DURVALUMAB AND LENALIDOMIDE SHOWS SUPERIOR EFFICACY OVER SINGLE-AGENT DURVALUMAB IN REFRACTORY/ADVANCED CUTANEOUS T CELL LYMPHOMA: RESULTS FROM A RANDOMIZED PHASE 2 TRIAL

Introduction: Advanced stages of cutaneous T cell lymphoma (CTCL) have an unfavorable prognosis. We have shown that CTCL escapes immune surveillance via immune checkpoint signaling such as the PD-1/PD-L1 axis. 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. We initiated the randomized Phase 2 portion to compare single agent durvalumab to durvalumab plus lenalidomide in relapsed/advanced CTCL (NCT03011814). The primary end point was objective response rate (ORR) using the global composite response (based on skin, blood, nodes, and viscera) according to consensus guidelines. Secondary end points included duration of response, progression-free survival, and toxicity. Relationships between gene expression profile, tumor-microenvironment (TME), and antitumor activity were exploratory end points.

Methods: Adult patients with histologically confirmed MF or SS, who had failed ≥ 2 systemic therapies were enrolled and randomized 1:1 to single agent durvalumab (1500 mg (day 1 of 28-day cycle) or durvalumab (same dose) & lenalidomide (10 mg for cycle 1, 15 mg for cycle 2, then 20 mg for subsequent cycles daily for 21 days of each 28-day cycle). The study used a “pick a winner” design based on ORR. Serial skin and blood samples were collected to assess the impact on the TME and anti-tumor activity.

Results: Among 25 patients [12 durvalumab; 13 durvalumab/lenalidomide; stage IB, 2 (17%) vs. 4 (31%); stage IIB, 5 (42%) vs. 3 (23%); stage III/IV, 5 (42%) vs. 6 (46%); large cell transformation 3 (25%) vs. 5 (38%)], the combination showed superior clinical activity, with an ORR of 75% versus 42% and a 12-month PFS of 73% (95% CI: 38%–91%) versus 36% (95% CI: 11%–63%) (Figure 1). Median PFS was 6.2 months for durvalumab and not reached for the combination. The most common treatment-emergent adverse events were more frequent in the durvalumab/lenalidomide arm versus durvalumab arm and included fatigue (n = 10), diarrhea (n = 6), anemia (5), decreased platelets (n = 5), leukopenia & neutropenia (n = 4), constipation (n = 4), and leg edema (n = 4). The majority of AEs with both treatment arms were mild to moderate in severity (grade I/II, 92%; grade III, 8 %). One grade IV neutropenia on combo arm was observed.

Conclusions: This randomized phase 2 trial of durvalumab +/− lenalidomide evaluating anti-tumor activity demonstrated superior clinical activity of combinatorial durvalumab/lenalidomide versus single-agent durvalumab in refractory/advanced CTCL. Responses were durable and ongoing, and treatment was well tolerated. Our correlative results from sequential skin biopsies demonstrated immune signatures for enhanced anti-tumor responses that may be predictive of response to checkpoint blockade and yield insights into mechanisms of therapeutic resistance.

Research funding declaration: Research is supported by the NIH/NCI grant (R01 CA229510-01) and Leukemia & Lymphoma Society Clinical Scholar Award (LLS Grant ID: 2325-19) to C. Querfeld, and NIH/NCI Cancer Center Support Grant (P30CA033572) to City of Hope.

Keywords: immunotherapy; cutaneous non-Hodgkin lymphoma; targeting the tumor microenvironment

Potential sources of conflict of interest:

C. Querfeld

Consultant or advisory role: Citius Pharmaceuticals, SLAM BioTherapeutics, Kyowa Kirin, Helsinn

Honoraria: Citius Pharmaceuticals, SLAM BioTherapeutics, Kyowa Kirin, Helsinn

J. Zain

Honoraria: speakers bureau, Kyowa Kirin

Other remuneration: research/grant support from Seattle Genetics, Daichi Seiko, Dreon, Myeloid Therapeutics, CRISPR, & Astrix.