Phase 1 trial of durvalumab (anti-PD-L1) combined with lenalidomide in relapsed/refractory cutaneous T-cell lymphoma.

Abstract: Selective targeting of the functionally exhausted malignant T cells in cutaneous T-cell lymphoma (CTCL) and distinct cells within the tumor microenvironment (TME) via programmed cell death 1/programmed cell death ligand 1 blockade (durvalumab) may restore an antitumor immune response. The oral immunomodulator lenalidomide, which has activity in CTCL, may enhance durvalumab immune checkpoint blockade. Our phase 1/2 clinical trial of durvalumab and lenalidomide in patients with refractory/advanced CTCL sought to assess the safety and tolerability and to identify the maximum tolerated dose and recommended phase 2 dose (RP2D) of lenalidomide plus fixed-dose durvalumab. Secondary and tertiary objectives were to investigate the efficacy and effects on the TME. Thirteen patients were evaluable for toxicities and 12 for dose decisions and response. No serious adverse events (AEs) or dose-limiting toxicities (DLTs) were observed during cycles 1 to 3 (DLT evaluation period), and dose level 3 was identified as the RP2D. The most frequent AEs were tumor flare, fatigue, neutropenia, and leukopenia. Three patients developed grade 1 or 2 autoimmune thyroiditis that resolved with treatment. Best overall and skin response rates were 58.3% (95% confidence interval (95% CI), 27.7-84.8%) and 75% (95% CI: 42.8-94.5%), respectively. The median cycles of treatment were 11, and the median duration of response was 25.5 months. The combination showed clinical activity with 7 partial responses and 4 stable disease. Potentially predictive immune signatures were downregulation of -α signaling via NF-κB, interferon gamma, and phosphoinositide 3 kinase-AKT-mammalian target of rapamycin signaling pathways in responders and upregulation of MYC targets and proinflammatory pathways in nonresponders. Profiling of immune cell compositions revealed changes in individual immune cell clusters based on treatment response. This trial was registered at www.ClinicalTrials.gov as #NCT03011814.