A New Standard of Care for Small Cell Lung Cancer?


Antibody-based DLL3-targeting agents and antibody-drug conjugates present exciting treatment possibilities in small cell lung cancer, according to a presentation by Charles Rudin, MD, at the 18th Annual New York Lung Cancer Symposium.

3D rendered illustration of lung cancer: ©appledesign - stock.adobe.com

3D rendered illustration of lung cancer: ©appledesign - stock.adobe.com

Antibody-based DLL3-targeted therapies and antibody-drug conjugates (ADCs) are potentially promising treatment options for patients with small cell lung cancer (SCLC), according to Charles Rudin, MD, PhD, chief, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, who presented on the topic at the 18th Annual New York Lung Cancer Symposium held on November 11, 2023, in New York, New York.1

Although anti–PD-(L)1 antibodies have changed the standard of care in several cancer types, this is not the case for SCLC. Rudin highlighted the phase 3 IMpower133 (NCT02763579) and CASPIAN (NCT03043872) trials.

Three-year survival data from the CASPIAN trial demonstrated an overall survival (OS) improvement with durvalumab (Imfinzi) and cisplatin or carboplatin vs cisplatin or carboplatin alone.2 Rudin noted that “the benefit is really in the tail of the curve,” and these differences in overall survival (OS) do not begin to appear until long after treatment.1

“So there’s a minority of patients that actually are benefiting from immunotherapy [in] small cell lung cancer. I would say probably on the order of 10% of patients are actually immuno-responsive. The majority of patients are not,” Rudin said. Adding antibody blockades of CTLA-4 or TIGIT did not have an additional effect on the anti-PD-(L)1 blockers, as shown in the CASPIAN and Skyscraper-02 (NCT04256421) trials, respectively.

Findings from the Skycraper-02 trial showed that adding tiragolumab, an anti-TIGIT agent, to atezolizumab (Tencentriq) plus carboplatin and etoposide (CE) did not improve progression-free survival (PFS) or OS compared with placebo, atezolizumab, and CE.3

However, Rudin noted that “the benefit is real” for patients with SCLC who do respond to immunotherapy.

“[There is a] tripling of career survival, admittedly, from about 5% to 17%. This difference is real, and these patients can have a truly durable response,” according to Rudin.

Antibody-based DLL3 Targeted Therapies

Rudin noted that while anti-PD-(L)1 blockers may not be the most effective SCLC treatment option, antibody therapeutics targeting the cell surface hold promise. Antibody-based DLL3 targeted therapies, specifically bispecific T cell engagers (BiTE), show potential, with several agents currently or soon-to-be recruiting in clinical trials . These agents include tarlatamab, BI 764532, PT217, and QLS31904.

A phase 2 study (NCT05060016) of tarlatamab, a DLL3/CD3-targeting BiTE, found that it delivered a 40% objective response rate (ORR) in patients administered 10 mg every 2 weeks (97.5% CI, 29%-52%) with a duration of response of 59% for a minimum of 6 months in those patients. Further, the estimated OS at 9 months was 68% in the 10-mg dose arm.4

Findings from a phase 1 dose-escalation trial (NCT04429087) of BI 764532, a DLL3/CD3-targeted BiTE, showed manageable tolerability, and the maximum tolerated dose was not yet reached. The study is still ongoing.5

Clinical trials of QLS31904, a DLL3/CD3-targeted BiTE, and PT217, a DLL3/CD47-targeted BiTE, are in early stages. Preclinical data of QLS31904 found that it inhibited tumor growth at a dose as low as 20 µg/kg.6 In September 2023, the clinical study sponsor of PT217 announced that the first patient in the phase 1 study (NCT05652686) of the agent was dosed.7

Of the potential of DLL3-directed therapies, Rudin said, “I think the durability of these responses for patients with recurrent metastatic small cell lung cancer is fairly impressive, with the durability of response of over a year.”

Antibody-Drug Conjugates

Along with anti-DLL3 agents, anti-CD56, -TROP2, -CD276, and -SEZ6 ADCs have been assessed in SCLC, according to Rudin.

“Conjugates are really having a bit of a moment. There [are] like 300 in the clinic right now… Slow initial growth, but then really, in the last couple of years, just an explosion,” Rudin said. Rudin highlighted 11 ADCs that have been approved across different cancer types since 2015.

Rudin showcased initial phase 1 (NCT04145622) efficacy data of DS-7300, a CD276-directed ADC. An ORR of 32% (95% CI, 24%-41%) was seen across various tumor types, including SCLC.8 Further, a dose-finding study (NCT05280470) is ongoing; however, no publicly released data are available.

“Even in these very early data among patients with small cell lung cancer, this agent is showing substantial promise,” Rudin said.

1. Rudin, C. Antibodies in small cell lung cancer (DLL3-B7-H3, etc). Presented at: 18th Annual New York Lung Cancer Symposium. November 11, 2023. New York, NY.
2. Paz-Ares L, Chen Y, Reinmuth N, et al. Durvalumab, with or without tremelimumab, plus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer: 3-year overall survival update from Caspian. ESMO Open. 2022;7(2):100408. doi:10.1016/j.esmoop.2022.100408
3. Rudin CM, Liu SV, Lu S, et al. Skyscraper-02: Primary results of a phase III, randomized, double-blind, placebo-controlled study of atezolizumab (atezo) + carboplatin + etoposide (CE) with or without tiragolumab (TIRA) in patients (PTS) with untreated extensive-stage small cell lung cancer (es-SCLC). J Clin Onc. 2022;40(17_suppl). doi:10.1200/jco.2022.40.17_suppl.lba8507
4. Ahn M-J, Cho BC, Felip E, et al. Tarlatamab for patients with previously treated small-cell lung cancer. New England Journal of Medicine. 2023;389(22):2063-2075. doi:10.1056/nejmoa2307980
5. Wermke M, Felip E, Kuboki Y, et al. First-in-human dose-escalation trial of BI 764532, a delta-like ligand 3 (DLL3)/CD3 IgG-like T-cell engager in patients (pts) with DLL3-positive (DLL3+) small-cell lung cancer (SCLC) and neuroendocrine carcinoma (NEC). Journal of Clinical Oncology 41, no. 16_suppl (June 01, 2023) 8502-8502. DOI: 10.1200/JCO.2023.41.16_suppl.8502
6. Liuqing Y, Ruimei L, Jiahua J, et al. QLS31904: An anti-DLL3/CD3 bispecific antibody for T cell immunotherapy of small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5550. doi: 10.1158/1538-7445.AM2022-5550
7. Phanes Therapeutics announces first patient dosed in phase 1 study of PT217 for small cell lung cancer and other neuroendocrine cancers expressing DLL3. News release. Phanes Therapeutics. September 7, 2023. Accessed December 12, 2023. http://tinyurl.com/y7rzvj9m
8. DS-7300 continues to show promising durable response in patients with several types of advanced cancer. News release. Daiichi Sankyo. September 10, 2022. Accessed December 12, 2023. http://tinyurl.com/3tdyadb
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