Nivolumab Combined With Brentuximab Vedotin for Relapsed/Refractory Primary Mediastinal Large B-Cell Lymphoma: Efficacy and Safety From the Phase II CheckMate 436 Study

Abstract

PURPOSE Primary mediastinal B-cell lymphoma (PMBL) is a rare but aggressive non-Hodgkin lymphoma with poor outcomes in patients with relapsed/refractory (R/R) disease. PMBL is characterized by high expression of programmed death-1 ligand and variable expression of CD30. Nivolumab, an anti–programmed death-1 immune checkpoint inhibitor, and brentuximab vedotin (BV), an anti-CD30 antibody–drug conjugate, may have synergistic activity in R/R PMBL. METHODS The expansion cohort of the open-label, phase I/II CheckMate 436 study enrolled patients with confirmed R/R PMBL who were previously treated with either autologous hematopoietic cell transplantation or two or more prior chemotherapy regimens if ineligible for autologous hematopoietic cell transplantation. Patients received nivolumab (240 mg intravenously) and BV (1.8 mg/kg intravenously) every 3 weeks until disease progression or unacceptable toxicity. Primary end points were investigator-assessed objective response rate (ORR) per the Lugano 2014 criteria and safety. RESULTS Thirty patients with PMBL were treated and evaluable. At a median follow-up of 11.1 months, ORR (95% CI) was 73% (54% to 88%), with a 37% complete remission rate per investigator, and ORR of 70% (51% to 85%), with a 43% complete metabolic response rate per independent review. Median duration of response, median progression-free survival, and median overall survival have not been reached. Eleven responders had consolidation with autologous (n = 5) or allogeneic (n = 6) transplantation. Treatment-related adverse events were reported in 25 patients (83%). Sixteen patients (53%) had grade 3 to 4 treatment-related adverse events; the most common were neutropenia (n = 9), thrombocytopenia (n = 3), and peripheral neuropathy (n = 3). There were no treatment-related deaths. CONCLUSION In patients with R/R PMBL, the combination of nivolumab plus BV represents a promising option, with high antitumor activity and a manageable safety profile.

The Many Facets of CD38 in Lymphoma: From Tumor–Microenvironment Cell Interactions to Acquired Resistance to Immunotherapy

“…Furthermore, they also demonstrated that CD38 knock out tumors exhibit delayed growth when compared to CD38 + wild-type tumors in wild-type mice and that in tumor-bearing mice, combination of anti-CD38 antibody and anti-PDL-1 acts synergistically to suppress tumor growth and dissemination. These findings support the use of this combination in the clinical setting in the attempt to overcome resistance to checkpoint blockade, especially in those tumors where PD-1/PDL-1 inhibitors are especially effective, such as r/r cHL or primary mediastinal B-cell lymphoma (PMBCL) [94][95][96][97]. So far, this combination has been investigated in MM, where patient recruitment has been completed and final results are being elaborated (clinicaltrials.gov), and is currently being tested in HL/NHL (Table 1).…”

Patient Case Studies and Panel Discussion: Lymphoma

“…14 Furthermore, combination brentuximab vedotin 1 nivolumab showed even more robust activity, with an overall response rate of 73%. 15 The patient in this case study received 5 cycles of pembrolizumab, and PET/CT scans showed a complete metabolic response.…”

Effectiveness of chemotherapy after anti‐PD‐1 blockade failure for relapsed and refractory Hodgkin lymphoma

“…Therefore, the attention is now focusing on how improving the response and on overcoming the resistance to CPis. Based on a rationale that DNA damaging agents are able to promote immunogenicity of cancer cells trough increasing neo‐antigen repertoire, inducing immunogenic cell death and changing the cytokine milieu into the tumor microenvironment, with a consequence redistribution and increase expression of PDL‐1 on tumor cells, good results are being achieved combining PD1 inhibitors with chemotherapy, both in solid tumors and in lymphomas setting 20‐24 . On the other side, patients who already failed anti‐PD1 therapy, seems to benefit from a re‐treatment with conventional CHT, leading to the idea that PD1 inhibitors can re‐sensitize tumor cells to conventional treatment, previously failed 12,13 .…”