Efficacy and Safety of Rovalpituzumab Tesirine Compared With Topotecan as Second-Line Therapy in DLL3-High SCLC: Results From the Phase 3 TAHOE Study

Abstract

Introduction: DLL3, an atypical Notch ligand, is expressed in SCLC tumors but is not detectable in normal adult tissues. Rovalpituzumab tesirine (Rova-T) is an antibody-drug conjugate containing a DLL3targeting antibody tethered to a cytotoxic agent pyrrolobenzodiazepine by means of a protease-cleavable linker. The efficacy and safety of Rova-T compared with topotecan as second-line therapy in patients with SCLC expressing high levels of DLL3 (DLL3-high) was evaluated.Methods: The TAHOE study was an open-label, two-to-one randomized, phase 3 study comparing Rova-T with topotecan as second-line therapy in DLL3-high advanced or metastatic SCLC. Rova-T (0.3 mg/kg) was administered intravenously on day 1 of a 42-day cycle for two cycles, with two additional cycles available to patients who met protocol-defined criteria for continued dosing. Topotecan (1.5 mg/m 2 ) was administered intravenously on days 1 to 5 of a 21-day cycle. The primary end point was overall survival (OS).Results: Patients randomized to Rova-T (n ¼ 296) and topotecan (n ¼ 148) were included in the efficacy analyses. The median age was 64 years, and 77% had the extensive disease at initial diagnosis. The median OS (95% confidence interval) was 6.3 months (5.6-7.3) in the Rova-T arm and 8.6 months (7.7-10.1) in the topotecan arm (hazard ratio, 1.46 [95% confidence interval: 1.17-1.82]). An independent data monitoring committee recommended that enrollment be discontinued because of the shorter OS observed with Rova-T compared with topotecan. Safety profiles for both drugs were consistent with previous reports.Conclusions: Compared with topotecan, which is the current standard second-line chemotherapy, Rova-T exhibited an inferior OS and higher rates of serosal effusions, photosensitivity reaction, and peripheral edema in patients with SCLC. A considerable unmet therapeutic need remains in this population.

Recent developments in the treatment of small cell lung cancer

“…As a result of this, the product was withdrawn and ongoing studies TAHOE (versus topotecan) and MERU (maintenance after chemotherapy) closed prematurely [103,104].…”

Targeting cancer with antibody-drug conjugates: Promises and challenges

“…88,89 Ultimately, the results of the phase III trials, TAHOE (NCT03061812) and MERU (NCT03033511), in which a lack of survival benefit over the control arm was observed, led to the complete discontinuation of the development of Rova-T by AbbVie. 90 Further challenges in the development of ADCs as therapeutic agents involve toxicities that can be attributed to constituents of the ADC product. Such events have been investigated, mainly focusing on different adverse effects that can be attributed to specific payloads.…”

Delta‐like canonical Notch ligand 3 as a potential therapeutic target in malignancies: A brief overview

“…Two randomized phase III studies, the TAHOE and MERU studies, were also carried out. The TAHOE study was an open‐label, two‐to‐one randomized study comparing ROVA‐T with topotecan, the second‐line standard treatment for DLL3‐high SCLC with first disease progression during or after first‐line platinum‐based chemotherapy 19 . The primary end‐point was OS.…”

“…The primary end‐point was OS. The median OS of the ROVA‐T group was 6.3 months (95% CI, 5.6‐7.3), and that of the topotecan group was 8.6 months (95% CI, 7.7‐10.1) 19 . The median PFS of the ROVA‐T group (3.0 months; 95% CI, 2.9‐3.6) was also inferior to that of the topotecan group (4.3 months; 95% CI, 3.8‐5.4), ORR was 15% in the ROVA‐T group compared to 21% in the topotecan group, and the median DOR was 3.5 months (95% CI, 2.8‐4.2) in the ROVA‐T treatment group, compared to 4.9 months with topotecan (95% CI, 3.9‐7.9).…”

“…The median PFS of the ROVA‐T group (3.0 months; 95% CI, 2.9‐3.6) was also inferior to that of the topotecan group (4.3 months; 95% CI, 3.8‐5.4), ORR was 15% in the ROVA‐T group compared to 21% in the topotecan group, and the median DOR was 3.5 months (95% CI, 2.8‐4.2) in the ROVA‐T treatment group, compared to 4.9 months with topotecan (95% CI, 3.9‐7.9). Based on these results, enrollment in the TAHOE study was discontinued 19 . The primary purpose of the MERU study was to evaluate the effect of ROVA‐T, given as maintenance therapy following first‐line chemotherapy compared to the placebo; the results could not meet their primary objective.…”