Rovalpituzumab Tesirine Single-Agent Activity and Safety Profile Prove Positive in SCLC

Treatment with the delta-like protein 3 (DLL3)-targeted antibody-drug conjugate rovalpituzumab tesirine demonstrated single-agent activity and a manageable safety profile for patients with recurrent/refractory SCLC.

Charles M. Rudin, MD, PhD

Rovalpituzumab tesirine, a delta-like protein 3 (DLL3)—targeted antibody-drug conjugate, was studied in a phase I trial for patients with recurrent/refractory small cell lung cancer (SCLC). The treatment showed single-agent activity and a manageable safety profile, according to data presented at the 2016 ASCO Annual Meeting.

Across the dose escalation study, the objective response rate (ORR) with rovalpituzumab tesirine was 18%, with stable disease observed in an additional 50% of patients. In those with high-expression of DLL3 (n = 32), the confirmed ORR was 39% and the stable disease rate was 50%, potentially representing the first effective biomarker-directed therapy for SCLC, according to lead investigator Charles M. Rudin, MD, PhD.

"This is a new type of therapy for small cell lung cancer—an antibody-drug conjugate that is biomarker selected," said Rudin, chief of the Thoracic Oncology Service at the Memorial Sloan Kettering Cancer Center. "Importantly, this is the first biomarker-directed therapy to be defined for the treatment of SCLC, and this is a biomarker that is expressed in a large majority of SCLC, it may have a lot of utility in the management of these patients."

DLL3 is an atypical inhibitory Notch ligand that is induced by ASCL1, a key neuroendocrine transcription factor. It is expressed exclusively on cancer stem cells and tumor cells but not in normal tissue. DLL3 is expressed across multiple tumor types, including melanoma and glioblastoma multiforme.

In the open-label study, 74 patients at a median age of 61 years received rovalpituzumab tesirine at doses ranging from 0.05 to 0.8 mg/kg every 3 or 6 weeks. The majority of patients had a baseline ECOG performance status of 1 (68%), and 76% had extensive disease at presentation, with 28% having CNS metastases. Overall, 88% of patients had DLL3 expression on ≥1% of tumor cells and 67% had ≥50% expression (DLL3 high).

Patients had received 1 (53%) or 2 (47%) prior lines of therapy. The most common prior treatments were platinum/etoposide (96%) and radiation therapy (82%). Prior to entry in the study, the treatment-free interval was 4.1 months.

The primary endpoints of the study were ORR and the identification of a maximum tolerated dose, which was found to be 0.4 mg/kg. Expansion cohorts were formed to explore 0.2 mg/kg and 0.3 mg/kg every 6 weeks. Secondary endpoints focused on overall survival (OS) and progression-free survival (PFS), which was not presented at the ASCO meeting.

In the full population of the study that received rovalpituzumab tesirine at 0.2 to 0.4 mg/kg (active dose), the median OS was 4.6 months and the 1-year OS rate was 18%. In those with DLL3 high expression, the median OS was 5.8 months and the 1-year OS rate was 32%.

In the second-line setting, those with chemotherapy-sensitive disease had an ORR of 43% and a 1-year OS rate of 38%. For those with recurrent/refractory disease, the ORR was 14% and the 1-year OS rate was 19%. In the third-line setting, the ORR was 50% and the 1-year OS was 33%.

Historically, the ORR in the second-line setting for patients with treatment-sensitive SCLC is 17% and the 1-year OS rate is 27%, Rudin noted. In the third-line setting, the historic ORR is 18% and the 1-year OS is 12%.

"Impressive numbers, but with caution, these are small numbers. These data really look promising to us as a novel new class for small cell lung cancer. Responses and survival improved versus historical controls," he said. "Single-agent activity was observed in recurrent/refractory SCLC that was comparable in the second- and third-line setting."

The most common treatment-emergent adverse events (AEs) seen with rovalpituzumab tesirine were fatigue (35%), pleural effusion (31%), peripheral edema (27%), nausea (19%), hypoalbuminemia (18%), thrombocytopenia (16%), maculopapular rash (16%), and decreased appetite (16%). The most common grade ≥3 AEs were thrombocytopenia (12%), serosal effusions (11%), and skin reaction (8%).

"It has a manageable safety profile," said Rudin. "The most common severe toxicities were thrombocytopenia and serosal effusions."

Based on the improvement seen over historical data for conventional chemotherapy, further trials are planned for rovalpituzumab tesirine in DLL3-expressing tumors. A phase II single-arm study, labeled TRINITY, was formed to assess rovalpituzumab tesirine as a third-line therapy for patients with DLL3-expressing SCLC (NCT02674568). This is a potential registration study, since no third-line options are currently FDA-approved for SCLC, Rudin said.

"SCLC is a terrible disease, which is really unchanged in terms of clinically meaningful endpoints. For patients with extensive stage disease, the median survival is 9 to 10 months from the time of diagnosis, so there's really a lot of room for improvement here," he said. "These results certainly justify further clinical development. TRINITY opened in 2016 and is currently enrolling."

Rovalpituzumab tesirine was initially developed by Stemcentrx, which submitted an application for the antibody-drug conjugate to the FDA for a breakthrough therapy designation. In late April 2016, AbbVie acquired Stemcentrx for $5.8 billion. In addition to rovalpituzumab tesirine, the acquisition included 4 other therapies in development for patients with solid tumors.

Rudin CM, Pietanza MC, Bauer TM, et al. 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).J Clin Oncol.2016;34 (suppl; abstr LBA8505).