Benmelstobart, anlotinib and chemotherapy in extensive-stage small-cell lung cancer: a randomized phase 3 trial

Abstract

Immunochemotherapy is the first-line standard for extensive-stage small-cell lung cancer (ES-SCLC). Combining the regimen with anti-angiogenesis may improve efficacy. ETER701 was a multicenter, double-blind, randomized, placebo-controlled phase 3 trial that investigated the efficacy and safety of benmelstobart (a novel programmed death-ligand 1 (PD-L1) inhibitor) with anlotinib (a multi-target anti-angiogenic small molecule) and standard chemotherapy in treatment-naive ES-SCLC. The ETER701 trial assessed two primary endpoints: Independent Review Committee-assessed progression-free survival per RECIST 1.1 and overall survival (OS). Here the prespecified final progression-free survival and interim OS analysis is reported. Patients randomly received benmelstobart and anlotinib plus etoposide/carboplatin (EC; n = 246), placebo and anlotinib plus EC (n = 245) or double placebo plus EC ('EC alone'; n = 247), followed by matching maintenance therapy. Compared with EC alone, median OS was prolonged with benmelstobart and anlotinib plus EC (19.3 versus 11.9 months; hazard ratio 0.61; P = 0.0002), while improvement of OS was not statistically significant with anlotinib plus EC (13.3 versus 11.9 months; hazard ratio 0.86; P = 0.1723). The incidence of grade 3 or higher treatment-related adverse events was 93.1%, 94.3% and 87.0% in the benmelstobart and anlotinib plus EC, anlotinib plus EC, and EC alone groups, respectively. This study of immunochemotherapy plus multi-target anti-angiogenesis as first-line treatment achieved a median OS greater than recorded in prior randomized studies in patients with ES-SCLC. The safety profile was assessed as tolerable and manageable. Our findings suggest that the addition of anti-angiogenesis therapy to immunochemotherapy may represent an efficacious and safe approach to the management of ES-SCLC. ClinicalTrials.gov identifier: NCT04234607 .

Fig. 1. Patients disposition.

The primary reason for treatment discontinuation is shown in each treatment group, mainly including disease progression or death.

Fig. 2. OS in ITT population.

a, The Kaplan–Meier curves for OS in three treatment groups. The tick marks indicate censored data. Differences between the treatment groups were evaluated with the stratified log-rank test. P values are two-sided. b, The subgroup analysis of OS. A stratified Cox regression model was used to estimate the HR for death and 95% CIs. The circles indicate HR among subgroups of patients, the horizontal lines indicate corresponding 95% CIs and the vertical dotted line indicates the HR for the overall population. *Metastatic lesions were categorized on the basis of their presence or absence. Any patient with liver metastasis, regardless of whether it was the sole metastatic site or coexisting with other metastases, was included in the liver metastasis group for analysis. ULN, upper limit of normal; TNM, tumor, node, metastasis.

Fig. 3. PFS in ITT population.

a, The Kaplan–Meier curves for PFS in three treatment groups. The tick marks indicate censored data. PFS was assessed according to RECIST 1.1, by an independent review committee. Differences between the treatment groups were evaluated with the stratified log-rank test. P values are two-sided. b, The subgroup analysis of PFS. A stratified Cox regression model was used to estimate the HR for death and 95% CIs. The circles indicate HR among subgroups of patients, the horizontal lines indicate corresponding 95% CIs and the vertical dotted line indicates the HR for the overall population. *Metastatic lesions were categorized on the basis of their presence or absence. Any patient with liver metastasis, regardless of whether it was the sole metastatic site or coexisting with other metastases, was included in the liver metastasis group for analysis. ULN, upper limit of normal; TNM, tumor, node, metastasis.

Extended Data Fig. 1. Patient-reported outcomes of health-related quality of life.

Mixed model repeated measures change from baseline in least squares means for Benmelstobart and anlotinib plus EC, anlotinib plus EC, and EC alone in the overall population. Data are presented as mean values +/− standard deviation. At each cycle data are based on (n/N) participants where n denotes the number of participants completing a section of the questionnaire at a specific cycle and N the total number of participants reaching that cycle. Note: In the intention-to-treat population across all treatment groups, there was an overall increase in the mean change from baseline over time in EuroQol visual analogue scale (EQ-VAS) scores through week 34 (indicating improvements). But there were no significant differences in EQ-VAS scores between the study groups at each visit (P > 0.05 at all visits). Within the benmelstobart and anlotinib plus EC group, there was an improvement from baseline starting at cycle 2 (2.0 ± 12.2; P = 0.0128) through cycle 8 (4.7 ± 12.8; P < 0.0001). Within the anlotinib plus EC group, there was an improvement from baseline starting at cycle 2 (2.3 ± 11.9; P = 0.0052) through cycle 8 (3.0 ± 14.3; P = 0.0255). Within the EC group, there was an improvement from baseline starting at cycle 2 (2.6 ± 13.6; P = 0.0011) through cycle 6 (4.5 ± 12.5; P = 0.0001). EC = Etoposide/carboplatin.