DISCUSSION
relapsed/refractory lymphoma, DLTs, Cemi, PTCL, DLBCL, + lymphoma, cHL, lymphoma, prostate cancer, NHL
LUNG CANCER, CHL, NHL, LYMPHOMA, EVENTS, CYTOTOXICITY, PROSTATE CANCER
In patients with relapsed/refractory lymphoma, treatment beyond the first line remains challenging and represents a significant unmet need.The expression of CD38 in lymphoma, together with preclinical evidence for anti‐CD38 antibodies against CD38+ lymphoma, suggests potential utility for these agents in patients with CD38+ lymphoma. The anti‐CD38 antibodies, Isa, daratumumab, and MOR202 kill CD38+ lymphoma cells via antibody‐dependent cellular cytotoxicity and antibody‐dependent cellular phagocytosisSeveral studies suggest a role for CD38 in the immunomodulatory and pro‐tumoral microenvironment. CD38 is expressed in many immunosuppressive cell typesTo address whether co‐inhibition of PD‐1 and CD38 may benefit patients with lymphoma, we assessed the safety, efficacy, and pharmacokinetics of Isa + Cemi in patients with cHL, DLBCL, and PTCL. During the Phase 1 safety run‐in part of this study, no DLTs were observed during Cycle 1 and the RP2D was confirmed for Phase 2. Isa + Cemi had a manageable safety profile with no new safety signals compared with known effects of the individual drugs. Infusion‐related reactions were the most common events. Grade ≥3, Grade 5, and serious TEAEs were higher in the DLBCL and PTCL cohorts compared with the cHL cohorts. Treatment‐related TEAEs were less frequent in all cohorts.Modest clinical efficacy was observed in patients with cHL, with responses achieved in patients who had or had not previously received anti‐PD‐1/PD‐L1 therapy. However, the study was terminated in view of other more efficacious therapeutic options available for this patient population. For the DLBCL and PTCL cohorts, results of the interim efficacy analysis did not meet prespecified criteria (i.e., ≥8/17 and ≥3/11 responders in the DLBCL and PTCL cohorts, respectively) to continue enrollment in Stage 2 of Phase 2. Consequently, accrual was stopped for the DLBCL and PTCL cohorts.Most patients with DLBCL were primary refractory/bulky and discontinued within weeks from treatment initiation; in such patients, a more aggressive combination therapy may be needed. Overall, these results demonstrated that the combination was not very active in DLBCL and PTCL populations. This is consistent with limited clinical benefit of daratumumab monotherapy in Phase 2 studies with patients with relapsed/refractory B‐cell NHL subtypes and natural killer/T‐cell lymphoma.Pharmacokinetic parameters of Isa in the current study were consistent with those observed in a recent Phase 1/2 study of Isa + Cemi in patients with metastatic castration‐resistant prostate cancer or advanced non‐small cell lung cancer, where the same assay method was used, suggesting no effect of Cemi on Isa exposure (