Findings from a multicenter, placebo-controlled, randomized Phase III trial showed the combination of benmelstobart, anlotinib, and chemotherapy significantly improved survival among patients with extensive-stage small cell lung cancer (SCLC) when compared with placebo plus etoposide/carboplatin. These results, which were recently presented during the during the International Association for the Study of Lung Cancer (IASLC) World Conference on Lung Cancer 2023 in Singapore, also demonstrated that the safety profile of this regimen is tolerable and manageable.
SCLC is a recalcitrant malignancy, according to study author Ying Cheng, MD, Professor in the Department of Thoracic Oncology at Jilin Province Cancer Hospital in Changchun, China. She noted that, although immunochemotherapy has shown promise with 2-4 month overall survival benefits in extensive-stage SCLC, improvement of long-term survival remains an unmet need.
"The limited benefit might attribute to the complicated SCLC microenvironment, which is characterized by immunosuppression, angiogenesis, and vascularization," Cheng said. "Based on the complexity and heterogeneity of the SCLC microenvironment, we made an advanced design combining the novel PD-L1 inhibitor, benmelstobart, with an antivascular agent, anlotinib, plus standard chemotherapy to improve efficacy, survival, and safety in extensive-stage SCLC."
Study Details
In this clinical trial, patients were randomized 1:1:1 to receive 4 cycles (21-day cycle) of benmelstobart, anlotinib, or placebo combined with etoposide/carboplatin chemotherapy. This was then followed by maintenance therapy of benmelstobart plus anlotinib, anlotinib alone, or placebo until disease progression or toxicity intolerance.
Eligible patients were ages 18-75 who had a pathologically confirmed diagnoses of extensive-stage SCLC. Additional eligibility criteria included no prior systemic therapy, measurable lesion (RECIST 1.1), ECOG performance status of 0 or 1, and adequate organ function. Asymptomatic or treated and stable brain metastases were also permitted. The primary endpoints were overall survival and progression-free survival assessed by an independent review committee in the intention-to-treat population.
From March 18, 2021, to December 18, 2021, Cheng and colleagues enrolled 738 patients from 72 participating centers in China. Of those, 246 received benmelstobart plus anlotinib plus etoposide/carboplatin, 245 placebo plus anlotinib plus etoposide/carboplatin, and 247 placebo plus placebo plus etoposide/carboplatin. As of the data cutoff of May 14, 2022, the median follow-up was 14 months. The researchers discussed the findings from the benmelstobart plus anlotinib plus chemotherapy versus placebo plus chemotherapy arms.
Data showed that the benmelstobart regimen had significant benefits over placebo plus chemotherapy with a median progression-free survival of 6.93 months versus 4.21 months, median overall survival of 19.32 months versus 11.89 months, objective response rate of 81.3 percent versus 66.8 percent, and duration of response of 5.8 months versus 3.1 months. Cheng reported that the 6-month and 12-month progression-free survival rates were 59.11 percent and 27.91 percent, respectively, among patients who received benmelstobart compared with 16.55 percent and 2.29 percent in their placebo counterparts.
Additionally, she noted during her presentation that the 12-month and 24-month overall survival rates for the benmelstobart combination were 64.12 percent and 41.83 percent, respectively, versus 49.00 percent and 24.24 percent for the placebo arm.
This analysis showed that the safety profile of benmelstobart, anlotinib, and chemotherapy was manageable, according to Cheng. Any grade and Grade >=3 treatment-related adverse events were reported in 100 percent and 93.1 percent of patients in the benmelstobart cohort, respectively.
Common treatment-related adverse events included the following: decreased neutrophil count, decreased platelet count, and decreased white blood cell count. Among patients who received benmelstobart, any-grade treatment-related adverse events led to a dose reduction or interruption in 50.4 percent, any discontinuation in 8.5 percent, and death in 4.5 percent.
Cheng and colleagues observed any-grade immune-related adverse events in 42.7 percent of patients treated with the benmelstobart regimen compared with 19.1 percent of those who received placebo plus chemotherapy. Grade 3 or higher immune-related adverse events were reported in 16.7 percent of patients in the benmelstobart group and 6.9 percent of in the placebo group. Immune-related adverse events resulted in dose reduction, discontinuation, or death in 6.5 percent, 8.1 percent, and 2.0 percent of patients who underwent treatment with benmelstobart, anlotinib, and chemotherapy, respectively.
"These results from the Phase III trial are extremely encouraging, as the combination of benmelstobart, anlotinib, and chemotherapy achieved historically long overall survival and progression-free survival in extensive-stage small cell lung cancer," Cheng concluded in a statement. "This treatment approach demonstrates a significant survival extension over chemotherapy alone and provides a tolerable safety profile."
Catlin Nalley is a contributing writer.