Abstract PO5-06-02: Phase II Trial of Combination of Atezolizumab, Cobimetinib and Eribulin (ACE) or Atezolizumab and Eribulin (AE) in patients with metastatic inflammatory breast cancer (IBC): Clinical data of both cohorts
Authors: Alexander Angela , Murphy Hope , Reuben James , Le-Petross H. T. Carisa , Lane Deanna , Huang Monica , Krishnamurthy Savitri , Gong Yun , Gombos Dan , Patel Nimisha , Allen Richard , Liu Suyu , Patel Anisha , Futreal Andrew , Wistuba Ignacio , Layman Rachel , Ueno Naoto , Tripathy Debu , Lim Bora , Valero Vicente 
Published: May 2024

Abstract
Background: Metastatic IBC is an unmet clinical need due to the aggressiveness of this breast cancer subtype. Gene expression analysis of IBC samples post-neoadjuvant chemotherapy has revealed that dysregulation of immune pathways is common in tumors that do not have a complete pathologic response (pCR) to chemotherapy. The immune checkpoint PD-L1 is expressed in a third of IBC cases, and the MEK inhibitor, cobimetinib, has been shown to enhance the expression of PD-L1, the target of atezolizumab. Taken together, dual targeted therapy with atezolizumab and cobimetinib is hypothesized to be synergistic. Eribulin is a standard of care chemotherapy used in patients who have progressed on anthracycline-taxane based regimens.
Materials and Methods: Patients received triple or double combination therapy depending on the timing of their enrollment. Patients with metastatic IBC who had measurable disease after at least 1 standard regimen were eligible. Any receptor subtype was allowed, and PD-L1 positivity was not required. The study began with a single cohort (n=17 patients) receiving all 3 agents with a lead-in phase to determine the MTD of cobimetinib in this setting. The study was later amended to include only atezolizumab and eribulin (cohort 2). Ten patients were treated in cohort 2. The study closed early due to lack of efficacy in cohort 2 and the changing landscape of metastatic breast cancer therapies. In cohort 1, atezolizumab was given every 2 weeks (840 mg), cobimetinib was given at 60/40/20 mg once daily, and eribulin was given at 1.4mg/m2 on day 1 and day 8 of 21-day cycles. In cohort 2, atezolizumab was given every 3 weeks (1200 mg) during the PD window and cycles 1-4, and then every 4 weeks (1680 mg) during maintenance, and eribulin was given at 1.4mg/m2 on day 1 and day 8 of 21-day cycles.
Results: The MTD of cobimetinib was 40mg. In cohort 1, 17 patients were treated, 14 had at least 1 restaging evaluation. Seven patients had a partial response (50%) and 3 stable disease. The cohort was predominantly triple receptor-negative (n=13/17), with a median age of 51 yrs. The median PFS for patients in cohort 1 was 6.2 months (0-54.1). There were 2 exceptional responders, both with triple negative subtype, one of whom remains on therapy for &gt;4.5 years without evidence of disease. The median overall survival was 29.6 months (2.9-133). The AE profile was largely expected, with 3 irAEs (1 grade 5 colitis, and 2 grade 2 pneumonitis), and one other patient with cardiac dysfunction requiring discontinuation of cobimetinib and atezolizumab. The MTD of cobimetinib was 40 mg. Cobimetinib-related toxicities were mild and largely gastrointestinal tract related.
In cohort 2, only 1 patient experienced PR, and the median PFS was 3 months (1.2-6.2) and overall survival 8.3 months (1.8-19.9). One patient experienced autoimmune related hepatitis requiring discontinuation of protocol therapy. Due to excesive myelosuppression, dose of erublin was reduced to 1.1 mg per meter squared on day 1 and 8 and pegfilgastrim was added on day 9&lt;
Conclusions: The response profile of the triple combination demonstrated promise, and suggests that MEK inhibition may warrant further investigation as a strategy in metastatic IBC in a larger sample size. However, there does not appear to be synergy between atezolizumab and eribulin without the addition of targeted therapy.
Citation Format: Angela Alexander, Hope Murphy, James Reuben, H. T. Carisa Le-Petross, Deanna Lane, Monica Huang, Savitri Krishnamurthy, Yun Gong, Dan Gombos, Nimisha Patel, Richard Allen, Suyu Liu, Anisha Patel, Andrew Futreal, Ignacio Wistuba, Rachel Layman, Naoto Ueno, Debu Tripathy, Bora Lim, Vicente Valero. Phase II Trial of Combination of Atezolizumab, Cobimetinib and Eribulin (ACE) or Atezolizumab and Eribulin (AE) in patients with metastatic inflammatory breast cancer (IBC): Clinical data of both cohorts [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-06-02.