Phase 1/2 Study of the CD56-Targeting Antibody-Drug Conjugate Lorvotuzumab Mertansine (IMGN901) in Combination With Carboplatin/Etoposide in Small-Cell Lung Cancer Patients With Extensive-Stage Disease

Lorvotuzumab mertansine (LM, IMGN901) is a CD56-targeting antibody-drug conjugate developed for tumor-selective delivery of the cytotoxic maytansinoid DM1. This phase 1/2 study evaluated the combination of LM with first-line carboplatin/etoposide chemotherapy in patients with extensive-disease small-cell lung cancer. Overall, modest improvements in patient tumor responses did not outweigh the increased safety risks of the triplet combination. Introduction This trial assessed the safety and efficacy of LM in combination with carboplatin/etoposide therapy compared to carboplatin/etoposide treatment alone in patients with previously untreated extensive-disease small-cell lung cancer (ED-SCLC). Patients and Methods A run-in phase 1 stage was used to determine the recommended phase 2 dose and characterize the dose-limiting toxicities of LM in combination with carboplatin/etoposide followed by LM alone in patients with CD56-positive solid tumors. In phase 2, chemotherapy-naive ED-SCLC patients were randomized 2:1 to carboplatin AUC (area under the plasma concentration vs. time curve) of 5 day 1 + etoposide 100 mg/m² days 1 to 3 plus LM (arm 1) or alone (arm 2). Results In the phase 1 study (n = 33), a dose of LM at 112 mg/m² with carboplatin/etoposide was identified as the recommended phase 2 dose. However, because of an increased incidence of peripheral neuropathy events during early phase 2, this dose was reduced to 90 mg/m². In phase 2, a total of 94 and 47 evaluable patients were assigned to arms 1 and 2, respectively. No difference in median progression-free survival was observed between arms 1 and 2 (6.2 vs. 6.7 months). The most common treatment-emergent adverse event leading to discontinuation was peripheral neuropathy (29%). A total of 21 patients had a treatment-emergent adverse event leading to death (18 in arm 1 and 3 in arm 2); for 10 individuals, this was an infection (pneumonia or sepsis) deemed to be related to the study drug. Conclusion The combination of LM plus carboplatin/etoposide did not improve efficacy over standard carboplatin/etoposide doublet therapy in ED-SCLC patients and showed increased toxicity, including a higher incidence of serious infections with fatal outcomes.