Phase 1b 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 (aTNBC)
Schmid P.1, Kümmel S.2, Loirat D.3, Savas P.4, Espinosa E.5, Boni V.6, Italiano A.7, White S.8, Singel S.9, Withana N.9, Mani A.9, Li S.9, Harris A.9, Wongchenko M.9, Sablin M.3
1Barts Cancer Institute, London, Vereinigtes Königreich, 2Klinikum Essen-Mitte, Essen, Deutschland, 3Institut Curie, Paris, Frankreich, 4Peter MacCallum Cancer Centre, Melbourne, Australien, 5Hospital Universitario LaPaz, Madrid, Spanien, 6START Madrid CIOCC, Madrid, Spanien, 7Institut Bergonie, Bordeaux, Frankreich, 8Austin Hospital, Melbourne, Australien, 9Genentech, Inc., South San Francisco, Vereinigte Staaten von Amerika

Purpose: Randomized trials in aTNBC have demonstrated improved efficacy with addition of Atezo to 1L nab-PAC in patients (pts) with PD-L1+ tumors, and with addition of the AKT inhibitor IPAT to 1L PAC. 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 unresectable aTNBC, ECOG-PS 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 (B), both given on days 1, 8, & 15, in combination with oral IPAT 400 mg/day (days 1-21) and IV Atezo 840 mg (days 1&15). Cycles were repeated every 28 days until loss of clinical benefit or unacceptable toxicity. After establishing tolerability (n=6), each arm was expanded to 20 pts. The primary endpoint is objective response rate (ORR; RECIST v1.1).
Results: We report preliminary efficacy/safety data for the first 26 pts (18 PAC, 8 nab-PAC). Median follow-up was 6.1 months. Confirmed responses were seen in 19/26 patients (ORR 73%), irrespective of PD-L1 status (82% PD-L1+, 75% PD-L1-, 57% PD-L1 unknown) or PIK3CA/AKT1/PTEN alteration status (71% Dx+, 82% Dx-; 63% Dx unknown). Treatment was generally tolerable. Grade ≥3 AE occurred in 54%. The most common AE were diarrhea (88%; grade ≥3 19%) and rash (69%; grade 3 27%, no grade >3).
Conclusions: The triplet regimen shows promising antitumor activity (73% ORR), irrespective of biomarker status, and has manageable toxicity. This triplet regimen warrants further investigation.