Second-line treatment with the antibody-drug conjugate (ADC) rovalpituzumab tesirine (Rova-T) resulted in inferior overall survival (OS) and higher adverse events (AEs) compared with the current standard of care, topotecan, among patients with DLL3-high small cell lung cancer (SCLC), according to results of the phase 3 TAHOE trial published in the Journal of Thoracic Oncology.
Although topotecan is the standard of care for the second-line treatment of SCLC, its associated median OS is less than 6 months. More than 80% of SCLC expresses the Notch receptor family ligand, DLL3, and is a potential target for treatment. The aim of this study was to evaluate an antibody-drug conjugate that targets DLL3 and delivers a toxic DNA crosslinking agent.
The open-label, phase 3 TAHOE trial (ClinicalTrials.gov Identifier: NCT03061812) randomly assigned 444 patients with previously treated, DLL3-high advanced or metastatic SCLC in a 2:1 fashion to Rova-T or topotecan. The primary endpoint was OS, and secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and duration of response (DOR). All tumors had at least 75% staining for DLL3 by immunohistochemistry.
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At baseline, the median age was 64 years, 62% of patients were men, and the majority of patients had an Eastern Cooperative Oncology Group performance status of 0 or 1. Extensive disease was identified among 77% of patients, and 53% of patients developed progressive disease to first-line platinum-based chemotherapy. Lactate dehydrogenase level was found to be higher than the upper limit of normal among 50% of patients.
Rova-T resulted in an inferior OS compared with topotecan. The median OS was 6.3 months with Rova-T compared with 8.6 months (hazard ratio [HR], 1.46; 95% CI, 1.17-1.82) with topotecan during a median follow-up of 8.3 months. PFS was also shorter with Rova-T, with a median of 3.0 months compared with 4.3 months with topotecan (HR, 1.51; 95% CI, 1.22-1.87).
The ORR was lower with Rova-T at 15% compared with 21% with topotecan. The median DOR was 3.5 and 4.9 months with Rova-T and topotecan, respectively.
Grade 3 to 4 treatment-emergent adverse events (TEAEs) occurred among 42% of patients who received Rova-T and 66% of patients who received topotecan. TEAEs of special interest occurred more frequently with Rova-T, including cutaneous reactions (39% vs 12%), edema (30% vs 10%), pleural effusion (29% vs 4%), pericardial effusion (20% vs 2%), and photosensitivity reaction (16% vs 0%). Grade 5 TEAEs occurred among 22% of patients in both groups.
The authors concluded that “TAHOE joins several setbacks in second-line therapy.” They added that “albeit disappointing, improvements in the understanding of SCLC gained in these trials may contribute to eventual breakthroughs in the treatment of SCLC.”
Reference
Blackhall F, Jao K, Greillier L, et al. Efficacy and safety of rovalpituzumab tesirine compared with topotecan as second-line therapy in DLL3-high small cell lung cancer: results from the phase 3 TAHOE study. J Thor Oncol. Published online February 16, 2021. doi:10.1016/j.jtho.2021.02.009
