Abstract PS12-28: Phase 1b study evaluating a triplet combination of ipatasertib (IPAT), atezolizumab, and a taxane as first-line therapy for locally advanced/metastatic triple-negative breast cancer (TNBC)
Authors: Schmid Peter , Savas Peter , Espinosa Enrique , Boni Valentina , Italiano Antoine , White Shane , Cheng Karen , Lam Lisa , Robert Lidia , Laliman Victor , Shah Kalpit , Sablin Marie-Paule 
Published: February 2021

Abstract
Background: The combination of immune checkpoint modulators with chemotherapy improves efficacy compared with chemotherapy alone in PD-L1+ advanced TNBC (IMpassion130; KEYNOTE-355). The addition of IPAT to paclitaxel (PAC) improved efficacy in a phase 2 trial in advanced TNBC (LOTUS). Preliminary overall response rate (ORR) data from a multicenter phase 1b study (NCT03800836) evaluating a triplet combination of IPAT, atezolizumab, and taxane chemotherapy showed promising anti-tumor activity in a similar patient population, irrespective of PD-L1 status [Schmid, AACR 2019]. Here, we report follow-up results including progression-free survival (PFS) from this study. Patients and Methods: Eligible patients had measurable unresectable locally advanced/metastatic TNBC, ECOG performance status 0/1, and had received no prior systemic therapy for advanced disease (prior [neo]adjuvant chemotherapy and/or radiation permitted if all chemotherapy was completed ≥12 months before first dose). Patients with brain metastases were excluded. Patients received oral IPAT 400 mg/day on days 1–21 and IV atezolizumab 840 mg on days 1 & 15 in combination with PAC 80 mg/m2 (Arm A) or nab-PAC 100 mg/m2 (Arm B) on days 1, 8, & 15. Cycles were repeated every 28 days until loss of clinical benefit, unacceptable toxicity, or consent withdrawal. Arms C and D evaluated sequential regimens comprising a doublet induction therapy with the third agent added on day 15 (Arm C: IPAT + PAC, then + atezolizumab; Arm D: atezolizumab + PAC, then + IPAT). Tumors were assessed every 8 weeks. Key endpoints were confirmed ORR (per RECIST v1.1), duration of response (DoR), PFS, and safety. Results: At the data cut-off (26 Jul 2020), results were available from 114 patients (Arm A n=70, Arm B n=20, Arm C n=12, Arm D n=12). Median duration of follow-up was 11.1 months. Efficacy results are summarized in the table. Safety of the combination appeared to be consistent with the known safety profile of the individual drugs. Grade ≥3 adverse events (AEs) occurred in 55% of patients (including rash [13%], diarrhea [12%], and neutropenia [10%]) and serious AEs in 34%. AEs led to discontinuation of IPAT in 6% of patients and atezolizumab in 4%. No new safety signals were identified.
Conclusions: Updated results demonstrate a lower ORR than in the preliminary report of the first 26 patients. Subgroup analyses according to PD-L1 or PIK3CA/AKT1/PTEN alteration status or taxane backbone show no consistent trend across endpoints, although small sample sizes limit interpretation. Further biomarker analyses focusing on subgroups and biology may identify subsets of patients deriving a benefit.
PopulationConfirmed ORR, n (%) [95% CI]Median DoR, months (95% CI)aMedian PFS, months (95% CI)All patients (n=114)61 (54) [44–63]7.3 (5.6–7.8)7.2 (5.5–7.4)PD-L1 statusbPositive (n=51)32 (63) [48–76]7.4 (5.0–12.9)7.3 (5.4–7.4)Negative (n=45)20 (44) [30–60]5.6 (3.7–7.4)7.2 (5.4–9.1)Unknown (n=18)9 (50) [26–74]11.1 (5.8–NE)6.3 (4.9–11.0)Arm (taxane backbone)A (PAC) (n=70)36 (51) [39–64]7.4 (5.6–12.9)7.2 (5.3–7.4)B (nab-PAC) (n=20)13 (65) [41–85]7.3 (3.9–7.4)6.6 (3.4–9.0)C+D (PAC) (n=12+12)12 (50) [29–71]6.8 (3.9–14.7)7.5 (5.5–11.3)PIK3CA/AKT1/PTEN statuscAltered (n=36)d19 (53) [35–70]6.8 (3.9–7.6)7.4 (5.5–9.1)Non-altered (n=45)28 (62) [47–76]7.3 (5.5–9.4)6.6 (5.2–9.0)Unknown (n=33)14 (42) [25–61]10.2 (5.8–NE)6.0 (5.1–9.1)aIn responding patients. bAssessed by VENTANA SP142 immunohistochemistry assay (Ventana Medical Systems, Tucson, AZ, USA); PD-L1+ defined as immune cell expression in ≥1% of the tumor area. cAssessed using FoundationOne CDx (Foundation Medicine, Cambridge, MA, USA). dPIK3CA/AKT mutation (n=12) or PTEN alteration (n=24). CI = confidence interval; nab = nanoparticle albumin-bound; NE = not estimable.
Citation Format: Peter Schmid, Peter Savas, Enrique Espinosa, Valentina Boni, Antoine Italiano, Shane White, Karen Cheng, Lisa Lam, Lidia Robert, Victor Laliman, Kalpit Shah, Marie-Paule Sablin. Phase 1b study evaluating a triplet combination of ipatasertib (IPAT), atezolizumab, and a taxane as first-line therapy for locally advanced/metastatic triple-negative breast cancer (TNBC) [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 PS12-28.