomic Health; Honoraria (self), Advisory/Consultancy: GRAIL; Honoraria (self), Advisory/Consultancy: Immunomedics; Honoraria (self), Advisory/Consultancy: Heron Therapeautics; Honoraria (self), Advisory/Consultancy: Ipsen Biopharmaceuticals; Honoraria (self), Advisory/Consultancy: Jounce Therapeutics; Honoraria (self), Advisory/Consultancy: Lilly; Honoraria (self), Advisory/Consultancy: Merck; Honoraria (self), Advisory/Consultancy: Myriad; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: Ondonate Therapeutics; Honoraria (self), Advisory/Consultancy: Pfizer; Honoraria (self), Advisory/Consultancy: Puma Biotechnology; Honoraria (self), Advisory/Consultancy: Prime Oncology; Honoraria (self), Advisory/Consultancy: Roche; Honoraria (self), Advisory/Consultancy: Seattle Genetics; Honoraria (self), Advisory/Consultancy: Syndax Pharmaceuticals; Honoraria (self), Advisory/Consultancy: Takeda. S-B. Kim: Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Lilly; Advisory/Consultancy: Enzychem; Advisory/Consultancy: Dae Hwa Pharmaceutical Co. Ltd; Advisory/Consultancy: ISU Abxis; Advisory/Consultancy: Daiichi-Sankyo; Research grant/Funding (institution): Sanofi-Aventis; Research grant/Funding (institution): Kyowa-Kirin Inc; Research grant/Funding (institution): DongKook Pharm Co. S. Isakoff: Advisory/Consultancy, Research grant/Funding (institution): Genentech; Advisory/Consultancy, Research grant/Funding (institution): AbbVie; Advisory/Consultancy: Hengrui; Advisory/Consultancy: Immunomedics; Advisory/Consultancy: Mylan; Advisory/Consultancy: Puma; Advisory/Consultancy, Research grant/Funding (institution): Oncopep Research ; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Merck. C.H. Barrios: Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Boehringer-Ingelheim; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: GSK; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Novartis; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Pfizer; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Lilly; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche/Genentech; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Eisai; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: MSD; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Bayer; Research grant/Funding (institution): AbbVie; Research grant/Funding (institution): Amgen; Research grant/Funding (institution): Astellas Pharma; Research grant/Funding (institution): Bristol-Myers Squibb; Research grant/Funding (institution): Celgene; Research grant/Funding (institution): Covance; Research grant/Funding (institution): Medivation; Research grant/Funding (institution): Merck Serono; Research grant/Funding (institution): PharmaMar. S. Saji: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Chugai; Honoraria (self), Research grant/Funding (institution): Eisai; Honoraria (self): AstraZeneca; Honoraria (self), Research grant/Funding (institution): Takeda; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Novartis; Honoraria (self), Advisory/Consultancy: Kyowa-Kirin; Honoraria (self): Eli Lilly; Honoraria (self): MSD; Honoraria (self): Pfizer; Research grant/Funding (institution): Daiichi Sankyo; Research grant/Funding (institution): Taiho Pharmaceutical. Z. Nowecki: Travel/Accommodation/Expenses: Roche. Q. Lian: Shareholder/Stockholder/Stock options: Roche; Shareholder/Stockholder/Stock options: AbbVie; Shareholder/Stockholder/Stock options: Gilead; Full/Part-time employment: GNE/Roche. S-J. Reilly: Full/Part-time employment: Roche. H. Hinton: Shareholder/Stockholder/Stock options, Full/Part-time employment: Roche. M. Wongchenko: Full/Part-time employment: GNE/Roche; Shareholder/Stockholder/Stock options: Roche. A. Mani: Full/Part-time employment: GNE/Roche; Shareholder/Stockholder/Stock options: Roche. M. Oliveira: Advisory/Consultancy, Research grant/Funding (institution): GNE; Advisory/Consultancy, Research grant/Funding (institution): GSK; Advisory/Consultancy, Research grant/Funding (institution): PUMA Biotechnology; Advisory/Consultancy, Research grant/Funding (institution): Roche; Advisory/Consultancy, Research grant/Funding (institution): Seattle Genetics; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Philips; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Immunomedics; Research grant/Funding (institution): Boehringer Ingelheim; Research grant/Funding (institution): Zenith Epigenetics; Research grant/Funding (institution): Cascadian Therapeutics; Research grant/Funding (institution): Sanofi; Research grant/Funding (institution): Celldex; Research grant/Funding (institution): Bayer; Research grant/Funding (institution): Piqur; Non-remunerated activity/ies, Member of Executive Board: SOLTI Breast Cancer Research Group. All other authors have declared no conflicts of interest.