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

Selective targeting of the functionally exhausted malignant T cells in cutaneous T-cell lymphoma (CTCL) and distinct cells within the tumor microenvironment (TME) via PD1/PD-L1 blockade (durvalumab) may restore an anti-tumor 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 (NCT03011814) sought to assess safety and tolerability and identify the maximum tolerated dose/recommended phase 2 dose (RP2D) of lenalidomide plus fixed-dose durvalumab. Secondary and tertiary objectives were to investigate efficacy and effects on the TME. Thirteen patients were evaluable for toxicities and 12 for dose decisions and response. No serious adverse events (SAEs) or dose-limiting toxicities (DLTs) were observed during cycles 1-3 (DLT evaluation period), and dose level 3 is the RP2D. The most frequent AEs were tumor flare, fatigue, neutropenia, and leukopenia. Three patients developed grade 1/2 autoimmune thyroiditis that resolved with treatment. Best overall and skin response rates were 58.3% (95% CI: 27.7% - 84.8%) and 75% (95% CI: 42.8% - 94.5%) respectively. Median cycles of treatment were 11 (range, 3-42+). Median duration of response was 25.5 (range 8-36.5) months. The combination showed clinical activity with 7 partial responses, and 4 stable disease. Potentially predictive immune signatures were downregulation of TNF-alpha signaling via NFκB, IFN-gamma, and PI3-AKT-mTOR signaling pathways in responders vs up-regulation of MYC targets and pro-inflammatory pathways in non-responders. Profiling of immune cell compositions revealed changes in individual immune cell clusters based on treatment response.