Randomized Phase 2 Trial of the Anti-PD-L1 Monoclonal Antibody Durvalumab Plus Lenalidomide Versus Single-Agent Durvalumab in Patients with Refractory/Advanced Cutaneous T Cell Lymphoma

Introduction: Mycosis fungoides (MF) and the leukemic variant Sézary syndrome (SS), commonly referred to as cutaneous T cell lymphoma (CTCL), are disfiguring and incurable malignancies with a poor prognosis for those with refractory/advanced-stage (R/A) disease. The dysregulated/exhausted immunophenotype is a hallmark of CTCL and a key feature in disease pathogenesis, influencing patients’ response and resistance to therapy. Here we present the randomized Phase 2 portion of our phase 1/2 trial to compare single agent durvalumab to durvalumab + 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. Exploratory endpoints were the relationships between gene expression profile, tumor microenvironment (TME), and antitumor activity.

Methods: Adult patients with histologically confirmed MF/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 gene expression profile, tumor microenvironment (TME), and antitumor activity was analyzed on matched pre- and on-treatment skin and blood samples.

Results: A total of 25 pts were randomized (intent-to-treat population: 12 durvalumab alone vs. 13 durvalumab + lenalidomide) with the following characteristics at the time of enrollment: median age 56 years (26–79) vs. 65 years (32–88); 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 median number of prior systemic treatments for both single and combo arm was 3. Global best ORR 42% (5/12) for single agent durva and 75% (9/12, 1 patient inevaluable for response). Median follow up time was 14.5 (range, 0.5-29.7) months. Median PFS was 6.2 months for durva arm, and not reached (2.8-NA) for durva/len arm. 12-month PFS was 36% (95% CI: 11%-63%) for durva arm and 73% (95% CI: 38%-91%) for durva/len arm. No serious AEs were observed. The most common treatment-emergent adverse events (shown below for combo arm) that were more frequent in the durvalumab/lenalidomide arm vs 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. Median cycles of treatment were 4.5 (range, 2-26+) and 8 (range 1-29+) for single and combo arms.) One death occurred on each arm at 2.2 months (durva) and 6.6 months (durva/len) after discontinuation of study drug. 2 pts remain on treatment on each arm arm. Molecular profiling using CIBERSORT and single cell analysis revealed distinct changes of daptive and innate immune cell signatures and cellular signaling interactions within the TME that occurred in each treatment arm when compared to baseline. Multiplex cytokine analysis highlights that durva/len promotes a Th1 cytokine microenvironment.

Conclusions: This randomized phase 2 trial of anti-PD-L1 (durvalumab) +/- lenalidomide evaluating anti-tumor activity demonstrated superior clinical activity of combinatorial durvalumab/lenalidomide vs single-agent durvalumab in refractory/advanced CTCL. Responses were durable and ongoing, and treatment was well tolerated. Correlative studies provided evidence for predictive adaptive and innate immune signatures and signaling pathways within the CTCL TME associated with clinical response.