Phase I study of ribociclib (CDK4/6 inhibitor) with spartalizumab (PD-1 inhibitor) with and without fulvestrant in metastatic hormone receptor-positive breast cancer or advanced ovarian cancer.

51 In contrast, the PD-L1 inhibitor avelumab was safely combined with fulvestrant and palbociclib in patients with HR-positive/HER2-negative MBC after progression on prior CDK4/6 inhibition in the PACE trial and, while the study was not powered to compare the triplet combination to fulvestrant alone, a 3.3-month absolute difference in median PFS that did not reach statistical significance was observed (8.1 vs 4.6 months; HR 0.75, p=0.23). 52 In another phase 1b/2 study, the incidence of G3–4 hepatotoxicity with letrozole and palbociclib plus pembrolizumab in HR-positive/HER2-negative MBC was 17% (4/23), demonstrating a more favorable safety profile despite combination with PD-1 inhibition. 53 It remains unclear if there are mechanistic differences between PD-1 and PD-L1 inhibitors that impact the toxicity profiles observed with these triplet combinations with CDK4/6 inhibitors and endocrine therapy.

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