S1601 NIVOLUMAB COMBINED WITH BRENTUXIMAB VEDOTIN FOR RELAPSED/REFRACTORY PRIMARY MEDIASTINAL LARGE B‐CELL LYMPHOMA: EFFICACY AND SAFETY RESULTS FROM THE PHASE 2 CHECKMATE 436 STUDY

Background: Primary mediastinal B‐cell lymphoma (PMBL) is an infrequent aggressive lymphoma, accounting for < 5% of all non‐Hodgkin lymphomas (NHLs). Patients (pts) with relapsed/refractory (R/R) PMBL have poor outcomes. Weak CD30 expression and increased programmed death‐1 (PD‐1) ligand expression are characteristic features of PMBL, with PD‐1 ligand expression potentially contributing to evasion of host immune responses (Green MR et al. Blood 2010). Nivolumab, a fully human IgG4 anti − PD‐1 immune checkpoint inhibitor monoclonal antibody, augments host antitumor immune responses. Brentuximab vedotin (BV), an anti‐CD30 antibody–drug conjugate, induces apoptosis of CD30‐expressing cells, and depletes immunosuppressive T regulatory cells, which may potentiate the activity of nivolumab. PD‐1 blockade alone and BV monotherapy have been associated with overall response rates (ORRs) of 41% and 13%, respectively, in R/R PMBL (Zinzani PL et al. Blood 2017a,b). Aims: To investigate the efficacy and safety of nivolumab + BV in pts with R/R PMBL from the phase 2 CheckMate 436 study (NCT02581631). Methods: CheckMate 436 is an international, open‐label, phase 1/2 study of nivolumab + BV to treat NHLs with CD30 expression. This expansion cohort enrolled pts with confirmed PMBL and R/R disease after either high‐dose conditioning chemotherapy and autologous hematopoietic cell transplantation (auto‐HCT) or ≥ 2 prior multi‐agent chemotherapy regimens if ineligible for auto‐HCT. Pts received nivolumab (240 mg IV) and BV (1.8 mg/kg IV, pre‐specified dose modifications allowed) every 3 weeks until disease progression or unacceptable toxicity. Primary endpoints were investigator‐assessed ORR per the Lugano 2014 classification and safety. Tumor response was assessed by PET‐CT at weeks 6 and 12, every 9 weeks for the following 4 assessments, and every 12 weeks after the first year until disease progression. Results: 30 pts were treated with nivolumab + BV and included in this primary analysis. At baseline, median (min, max) age was 35.5 (19, 83) years, pts had received a median (min, max) of 2 (2, 5) prior systemic therapies, and 4 (13%) had received prior auto‐HCT. With a median follow‐up of 11.1 months, ORR (95% CI) was 73% (54–88), with 11 pts (37%) achieving complete remission (CR) per Lugano 2014; 13 (52%) of the 25 evaluable pts had a best reduction in target lesion of > 50% (Figure). The median duration of response has not been reached. Treatment‐related AEs (TRAEs) were reported in 25 (83%) pts. The most frequently reported TRAEs were neutropenia (30%), peripheral neuropathy (27%), peripheral sensory neuropathy, thrombocytopenia, rash, and hyperthyroidism (13% each). Grade 3–4 TRAEs were reported in 16 (53%) pts, including 9 (30%) with neutropenia, 3 (10%) each with thrombocytopenia or peripheral neuropathy, 2 (7%) with decreased neutrophil count, and 1 (3%) each with hypersensitivity, colitis, rash, maculopapular rash, or immune‐mediated hepatitis. Four pts (13%) had treatment‐related serious AEs, including 2 pts with grade 3–4 colitis, maculopapular rash, or immune‐mediated hepatitis. Summary/Conclusion: In pts with R/R PMBL, nivolumab + BV demonstrated a high investigator‐assessed ORR of 73%, with 37% CR. TRAEs were consistent with the safety profiles of nivolumab and BV treatment alone. The combination of nivolumab + BV may be synergistic and is active in pts with R/R PMBL. image

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