Abstract GS3-04: Double-blind placebo (PBO)-controlled randomized phase III trial evaluating first-line ipatasertib (IPAT) combined with paclitaxel (PAC) for PIK3CA/AKT1/PTEN-altered locally advanced unresectable or metastatic triple-negative breast cancer (aTNBC): primary results from IPATunity130 Cohort A
Authors: Dent Rebecca , Kim Sung-Bae , Oliveira Mafalda , Barrios Carlos , O’Shaughnessy Joyce , Isakoff Steven J , Saji Shigehira , Freitas-Junior Ruffo , Philco Manuel , Bondarenko Igor , Lian Qinshu , Bradley Denise , Hinton Heather , Wongchenko Matthew J , Mani Aruna , Turner Nicholas 
Published: February 2021

Abstract
Background: In the randomized phase II LOTUS trial [Kim, Lancet Oncol 2017], adding IPAT to PAC improved progression-free survival (PFS), with a more pronounced effect in patients with PIK3CA/AKT1/PTEN-altered tumors. This effect provided the rationale for the biomarker-selected IPATunity130 phase III trial. Here we report primary results from Cohort A in aTNBC. Patients and methods: In Cohort A of this pivotal phase III trial (NCT03337724), eligible patients had PIK3CA- and/or AKT1- and/or PTEN-altered measurable aTNBC, ECOG performance status 0/1, were appropriate candidates for taxane monotherapy, and had received no prior chemotherapy for aTNBC. Patients were randomized 2:1 to receive either oral IPAT 400 mg or PBO (days 1-21), both combined with IV PAC 80 mg/m2 (days 1, 8, & 15). Cycles were repeated every 28 days until disease progression, unacceptable toxicity, or patient withdrawal. Stratification factors were: prior (neo)adjuvant chemotherapy (yes vs no); geographic region (Asia-Pacific vs Europe vs North America vs rest of world); and tumor alteration status (PIK3CA/AKT1-activating mutation vs PTEN alteration without PIK3CA/AKT1-activating mutation). The primary endpoint was investigator-assessed PFS; secondary endpoints included overall survival (OS; key secondary), objective response rate (ORR), duration of response, clinical benefit rate (CBR), patient-reported outcomes, and safety. Results: Between 6 Feb 2018 and 8 Apr 2020, 255 patients were enrolled, of whom 51% had received (neo)adjuvant chemotherapy and 59% had visceral disease; 51% had PIK3CA/AKT1-activating mutations and the remaining 49% had PTEN alterations (without PIK3CA/AKT1-activating mutations). At the clinical cut-off date (7 May 2020), median duration of follow-up was 8.3 months (range 0-26.8 months) and 33% of patients remained on treatment. Mean duration of PAC was similar in the two groups (5.5 vs 5.4 months in the IPAT vs PBO arms, respectively). There was no difference in PFS between treatment groups overall (Table) nor in any prespecified subgroups. OS results are immature (deaths in 20% of patients). Similar proportions of patients in the IPAT and PBO arms experienced grade ≥3 adverse events (AEs) (46% vs 44%, respectively), fatal AEs (1% vs 1%), and AEs leading to discontinuation of any treatment (14% vs 15%), although AEs leading to dose reduction of any treatment were more common with IPAT (35% vs 14%). The most common AEs (any grade) were diarrhea (80% vs 31%; grade ≥3 9% vs 2%), alopecia (46% vs 44%), and nausea (36% vs 23%). Conclusions: In contrast to results from the phase II LOTUS trial, this trial showed no PFS improvement with the addition of IPAT to first-line PAC in patients with PIK3CA/AKT1/PTEN-altered aTNBC. Biomarker analyses are ongoing to evaluate potential markers of IPAT benefit. Safety was consistent with previously reported results for this combination.
Summary of efficacyIPAT + PAC PBO + PACITT population(n=168)(n=87)PFS events, n (%)92 (55)48 (55)Median PFS, months (95% CI)7.4 (5.6-8.5)6.1 (5.5-9.0)PFS stratified hazard ratio (95% CI)1.02 (0.71-1.45)Log-rank p=0.9237Measurable disease population(n=167)(n=86)ORR, n (%) [95% CI]65 (39) [32-47]30 (35) [25-46]CBR, n (%) [95% CI]78 (47) [39-55]39 (45) [35-56]
Citation Format: Rebecca Dent, Sung-Bae Kim, Mafalda Oliveira, Carlos Barrios, Joyce O’Shaughnessy, Steven J Isakoff, Shigehira Saji, Ruffo Freitas-Junior, Manuel Philco, Igor Bondarenko, Qinshu Lian, Denise Bradley, Heather Hinton, Matthew J Wongchenko, Aruna Mani, Nicholas Turner. Double-blind placebo (PBO)-controlled randomized phase III trial evaluating first-line ipatasertib (IPAT) combined with paclitaxel (PAC) for PIK3CA/AKT1/PTEN-altered locally advanced unresectable or metastatic triple-negative breast cancer (aTNBC): primary results from IPATunity130 Cohort A [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS3-04.