Brentuximab Vedotin in Combination with Nivolumab in CD30+ Malignancies Refractory to Brentuximab Vedotin

Abstract

Introduction Brentuximab vedotin (BV), in combination with multi-agent chemotherapy, is considered a standard of care for newly diagnosed CD30+ lymphomas. Despite high reported efficacy, some patients fail to respond to initial BV exposure and many more eventually progress despite ongoing BV therapy. In addition to direct cytotoxicity, BV may also induce immunogenic cell death (Gardai, et al. Cancer Res 2015) and foster a reduction of regulatory T-cells (Herrera, et al. Blood 2018) that may synergize with immune checkpoint inhibitors. To date, the high response rates reported with BV and anti-PD-1 combinations have been limited to patients naïve to both of these agents (Advani, et al. Blood 2021). To address the more clinically relevant scenario of prior BV +/- anti-PD-1 exposure, we designed a study to evaluate the combination of BV and nivolumab in patients with CD30+ lymphoma refractory to prior BV, including those with prior anti-PD-1 therapy. We report the final safety, efficacy and correlative analysis of BV in combination with nivolumab in R/R CD30+ lymphomas refractory to BV. Methods We conducted an open-label trial (NCT01703949) involving patients 18 years and older with CD30+ lymphomas refractory to BV therapy. Refractoriness was defined as lack of disease response or progression within 6 months following a minimum of 2 cycles of BV. BV was given at 1.8 mg/kg in combination with nivolumab at 3 mg/kg every 3 weeks for 4 cycles. The primary endpoint was overall response rate (ORR). Secondary endpoints included complete response (CR) rate, progression-free survival, overall survival, time to next treatment, safety and tolerability and immune response biomarkers. Results As of July 27, 2023, 19 patients have enrolled and 17 have initiated therapy (Table 1). Fourteen patients had classical Hodgkin lymphoma (cHL), 2 had ALK-negative anaplastic large cell lymphoma (ALK- ALCL) and 3 had CD30+ mycosis fungoides (MF). Median age was 35 (range 27-71) years and the median number of prior regimens was 5 (range 1-9), including a median of 6 prior cycles of BV (range 2-19). All patients had BV-refractory disease including 16 (84%) who were non-responsive to and 3 (16%) who relapsed within 6 months of BV. Five (26%) patients with cHL received prior anti-PD-1 therapy and 4 (21%) had anti-PD-1 refractory disease. Median time from last BV and anti-PD-1 therapy to study treatment was 5.2 and 1.1 months, respectively. Eight (42%) patients had prior autologous stem cell transplant. Of response evaluable patients, the ORR and CR rate was 44% and 6% after 2 cycles and 44% and 19% after 4 cycles of therapy. Of patients who were refractory to prior BV and anti-PD-1 therapy, 1 (25%) and 1 (25%) achieved a PR and CR, respectively. ORR and CR rate was 43% and 14% for patients with cHL, 100% and 50% for patients with ALK- ALCL, and 100% and 100% for patients with MF, respectively. At completion of study, 1 patient with cHL, 1 with MF and 2 with cHL continued BV with nivolumab, BV monotherapy and nivolumab monotherapy, respectively. Median time to progression and next therapy was 4.5 (range 1.8-45.6) and 5.0 (range 1.8-45.6) months, respectively. Of the 3 patients who achieved a CR after 4 cycles of therapy, 2 (67%) continued treatment (1 with BV and nivolumab and 1 with BV monotherapy), and 1 (33%) has been on surveillance for 45.6 months with no evidence of relapse. At a median follow-up of 21.7 (range 0.5-60.4) months, 15 (79%) patients are alive with 3 in CR. Eleven (58%) and 8 (42%) patients reported no and grade 1 peripheral neuropathy (PN) at baseline, respectively. At end of treatment, 12 (63%) and 1 (5%) patients reported grade 1 and 2 PN, respectively. No patients experienced grade ≥3 PN, transaminitis, infections or infusion reactions. One (5%) patient had a 1-week dose delay due to grade 1 ALT/AST elevation. Two (11%) deaths were noted on study; one patient developed respiratory failure secondary to pneumonitis and influenza and another patient experienced cardiac arrest due to benzodiazepine withdrawal. Correlative PD-1 levels drawn at baseline and at the end of treatment did not correlate with response. Conclusions Despite the presence of BV-refractory disease, 4 cycles of BV and nivolumab is tolerable and associated with encouraging efficacy in patients with heavily treated CD30+ lymphoma. This treatment option may have increasing relevance as more patients receive BV or anti-PD-1 therapy as part of initial treatment.