A Look at the Past, Present, and Future of Small Cell Lung Cancer Treatment

The landscape of small cell lung cancer (SCLC) is undergoing a significant transformation, marked by decreasing incidence rates due to reduced smoking and unprecedented therapeutic advancements. While historical progress has been slow, recent breakthroughs, particularly in 2024 and 2025, are set to redefine the standard of care.

In limited-stage SCLC, the integration of immunotherapy post chemoradiotherapy has pushed potential 5-year survival rates toward the 40% to 50% range, a substantial improvement from single-digit outcomes decades ago.

T-cell engagers, exemplified by tarlatamab (Imdelltra), are demonstrating unprecedented survival curves across second-line, maintenance, and even first-line settings. Concurrently, antibody-drug conjugates are showing exceptionally high response rates, nearing 60%, suggesting they could potentially displace traditional first-line chemotherapy. These developments, alongside research into overcoming immunotherapy resistance by targeting epigenetic pathways, signal a new, more hopeful era for patients with SCLC.¹

At the 43rd Annual Chemotherapy Foundation Symposium in New York, New York, on November 14, 2025, Charles Rudin, MD, PhD, deputy director at Memorial Sloan Kettering Cancer Center, discussed the changing landscape of SCLC treatment.

Historic Survival in SCLC

During Rudin’s session, he shared graphs comparing the overall survival (OS) of patients with SCLC before 2018 and today. According to data published in the Journal of Clinical Oncology in 2009, in a comparison of 2 platinum doublet regimens before 2018, the 3-year survival of patients was under 5%. A comparison of platinum doublet with or without immunotherapy data after 2018 showed that 3-year survival was 17.6% vs 5.8%.

According to data published in the New England Journal of Medicine in 2024, the addition of immunotherapy increased OS in patients with SCLC (HR, 0.73; P < .01). A median OS of 55.9 vs 33.4 months was observed in patients treated with durvalumab (Imfinzi) vs placebo. The data show that at 24 months since randomization, 58.5% of patients receiving the placebo treatment remained alive (95% CI, 52.3%-64.3%) vs 68% of patients receiving durvalumab (95% CI, 61.9%-73.3%). At the 36-month mark, the OS rate was 56.5% (95% CI, 50%-62.5%) in the durvalumab arm vs 47.6% (95% CI, 41.3-53.7) in the placebo arm.

In data comparing 5-year survival from 1992, 1999, and 2017, chemoradiotherapy treatment produced better OS rates. In data from 1992, 5-year survival was 10% (chemoradiotherapy) vs 6% (chemotherapy). In data from 1999, 5-year survival was 26% (chemoradiotherapy twice daily) vs 16% (once daily). In 2017, 5-year survival was 34% (modern chemoradiotherapy twice daily) vs 31% (modern chemoradiotherapy once daily).

Novel Agents in SCLC

Data published in the New England Journal of Medicine in 2025 show that the bispecific T-cell engager tarlatamab outperformed chemotherapy in progression-free survival (PFS) and OS. At 12 months after randomization, 20% of patients receiving tarlatamab were free from progression or death vs 4% of patients receiving chemotherapy. A total of 53% of patients receiving tarlatamab were alive vs 37% of patients receiving chemotherapy.

Data published in The Lancet in 2025 from the phase 3 IMforte trial (NCT05091567) show that the combination treatment of the alkylating agent lurbinectedin (Zepzelca) plus PD-L1 inhibitor atezolizumab (Tecentriq) yielded more significant results in PFS and OS compared with atezolizumab alone. The median PFS was 5.4 months vs 2.1 months (HR, 0.54; 95% CI, 0.43-0.67; P < .0001), and the median OS was 13.2 months vs 10.6 months (HR, 0.73; 95% CI, 0.57-0.95; P = .0174).

The FDA approved the combination of lurbinectedin and atezolizumab as a first-line maintenance treatment in patients with extensive-stage SCLC in October 2025.

“This is clearly an advance for our patients, and this got a nod from the FDA,” said Rudin of the IMforte trial during his presentation. “So this is an available option for our patients. I would say, in my mind, it’s a little bit disappointing that we’re not really raising the tail of the curve here, and we’re really bringing the second-line cytotoxic therapy into maintenance, more of a switch maintenance approach than, I think, a real new therapy. The survival curves are clearly separating here, and this is clearly an option here.”

Looking Ahead in SCLC

Rudin noted during his presentation the role of antigens in a patient’s response to immunotherapy, calling antigen presentation a “leading determinant.”

“[SCLC] tends to downregulate expression of antigen presentation as a whole pathway. And this is actually a multigene silencing. It’s epigenetic silencing of many genes that are involved in antigen processing and presentation,” said Rudin.

As for the future of SCLC care, Rudin suggested adding a T-cell engager into a standard immune checkpoint inhibitor combination.

“I think it’s a really exciting time for our patients,” concluded Rudin during his presentation.

REFERENCE

1. Rudin C. Sea changes in small cell lung cancer. Presented at: Chemotherapy Foundation Symposium; November 11-13, 2025; New York, NY.