Anlotinib Combo Improves PFS/OS in Extensive-Stage Small Cell Lung Cancer

"This [network meta-analysis] demonstrated for the first time that [anlotinib/benmelstobart plus chemotherapy] is the most efficacious regimen for extending survival in ES-SCLC, highlighting its potential as a preferred first-line treatment option for this patient population," according to the study authors.

Combining anlotinib and benmelstobart with chemotherapy significantly prolonged progression-free survival (PFS) and overall survival (OS) among patients with extensive-stage small cell lung cancer (ES-SCLC) across randomized clinical trials, according to findings from a network meta-analysis published in Translational Lung Cancer Research.1

Across 12 randomized clinical trials assessing 6178 patients with ES-SCLC, most immunotherapy-based regimens significantly improved PFS vs chemotherapy alone, especially anlotinib/benmelstobart plus chemotherapy (HR, 0.32; 95% CI, 0.25-0.40). Of note, tislelizumab-jsgr (Tevimbra) plus chemotherapy showed superior PFS outcomes vs durvalumab (Imfinzi) in combination with tremelimumab (Imjudo) and chemotherapy (HR, 0.75; 95% CI, 0.57-0.99).

Most immunotherapy-containing regimens also significantly improved OS vs chemotherapy alone, with investigators noting a prominent benefit with anlotinib/benmelstobart plus chemotherapy (HR, 0.61; 95% CI, 0.47-0.80). Additionally, the anlotinib combination demonstrated superior OS relative to nivolumab (Opdivo) plus ipilimumab (Yervoy) and chemotherapy (HR, 0.68; 95% CI, 0.49-0.95) and ipilimumab/chemotherapy (HR, 0.65; 95% CI, 0.48-0.88).

Objective response rate (ORR) data were available for 11 trials assessing 5691 patients; most immunotherapy-based regimens improved responses vs chemotherapy alone. Additionally, anlotinib/benmelstobart plus chemotherapy improved ORRs vs other immunotherapeutic combinations, which included adebrelimab (KN035) plus chemotherapy (OR, 1.76; 95% CI, 1.0-3.14), concurrent ipilimumab plus chemotherapy (OR, 2.61; 95% CI, 1.02-6.76), and atezolizumab (Tecentriq) plus chemotherapy (OR, 2.6; 95% CI, 1.46-4.66).

Bayesian ranking probabilities demonstrated that the likelihood of anlotinib/benmelstobart plus chemotherapy ranking first was the highest across all regimens in terms of PFS (98.9%), OS (41.4%), or ORR (23.5%). Chemotherapy alone had the highest probability of ranking lowest for PFS (82.1%) and OS (32.1%). Of note, serplulimab/chemotherapy had the highest likelihood of ranking the second best in terms of PFS (78.6%) and OS (27.7%).

“To the best of our knowledge, our study is currently the [network meta-analysis] that incorporates the most comprehensive [randomized clinical trials] involving immunotherapy for ES-SCLC. This [network meta-analysis] demonstrated for the first time that [anlotinib/benmelstobart plus chemotherapy] is the most efficacious regimen for extending survival in ES-SCLC, highlighting its potential as a preferred first-line treatment option for this patient population,” lead study author Wengang Zhang, from the Department of Medical Oncology at Shanghai Pulmonary Hospital, School of Medicine, of Tongji University in Shanghai, China, wrote with coauthors.1 “[T]he use of immunotherapy in conjunction with chemotherapy, despite its benefits, can result in the development of resistance, which is a persistent challenge for achieving sustained long-term survival. Enhancing long-term survival rates in this context continues to be an area where further advancements are required.”2

Investigators conducted a literature search across PubMed, Embase, Cochrane Library databases, and international conferences for relevant ES-SCLC trials published up to December 28, 2023. The analysis included phase 2 or 3 randomized clinical trials that evaluated patients with newly diagnosed treatment-naïve ES-SCLC and assessed immunotherapy-based combinations in the frontline therapy setting. Eligible studies also included PFS, OS, ORR, and grade 3 or higher adverse effects (AEs) as end points.

The 12 studies ultimately included in the network meta-analysis, as well as their interventional regimens, included the following:

• Tislelizumab plus carboplatin/etoposide in the phase 3 RATIONALE-312 trial (NCT0400571);
• Toripalimab-tpzi (Loqtorzi) plus etoposide and cisplatin/carboplatin in the phase 3 EXTENTORCH trial (NCT04012606);
• Benmelstobart plus anlotinib, etoposide, and cisplatin/carboplatin in the phase 3 ETER701 trial;
• Adebrelimab plus carboplatin and etoposide in the phase 3 CAPSTONE-1 trial (NCT03711305);
• Serplulimab plus carboplatin and etoposide in the phase 3 ASTRUM-005 trial (NCT04063163);
• Nivolumab/ipilimumab plus chemotherapy in the phase 3 CheckMate-451 trial (NCT02538666);
• Pembrolizumab (Keytruda) plus carboplatin/etoposide in the phase 3 KEYNOTE-604 trial (NCT03066778);
• Nivolumab plus etoposide and cisplatin/carboplatin in the phase 2 ECOG-ACRIN EA5161 trial (NCT03382561);
• Durvalumab with or without tremelimumab plus carboplatin/cisplatin and etoposide in the phase 3 CASPIAN trial (NCT03043872);
• Atezolizumab plus carboplatin and etoposide in the phase 3 Impower133 trial (NCT02763579);
• Ipilimumab plus carboplatin and etoposide in the phase 3 CA184-156 trial (NCT01450761);
• Concurrent or phased ipilimumab plus paclitaxel and carboplatin in the phase 2 CA184-041 trial (NCT00527735).

Relative to chemotherapy alone, grade 3 or higher AEs were more likely with anlotinib/benmelstobart plus chemotherapy (OR, 2.03. 95% CI, 1.11-3.86), nivolumab/chemotherapy (OR, 1.73; 95% CI, 1.12-2.7), phased ipilimumab plus chemotherapy (OR, 2.43; 95% CI, 1.0-6.07), nivolumab/ipilimumab plus chemotherapy (OR, 13.52; 95% CI, 8.66-21.63), and durvalumab/tremelimumab plus chemotherapy (OR, 1.51; 95% CI, 1.04-2.2). Anlotinib/benmelstobart plus chemotherapy did not significantly increase the likelihood of grade 3 or higher toxicities compared with other immunotherapeutic combinations apart from tislelizumab/chemotherapy (OR, 2.36; 95% CI, 1.01-5.69) and durvalumab/chemotherapy (OR, 2.08; 95% CI, 1.03-4.33).

References

1. Zhang W, Zhao W, Zhang X, et al. Efficacy and safety of first-line immunotherapy-based regimens for patients with extensive-stage small cell lung cancer: a systematic review and network meta-analysis. Transl Lung Cancer Res. 2025;14(1):163-175. doi:10.21037/tlcr-24-636.
2. Petty WJ, Paz-Ares L. Emerging strategies for the treatment of small cell lung cancer: a review. JAMA Oncol. 2023;9(3):419-429. doi:10.1001/jamaoncol.2022.5631.