Safety and efficacy of single-agent rovalpituzumab tesirine (SC16LD6.5), a delta-like protein 3 (DLL3)-targeted antibody-drug conjugate (ADC) in recurrent or refractory small cell lung cancer (SCLC).

Abstract

LBA8505 Background: SCLC remains among the most deadly of malignancies. Rovalpituzumab tesirine is a first-in-class ADC comprised of a humanized monoclonal antibody against DLL3, a dipeptide linker, and a pyrrolobenzodiazepine (PBD) dimer toxin. DLL3 is highly expressed in neuroendocrine tumors, including approximately 80% of SCLC. The emerging results of the SCLC patients (pts) in a first-in-human study (NCT01901653) are reported here. Methods: Pts with progressive SCLC after at least 1 previous systemic therapy were eligible. Efficacy was assessed by the investigator via RECIST v1.1, and toxicity graded per CTCAE v4.03. When available, archived tumor tissue was assessed retrospectively for DLL3 expression by immunohistochemistry. Results: Seventy-four (74) pts were enrolled at dose levels ranging from 0.05 to 0.8 mg/kg at either q3w or q6w. Among evaluable pts treated at doses of 0.2-0.4 mg/kg, 15/61 (25%; 95% CI 15-37%) achieved a best response of PR or CR, and 44/61 (72%; 95% CI 59-83%) achieved clinical benefit (best response of at least SD). Among pts with available archive tissue specimens and ≥ 50% of cells expressing DLL3 (DLL3hi, an intended companion diagnostic cutoff), 12/22 (55%; 95% CI 32-76%) achieved a best response of PR or CR, and 20/22 (91%; 95% CI 71-99%) achieved clinical benefit, with a median overall survival of 8 (range 1-18+) months. In 3rd line DLL3hi pts (n = 10), where no approved therapy currently exists, the ORR and CBR were 70% and 90%, respectively, with at least 4 evaluable pts achieving OS of > 6 (8, 15, 18 and 18) months. Among responders treated at the phase 2 dose of 0.3 mg/kg, the median duration of response was 6 (range 1-8+) months. Among all SCLC pts, the most common grade 3+ toxicities considered study drug-related have included serosal effusions (14%), thrombocytopenia (12%) and skin reactions (8%). Conclusions: With manageable toxicity, rovalpituzumab tesirine demonstrates encouraging single-agent anti-tumor activity and durability in recurrent or refractory SCLC. A single-arm pivotal study in 3rd line DLL3-expressing SCLC has been initiated. Clinical trial information: NCT01901653.