Phase III Trial Shows Novel Four-Drug Regimen Improves Survival Outcomes in Extensive-Stage Small Cell Lung Cancer

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The addition of anlotinib to immunochemotherapy has achieved the historically longest progression-free survival and overall survival in the first-line setting of extensive-stage small cell lung cancer, according to data presented at the International Association for the Study of Lung Cancer 2023 World Conference on Lung Cancer.1

The results of the phase III ETER701 trial showed that patients who were randomly assigned to receive the antiangiogenic agent anlotinib and the novel PD-1 inhibitor benmelstobart plus chemotherapy experienced a 7.4-month improvement in overall survival over chemotherapy alone (19.3 months vs 11.9 months; P = .0002). Treatment with the novel four-drug regimen was also associated with a significant improvement in progression-free survival vs chemotherapy alone (6.9 months vs 4.2 months; P < .0001), exceeding 6 months for the first time in this patient population.

“Compared with chemotherapy [alone], these data confirm that our novel four-drug regimen significantly improved overall survival and progression-free survival with measurable safety in extensive-stage small cell lung cancer,” said lead study author Ying Cheng, MD, Professor of Medical Thoracic Oncology, Jilin Cancer Hospital, Changchun, China. “This study supports the use of immunochemotherapy plus chemotherapy and the antiangiogenic anlotinib as a new first-line option for this patient population.”

“Treatment with the four-drug regimen [benmelstobart with anlotinib plus etoposide and carboplatin] reduced the risk of death by 39% [in extensive-stage small cell lung cancer].”

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Small cell lung cancer remains a recalcitrant malignancy. Although immunochemotherapy has shown promise with a 2-month overall survival benefit in extensive-stage small cell lung cancer, said Dr. Cheng, improving long-term survival is an unmet need.

According to Dr. Cheng, the limited benefits seen with current treatment approaches might be attributable to the complicated microenvironment of small cell lung cancer, which is characterized by immunosuppression, angiogenesis, and vascularization. Tumor microenvironment reprogramming and tumor vessel normalization may promote immune cell infiltration, obtaining synergistic effects with immunotherapy, she explained.

ETER701 Design

To deal with the complexity and heterogeneity of the small cell lung cancer microenvironment, Dr. Cheng and colleagues combined benmelstobart with anlotinib, plus standard chemotherapy (etoposide plus carboplatin). ETER701 was a multicenter, placebo-controlled, randomized phase III trial in the first-line setting. Investigators randomly assigned patients to receive four cycles (21-day cycle) of benmelstobart and anlotinib, or placebo, and the etoposide/carboplatin regimen, followed by benmelstobart plus anlotinib, anlotinib, or placebo as maintenance therapy until disease progression or toxicity intolerance.

The study’s primary endpoints were overall survival and independent review committee–assessed progression-free survival in the intention-to-treat population.

Survival Outcomes and Toxicity

Between March 18, 2021, and December 18, 2021, investigators enrolled 738 patients from 72 participating centers in China; of these patients, 246 were assigned to receive benmelstobart and anlotinib plus chemotherapy, and 247 were assigned to receive placebo plus chemotherapy. As of the cutoff date (May 14, 2022), the median follow-up was 14.0 months.

According to Dr. Cheng, the study results showed significant benefits with the four-drug regimen compared with chemotherapy alone as first-line therapy in extensive-stage small cell lung cancer. Median progression-free survival in the experimental arm exceeded 6 months for the first time (6.9 months vs 4.2 months; HR = 0.32; P < .0001), and median overall survival increased by 7.4 months (19.3 months vs 11.9 months; HR = 0.61; P = .0002).


  • The novel PD-1 inhibitor benmelstobart with the antiangiogenic agent anlotinib plus chemotherapy (etoposide and carboplatin) in the first-line setting resulted in the historically longest overall survival in extensive-stage small cell lung cancer, with a 7.4-month improvement over chemotherapy alone (P = .0002).
  • The median progression-free survival of the combination therapy also exceeded 6 months for the first time (P < .0001).
  • The ETER701 trial data are still immature, however, with a median follow-up of just 14 months.

“Treatment with the four-drug regimen [benmelstobart with anlotinib plus etoposide and carboplatin] reduced the risk of death by 39%,” said Dr. Cheng. She noted that 41.8% of patients who received the experimental combination were alive at 2 years vs 24.2% of those who received chemotherapy alone. The objective response rate also improved from 66.8% with chemotherapy alone to 81.3% with the experimental regimen. The duration of response improved from 3.1 months to 5.8 months, respectively.

The incidence of any-grade or grade ≥ 3 treatment-related adverse events was similar in both arms, Dr. Cheng reported. The most common treatment-related adverse events were decreased neutrophil count, decreased platelet count, and decreased white blood cell count in both arms.

In patients who received the four-drug regimen, the incidence of any-grade immune-related adverse events was 42.7%, and grade 3 or higher immune-related adverse events occurred in 16.7% of patients in the experimental arm. Treatment-related adverse events led to death in 4.5% of patients who received the four-drug regimen vs 1.6% of patients randomly assigned to receive chemotherapy alone. Dr. Cheng called the safety profile of the four-drug regimen manageable. 

DISCLOSURE: Dr. Cheng reported no conflicts of interest.


1. Cheng Y, Yang R, Chen J, et al: Benmelstobart with anlotinib plus chemotherapy as first-line therapy for ES-SCLC: A randomized, double-blind, phase III trial. 2023 World Conference on Lung Cancer. Abstract OA01.03. Presented September 10, 2023.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.

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Abstract discussant Noemí Reguart, MD, PhD, an oncologist at the Hospital Clinic Barcelona, underscored the “impressive” progression-free and overall survival results of the phase III ETER701 trial, which have “never been achieved before in extensive-stage small cell lung cancer.”

Noemí Reguart, MD, PhD