A Multicenter Phase II Trial of Ipilimumab and Nivolumab in Unresectable or Metastatic Metaplastic Breast Cancer: Cohort 36 of Dual Anti–CTLA-4 and Anti–PD-1 Blockade in Rare Tumors (DART, SWOG S1609)

Abstract

Purpose: Metaplastic breast cancer (MpBC) is a rare aggressive subtype that responds poorly to cytotoxics. Median survival is approximately 8 months for metastatic disease. We report results for advanced MpBC treated with ipilimumab + nivolumab, a cohort of S1609 for rare cancers (DART: NCT02834013). Patients and Methods: Prospective, open-label, multicenter phase II (two-stage) trial of ipilimumab (1 mg/kg i.v. every 6 weeks) plus nivolumab (240 mg i.v. every 2 weeks) for advanced MpBC. Primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity. Results: Overall, 17 evaluable patients enrolled. Median age was 60 years (26–85); median number of prior therapy lines was 2 (0–5). ORR was 18%; 3 of 17 patients achieved objective responses (1 complete, 2 partial responses; 2 spindle cell, 1 chondromyxoid histology), which are ongoing at 28+, 33+, and 34+ months, respectively. Median PFS and OS were 2 and 12 months, respectively. Altogether, 11 patients (65%) experienced adverse events (AE), including one grade 5 AE. Eight patients (47%) developed an immune-related AE (irAE), with adrenal insufficiency observed in all 3 responders. Responses occurred in tumors with low tumor mutational burden, low PD-L1, and absent tumor-infiltrating lymphocytes. Conclusions: The ipilimumab and nivolumab combination showed no new safety signals and met its primary endpoint with 18% ORR in advanced, chemotherapy-refractory MpBC. All responses are ongoing at >2 to almost 3 years later. The effect of ipilimumab and nivolumab was associated with exceptional responses in a subset of patients versus no activity. This combination warrants further investigation in MpBC, with special attention to understanding mechanism of action, and carefully designed to weigh against the significant risks of irAEs.

Partial Response After Toripalimab Plus Anlotinib for Advanced Metaplastic Breast Carcinoma: A Case Report

“…In a single-arm, phase 2 trial (DART trial), 17 MBC patients received the nivolumab and ipilimumab combination therapy. The ORR, median PFS, and median OS were 18%, 2 months, and 12 months, respectively ( 17 ). Previously, four case reports observed the efficacy of ICIs in advanced MBC ( Table 1 ).…”

Role of Immunotherapy in Breast Cancer

“…The phase II DART trial evaluated the use of ipilimumab (a CTLA-4 inhibitor) in combination with nivolumab (PD-1 inhibitor) in patients with metaplastic breast cancer who had received several prior lines of therapy. 63 An ORR of 18% was observed in 17 patients with eight patients experiencing irAEs, three of which were adrenal insufficiency. Additional studies are underway to evaluate the combination of durvalumab and tremelimumab (another CTLA-4 inhibitor) and ipilimumab and nivolumab in HER2– breast cancer.…”

Targeted Approaches to HER2-Low Breast Cancer: Current Practice and Future Directions

“…In preclinical experiments, blocking the inhibitory pathway of ICR–ligand interactions in the tumor microenvironment restores the functional immune response of TAAs [ 125 , 126 ]. Several monoclonal antibodies targeting ICR markers, including cytotoxic T lymphocyte-associated antigen (CTLA-4), programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1), have shown good clinical activity in BC [ 127 , 128 , 129 , 130 ].…”