Abstract PD10-04: Phase Ib/II open-label, randomized trial of atezolizumab (atezo) with ipatasertib (ipat) and fulvestrant (fulv) vs control in MORPHEUS-HR+ breast cancer (M-HR+ BC) and atezo with ipat vs control in MORPHEUS triple negative breast cancer (M-TNBC) (2022)

Abstract Background: The MORPHEUS platform consists of multiple, global, open-label, randomized Phase Ib/II trials designed to gauge safety and identify early efficacy signals in treatment (tx) combinations across cancers. Within MORPHEUS, atezo (anti-PD-L1) was evaluated with ipat, an oral AKT inhibitor, with (M-HR+ BC) and without (M-TNBC) fulv. Methods: In 2 separate randomized trials, eligible immune checkpoint inhibitor naive pts with either 2L/3L HR+ chemotherapy-naive BC who had prior CDK4/6 inhibitor treatment or 2L TNBC, received atezo (840 mg D1, 15) with ipat (400 mg D1-21); pts with HR+ BC also received fulv monthly. Control tx for M-HR+ BC (NCT03280563) was fulv and for M-TNBC (NCT03424005) was capecitabine; given the adaptive nature of the MORPHEUS platform only some of the control arm pts were enrolled concurrently with pts in the ipat arms for M-HR+ BC. Primary endpoints were ORR (overall response rate; investigator-assessed RECIST 1.1) and safety. Progression-free survival (PFS) and overall survival (OS) were secondary endpoints. Results: Median duration of survival follow-up was 7.6 months for M-HR+ BC (data cutoff: Aug 2020) and 10.8 for M-TNBC (data cutoff: Mar 2021). In M-HR+ BC, none of whom received prior fulvestrant, 26 pts received atezo + ipat + fulv and 15 received fulv. Confirmed ORRs were 23.1% (95% CI: 9.0, 43.7) and 0% (95% CI: 0, 21.8), respectively. Median PFS was 4.4 mo (95% CI: 1.6, not evaluable) and 1.9 mo (95% CI: 1.6, 3.9), respectively. Updated survival data will be presented. Respectively, 61.5% and 20.0% of pts had Gr 3-4 AEs; no G5 AEs were observed; serious AEs (SAEs) occurred in 38.5% and 13.3% of pts; 7.7% and 0% of pts had tx-related AEs leading to tx withdrawal. The most common tx-related AEs were rash (73.0%), diarrhea (53.8%), nausea (42.3%), fatigue (26.9%), vomiting (23.1%), decreased appetite (19.2%), headache (15.4%), pyrexia (11.5%), hyperglycemia (11.5%), and aspartate aminotransferase (AST) increase (11.5%), in the combination arm; of these, rash (38.4%), diarrhea (7.7%), and AST increase (7.7%) included Grade 3-4 tx-related AEs. In M-TNBC, 29 pts received atezo + ipat and 24 received capecitabine. Confirmed ORRs were 3.4% (95% CI: 0.1, 17.8) and 20.8% (95% CI: 7.1, 42.2), respectively. Median PFS was 1.7 mo (95% CI: 1.5, 2.8) and 4.1 mo (95% CI: 2.3, 5.7), respectively. Median OS was 10.8 mo (95% CI: 7.0, 18.1) and 15.2 mo (95% CI: 14.4, 20.8). Gr 3-4 AEs were seen in 51.7% and 37.5% of pts, respectively; Gr 5 AEs were seen in 1 pt in the combination arm (encephalitis due to atezo). SAEs occurred in 51.7% and 16.7% of pts, respectively; 6.9% and 4.2% of pts had tx-related AEs leading to tx withdrawal. The most common tx-related AEs were rash (55.2%), diarrhea (48.3%), nausea (37.9%), pyrexia (31.0%), and fatigue (24.1%) in the combination arm; of these, rash (24.1%), fatigue (3.4%), and pyrexia (3.4%) included Gr 3-4 tx-related AEs. Biomarker data, including PI3K pathway status, PD-L1 and CD8-panCK expression, will also be presented. Conclusion: Atezo + ipat + fulv was tolerable with a preliminary efficacy signal in HR+ BC. Atezo + ipat had limited efficacy in biomarker unselected TNBC. Citation Format: Sara A. Hurvitz, Valentina Boni, Elizabeth Comen, Seock-Ah Im, Kyung Hae Jung, Sung-Bae Kim, Keun Seok Lee, Sherene Loi, Hope S. Rugo, Amir Sonnenblick, Melinda L. Telli, Kelly DuPree, Marcella Fasso, Ya-Chen Lin, Mina Nikanjam, Frauke Schimmoller, Xiaosong Zhang, Jing Zhu, Peter Schmid. Phase Ib/II open-label, randomized trial of atezolizumab (atezo) with ipatasertib (ipat) and fulvestrant (fulv) vs control in MORPHEUS-HR+ breast cancer (M-HR+ BC) and atezo with ipat vs control in MORPHEUS triple negative breast cancer (M-TNBC) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD10-04.