139O - Final results of the double-blind placebo (PBO)-controlled randomised phase II LOTUS trial of first-line ipatasertib (IPAT) + paclitaxel (PAC) for inoperable locally advanced/metastatic triple-negative breast cancer (mTNBC)

Background

In LOTUS (NCT02162719), adding the oral AKT inhibitor IPAT to 1st-line PAC for mTNBC improved progression-free survival (PFS; primary endpoint) [Kim, Lancet Oncol 2017]. The stratified PFS hazard ratio in the intent-to-treat (ITT) population was 0.60 (95% CI 0.37–0.98; p=0.037; median PFS 6.2 vs 4.9 mo with IPAT vs PBO, respectively), with an enhanced effect in patients (pts) with PIK3CA/AKT1/PTEN-altered tumours. Overall survival (OS) results were immature at the primary and updated analyses (deaths in 21% and 55% of pts, respectively). Here we report final results.

Methods

Eligible pts had measurable mTNBC previously untreated with systemic therapy. Pts were stratified by prior (neo)adjuvant therapy, chemotherapy-free interval and tumour IHC PTEN status and randomised 1:1 to PAC 80 mg/m² (d1, 8 & 15) plus either IPAT 400 mg or PBO (d1–21) q28d until disease progression (PD) or unacceptable toxicity. OS (ITT, PTEN-low and PI3K/AKT pathway-actived [PIK3CA/AKT1/PTEN-altered] populations) was a prespecified secondary endpoint.

Results

By the final data cut-off (3 Sep 2019) all pts had discontinued treatment, predominantly because of PD. In the ITT population, median OS was numerically longer in the IPAT + PAC arm (Table). Similarly, median OS favoured IPAT + PAC vs PBO + PAC in the PTEN-low (n=48; 23.1 vs 15.8 mo) and PIK3CA/AKT1/PTEN-altered (n=42; 25.8 vs 22.1 mo) subgroups. There were few additional adverse events since previous reports and the safety profile of IPAT + PAC was unchanged. Table: 139O

n=61 (safety population, all treated pts)

Conclusions

Final OS results show a numerical trend favouring IPAT + PAC; median OS exceeds 2 years with IPAT + PAC. Consistent with the previously observed PFS benefit, these findings support further evaluation of first-line IPAT + PAC for mTNBC in the ongoing IPATunity130 (NCT03337724) randomised phase III trial.

Clinical trial identification

NCT02162719.

Editorial acknowledgement

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

Legal entity responsible for the study

F Hoffmann-La Roche Ltd.

Funding

F Hoffmann-La Roche Ltd.

Disclosure

R. Dent: Honoraria (self): Roche; Honoraria (self): Pfizer; Honoraria (self): Eisai; Honoraria (self): Merck; Honoraria (self): AstraZeneca. M. Oliveira: Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche; Advisory/Consultancy: Roche/Genentech; Advisory/Consultancy, Research grant/Funding (institution): GlaxoSmithKline; Advisory/Consultancy, Research grant/Funding (institution): Puma Biotechnology; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Philips Healthcare; Research grant/Funding (institution): Genentech; Research grant/Funding (institution), Travel/Accommodation/Expenses: Novartis; Research grant/Funding (institution): Immunomedics; Research grant/Funding (institution): Seattle Genetics; Research grant/Funding (institution): Boehringer Ingelheim; Travel/Accommodation/Expenses: Grunenthal Group; Travel/Accommodation/Expenses: Pierre Fabre; Travel/Accommodation/Expenses: GP Pharm. S.J. Isakoff: Honoraria (self), Research grant/Funding (institution): Genentech; Honoraria (self): Hengrui; Honoraria (self): Puma; Honoraria (self): Immunomedics; Honoraria (self): Myriad; Research grant/Funding (institution): PharmaMar; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Merck. S-A. Im: Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Advisory/Consultancy: Amgen; Advisory/Consultancy: Eisai; Advisory/Consultancy: Medipacto; Advisory/Consultancy: Novartis; Advisory/Consultancy: Daiichi-Sankyo; Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Advisory/Consultancy, Research grant/Funding (institution): Roche; Advisory/Consultancy: Lilly. M. Espié: Research grant/Funding (institution): Roche; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Pfizer. S. Blau: Spouse/Financial dependant, Husband is owner: All4cure. A.R. Tan: Advisory/Consultancy: Immunomedics; Advisory/Consultancy: Celgene; Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Advisory/Consultancy, Research grant/Funding (institution): Genentech/Roche; Advisory/Consultancy: Novartis; Advisory/Consultancy: AbbVie; Advisory/Consultancy: Eisai; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Tesaro; Research grant/Funding (institution): G1Therapeutics; Research grant/Funding (institution): Daiichi-Sankyo. C. Saura: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Honoraria (self): Celgene; Honoraria (self): Daiichi Sankyo; Honoraria (self), Advisory/Consultancy: Eisai; Honoraria (self), Advisory/Consultancy: Roche; Honoraria (self), Advisory/Consultancy: Genomic Health; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: Pfizer; Honoraria (self): Pierre Fabre; Honoraria (self), Advisory/Consultancy: Puma; Honoraria (self), Advisory/Consultancy: Synthon; Advisory/Consultancy: Sanofi; Research grant/Funding (institution): Genentech. M. Wongchenko: Full/Part-time employment: Genentech/Roche; Shareholder/Stockholder/Stock options: Roche. N. Xu: Full/Part-time employment: Genentech/Roche; Shareholder/Stockholder/Stock options: Roche. D. Bradley: Shareholder/Stockholder/Stock options, Full/Part-time employment: Roche; Licensing/Royalties, Named as an inventor on Roche/Genentech patent application: Roche. S-J. Reilly: Shareholder/Stockholder/Stock options, Full/Part-time employment: Roche. A. Mani: Full/Part-time employment: Genentech/Roche; Shareholder/Stockholder/Stock options: Roche; Licensing/Royalties, Named as an inventor on Roche/Genentech patent application: Roche/Genentech. 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 Pharma Co, Ltd.