Benmelstobart plus anlotinib and chemotherapy as first-line treatment for extensive-stage SCLC

For patients with extensive-stage small-cell lung cancer (ES-SCLC), improving long-term survival remains an unmet need. Results of a Chinese phase III trial now demonstrate that the combination of benmelstobart (a novel developed PD-L1 inhibitor), anlotinib (an anti-vascular agent) and chemotherapy results in significant benefits compared to placebo and chemotherapy in terms of median progression-free survival and overall survival in this difficult to treat patient population.

Despite the promise of immunotherapy, ES-SCLC remains a challenging malignancy to treat, with limited long-term survival benefits. The limited benefit might be attributed to the complex SCLC microenvironment that is characterised by immunosuppression, angiogenesis and vascularisation. In an attempt to circumvent these obstacles, a study was developed to reprogram the tumour microenvironment and promote immune cell infiltration by combining benmelstobart (a novel developed PD-L1 inhibitor) and anlotinib (an anti-vascular agent) with standard chemotherapy.

Study design

The study was a multicentre, placebo-controlled, randomised phase III trial in first-line ES-SCLC. Patients were randomly assigned in a 1:1:1 ratio to receive 4 cycles (21-day cycle) of benmelstobart plus anlotinib, anlotinib or placebo in combination with etoposide/carboplatin (EC). This regimen was followed by maintenance with respectively benmelstobart plus anlotinib, anlotinib alone, or placebo until disease progression or unacceptable toxicity. Primary endpoints were overall survival (OS) and independent review committee (IRC)-assessed progression-free survival (PFS) in the intention-to-treat (ITT) population. At WCLC, Prof. Cheng reported the data of benmelstobart plus anlotinib plus EC versus placebo plus EC.

Results

The trial enrolled a total of 738 patients, from 72 participating centres in China. Of them, 246 patients were assigned to benmelstobart, anlotinib and chemotherapy, and 247 patients were assigned to placebo and chemotherapy. Median follow-up was 14.0 months. Median PFS was 6.93 months for patients in the benmelstobart plus anlotinib and EC arm and 4.21 months for patients in the placebo plus EC arm, resulting in a 68% reduction in the risk of disease progression or death (HR[95%CI]: 0.32[0.26-0.41], p< 0.0001). In addition, median OS was significantly longer for patients receiving benmelstobart and anlotinib, as compared to those in the placebo arm (19.32 vs. 11.89 months, HR[95%CI]: 0.61[0.46-0.79], p= 0.0002). The combination of benmelstobart, anlotinib and chemotherapy also demonstrated significant benefits compared to placebo and chemotherapy in terms of objective response rate (81.3% vs. 66.8%, p= 0.0001) and median duration of response (5.8 vs. 3.1 months, p< 0.0001).

The safety profile of the benmelstobart, anlotinib, and chemotherapy regimen was manageable and tolerable, with grade ≥3 treatment-related adverse events reported in 93.1% of patients in the treatment arm (vs. 87.0% in the placebo arm). The most common grade ≥3 treatment-related adverse events included decreased neutrophil count (69.5%), decreased platelet count (49.6%), and decreased white blood cell count (38.2%). Immune-related adverse events of grade ≥3 were reported in 16.7% of patients.

Conclusion

The addition of an anti-angiogenic agent to immunochemotherapy in the first-line treatment of ES-SCLC resulted in the historically longest PFS and OS, supporting the use of immunochemotherapy plus anlotinib as a new treatment option for this patient population. In addition, the safety profile of the combination is tolerable and manageable.

Reference

Cheng Y, et al. Benmelstobart with Anlotinib plus Chemotherapy as First-line Therapy for ES-SCLC: A Randomized, Double-blind, Phase III Trial. Presented at WCLC 2023; Abstract OA01.