Abstract CT049: Phase Ib study evaluating a triplet combination of ipatasertib (IPAT), atezolizumab (atezo), and paclitaxel (PAC) or nab-PAC as first-line (1L) therapy for locally advanced/metastatic triple-negative breast cancer (TNBC)
Authors: Schmid Peter , Loirat Delphine , Savas Peter , Espinosa Enrique , Boni Valentina , Italiano Antoine , White Shane , Singel Stina M. , Withana Nimali , Mani Aruna , Li Suwen , Harris Adam , Wongchenko Matthew , Sablin Marie 
Published: August 2019

Abstract
Purpose: Recent randomized trials in advanced TNBC have demonstrated improved efficacy with the addition of atezo to 1L nab-PAC in patients (pts) with PD-L1+ tumors (IMpassion130 [Schmid 2018]), and with the addition of the oral AKT inhibitor IPAT to 1L PAC, particularly in pts with PIK3CA/AKT1/PTEN-altered tumors (LOTUS [Kim 2017]). Loss of PTEN, a negative regulator of AKT, has emerged as a potential mechanism for resistance to checkpoint inhibitor therapy; inhibiting the PI3K/AKT pathway has led to reversal of T-cell-mediated immunotherapy resistance [Peng 2016]. We report first results from a multicenter phase 1b study (NCT03800836) evaluating a triplet of IPAT, atezo, and PAC or nab-PAC.
Methods: Eligible pts had measurable unresectable locally advanced/metastatic TNBC, ECOG performance status 0/1, and no prior systemic therapy for advanced disease. Pts were assigned to PAC 80 mg/m2 (Arm A) or nab-PAC 100 mg/m2 (Arm B), both given on days 1, 8, & 15, in combination with oral IPAT 400 mg/day on days 1-21 and IV atezo 840 mg on days 1 & 15. Cycles were repeated every 28 days until loss of clinical benefit, unacceptable toxicity, or consent withdrawal. After establishing tolerability in a safety run-in (n=6), each arm was expanded to a total of 20 pts. The primary efficacy endpoint is confirmed objective response rate (ORR) per RECIST v1.1. Tumors are assessed every 8 weeks.
Results: We report preliminary efficacy and safety data up to Jan 5, 2019, for the first 26 pts enrolled (18 PAC, 8 nab-PAC). The median duration of follow-up was 6.1 (range 3.1-10.6) months. Confirmed responses were seen in 19/26 pts, giving a confirmed ORR of 73% (95% CI 53-88%). Responses were seen irrespective of PD-L1 status (9/11 [82%] PD-L1+; 6/8 [75%] PD-L1-; 4/7 [57%] PD-L1 unknown) or PIK3CA/AKT1/PTEN alteration status (5/7 [71%] Dx+, 9/11 [82%] Dx-; 5/8 [63%] Dx unknown). Treatment was generally tolerable. Grade ≥3 adverse events occurred in 14 pts (54%). The most common all-grade adverse events were diarrhea (88%; grade ≥3 19%, manageable with loperamide; no colitis was reported) and rash (including pruritic, pustular, and maculopapular rash and drug eruption: 69%; grade ≥3 27%, manageable and reversible with antihistamine and steroids). The most severe rash was grade 3 and typically occurred in cycle 1. Hyperglycemia was absent. Enrollment is ongoing.
Conclusions: The triplet regimen shows promising antitumor activity (73% confirmed ORR), irrespective of biomarker status, and has manageable toxicity. This triplet regimen warrants further investigation.
Citation Format: Peter Schmid, Delphine Loirat, Peter Savas, Enrique Espinosa, Valentina Boni, Antoine Italiano, Shane White, Stina M. Singel, Nimali Withana, Aruna Mani, Suwen Li, Adam Harris, Matthew Wongchenko, Marie Sablin. Phase Ib study evaluating a triplet combination of ipatasertib (IPAT), atezolizumab (atezo), and paclitaxel (PAC) or nab-PAC as first-line (1L) therapy for locally advanced/metastatic triple-negative breast cancer (TNBC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT049.