Novel Combination Study Planned for SCLC

Scott J. Dylla, PhD

A phase I/II study will explore the delta-like protein 3 (DLL3)-targeted antibody-drug conjugate rovalpituzumab tesirine (Rova-T) with the PD-1 inhibitor nivolumab (Opdivo) alone or in combination with the CTLA-4 inhibitor ipilimumab (Yervoy) for patients with relapsed extensive-stage small cell lung cancer (SCLC).

AbbVie, the developer of rovalpituzumab tesirine, and Bristol-Myers Squibb, the company marketing nivolumab and ipilimumab announced the phase I/II study in a joint press release. As single-agents, rovalpituzumab tesirine and nivolumab have each demonstrated promising early findings for patients with SCLC. Additionally, nivolumab plus ipilimumab sparked promising response rates and overall survival (OS) findings. Data for the 3 agents were recently presented at the 2016 ASCO Annual Meeting.^1,2

“We believe the combination of these cancer-fighting agents may offer patients a new treatment option in a disease with limited therapies,” Scott J. Dylla, PhD, vice president, research and development, AbbVie, said in a statement. “By combining immune-checkpoint inhibitors that prime the body’s immune system to fight cancer cells with Rova-T’s approach to target cancer stem cells, we hope to build on our goal to develop differentiated treatments with therapeutic benefit that elevate the standard of care for small cell lung cancer 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 an open-label study,¹ 74 patients with SCLC 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. 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.

Across all doses in the 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 the DLL3 (n = 32), the confirmed ORR was 39% and the stable disease rate was 50%.

In those receiving 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%.

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%).

"This is a new type of therapy for small cell lung cancer—an antibody-drug conjugate that is biomarker selected," said lead investigator Charles M. Rudin, MD, PhD, chief of the Thoracic Oncology Service at the Memorial Sloan Kettering Cancer Center, when he presented the findings at ASCO. "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."

Impressive findings were also shown for the combination of nivolumab and ipilimumab, which elicited a 1-year OS rate of 43% as a treatment for patients with recurrent SCLC in the CheckMate-032 study.2 This study randomized 216 patients with progressive SCLC following ≥1 prior line of therapy to receive single-agent nivolumab or the combination of nivolumab and ipilimumab at one of two doses.

In the monotherapy arm, 98 patients received nivolumab at 3 mg/kg every 2 weeks. In the combination arms, patients received nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg every 3 weeks (N1/I3; n = 61) or nivolumab at 3 mg/kg and ipilimumab at 1 mg/kg every 3 weeks (N3/I1; n = 54). After 4 cycles, those in the combination arm went on to receive nivolumab monotherapy at 3 mg/kg every 2 weeks.

The median OS in the monotherapy arm was 4.4 months and the 1-year OS rate was 33%. In the N3/I1 group, the median OS was 6.0 months and the 1-year OS rate was 35%. In the N1/I3 arm, median OS was 7.7 months and the 1-year OS was 43%. The median PFS was 1.4, 1.4, and 2.6 months, in the single-agent, N3/I1, and N1/I3 arms, respectively. The ORR in the single-agent nivolumab arm was 10% and the ORRs were 23% and 19% in the N1/I3 and N3/I1 arms, respectively.

AEs were more common in the combination arms versus the single-agent. All-grade AEs were experienced by 53% of those in the monotherapy arm, with a grade 3/4 AE rate of 13%. In the N3/I1 and N1/I3 arms, 74% and 79% of patients experienced AEs of any grade, respectively. Grade 3/4 AEs occurred in 19% and 30% of patients, in the N3/I1 and N1/I3 groups, respectively.

“We are excited to explore the potential benefits of combining Bristol-Myers Squibb’s immunotherapies with a targeted approach like Rova-T in small cell lung cancer where the need for new therapies is particularly acute for this aggressive form of lung cancer,” Jean Viallet, MD, global clinical research lead, Oncology, Bristol-Myers Squibb, said in a statement. “As the science around cancer research continues to rapidly evolve, we are building on our leadership in Immuno-Oncology with numerous collaborations that may help advance new therapies for cancers in need of better options.”

The phase I/II study combining the combination of rovalpituzumab tesirine and nivolumab and/or ipilimumab is expected to begin patient enrollment in 2016. The study will focus on safety and the efficacy of the combination.

In addition to the combination study, 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). Additionally, two phase III studies are assessing nivolumab and ipilimumab as treatments for patients with SCLC (NCT02481830, NCT02538666).

References

1. 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).
2. Antonia SJ, Lopez-Martin JA, Bendell JC, et al. Checkmate 032: Nivolumab (N) alone or in combination with ipilimumab (I) for the treatment of recurrent small cell lung cancer (SCLC). J Clin Oncol. 2016;34 (suppl; abstr 100).