Immunotherapy Advances in SCLC Highlight Promise, Limitations, and Biomarker Needs

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The current state of the small cell lung cancer (SCLC) treatment paradigm rests on meaningful efficacy gains with immunotherapy approaches, although there remains an urgent need to identify predictive biomarkers to better tailor therapy and explore the utility of agents beyond immune checkpoint inhibitors (ICIs), according to Christine Hann, MD, PhD.1

In a presentation at the 20th Annual New York Lung Cancers Symposium®, Hann highlighted how recently presented SCLC data inform treatment decision-making across the limited-stage and extensive-stage settings. She explored various findings with consolidation durvalumab (Imfinzi), ups and downs regarding atezolizumab (Tecentriq) data, and the importance of identifying novel biomarkers to further individualize SCLC management.

Hann is an associate professor of oncology at the Johns Hopkins School of Medicine and a physician at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, Maryland.

What are some of the most recent advances and setbacks in therapeutic development for LS-SCLC?

The ADRIATIC Trial

Hann began by discussing the significance of data that have been reported from the phase 3 ADRIATIC trial (NCT03703297), which is investigating durvalumab as consolidation therapy in patients with stage III inoperable limited-stage SCLC (LS-SCLC). Data presented at the 2024 ASCO Annual Meeting showed that patients who received durvalumab monotherapy (n = 264) experienced a median progression-free survival (PFS) of 16.6 months (95% CI, 10.2-28.2) vs 9.2 months (95% CI, 7.4-12.9) with placebo (n = 266; HR, 0.76; 95% CI, 0.61-0.95; P = .0161).2 The median overall survival (OS) was 55.9 months (95% CI, 37.3-not evaluable) vs 33.4 months (95% CI, 25.5-39.9) with placebo (HR, 0.73; 95% CI, 0.57-0.93; P = .0104).

Hann also homed in on the safety findings from ADRIATIC, which showed that patients in the durvalumab arm received a median of 9.0 doses (range, 1-26) of the treatment. In this arm, the rate of any-grade all-cause adverse effects (AEs) was 94.3%, and the rate of any-grade immune-mediated AEs was 32.1%. Notably, any-grade radiation pneumonitis was seen in 22.9% of patients in this arm.

“Notable findings [from subgroup analyses] were that [patients who received] once-daily and twice-daily [dosing] both seem to benefit [from durvalumab],” Hann said, adding that “These are trends, not absolutes.”

Based on these data, in December 2024, the FDA approved durvalumab for the treatment of adult patients with LS-SCLC whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy.3

Hann added that data from the durvalumab/tremelimumab of ADRIATIC are still awaited.

The NRG-LU005 Study

Hann pivoted to provide context about findings from the phase 3 NRG-LU005 trial (NCT03811002), which investigated the use of concurrent atezolizumab and chemoradiotherapy in patients with limited-stage disease. Data from the second planned interim analysis showed no PFS or OS improvements with the concurrent administration of atezolizumab and standard-of-care (SOC) chemoradiotherapy vs chemoradiotherapy alone.4

“This was reminiscent of data that we’ve seen in [the phase 3] PACIFIC-2 [trial (NCT03519971)],” Hann explained. “It seems like immunotherapy given concurrently with chemoradiation offers no benefit.”

Notably, data from the final analysis of PACIFIC-2 showed that concurrent administration of durvalumab and SOC chemoradiotherapy followed by consolidation durvalumab (n = 219) did not result in a significant PFS benefit vs placebo plus SOC chemoradiotherapy (n = 109; HR, 0.85; 95% CI, 0.65-1.12; P = .247).5

The ACHILES Trial

Additional data with atezolizumab in the context of chemoradiotherapy in LS-SCLC came from the phase 2 ACHILES trial (NCT03540420) and were presented at the 2025 ASCO Annual Meeting. In this study, patients who received consolidation atezolizumab after chemoradiotherapy (n = 85) had a median OS of 43.4 months (95% CI, 25.1-51.2); the median OS was 38.8 months (95% CI, 25.8-57.6) among patients who underwent observation following chemoradiotherapy (n = 85). Although there was a numerical improvement in OS in the atezolizumab arm, this did not meet statistical significance (HR, 1.14; 95% CI, 0.76-1.71; P = .53).6

“It’s notable that the observation arm performed better than [in] other studies,” Hann stated. “For immunotherapy in LS-SCLC, the [optimal population] are patients with at least stable disease after chemoradiation, [and the ideal treatment and duration are] up to 2 years of durvalumab consolidation, which improves PFS and OS. Toxicity is manageable. Benefits [were] observed over the different subgroups, so [we should be] comfortable [using] once-daily or twice-daily radiation and either platinum agent.”

Hann summarized that, so far, clinical trial data have not shown a benefit with atezolizumab given concurrently with chemoradiation as maintenance or consolidation therapy. However, she explained that data from ongoing phase 3 trials with immunotherapy agents in LS-SCLC may add nuance to the question of the optimal role for immunotherapy-based combinations, in terms of efficacy as well as safety.

What do clinical data indicate about the role of immunotherapy in patients with ES-SCLC?

Turning to paradigm-defining data in extensive-stage SCLC (ES-SCLC), Hann focused on the benefits and limitations seen with the use of first-line immunotherapy in the phase 3 Impower133 (NCT02763579) and CASPIAN (NCT03043872) trials.

“The trials were designed slightly differently, but the outcomes were similar,” she reported. “There is a small population [of patients who] are doing well [with frontline immunotherapy]. In the rest, we could probably use additional therapy. [Across clinical studies], whether [patients received] PD-1 or PD-L1 [inhibition plus platinum/etoposide], there seems to be consistent benefit [in terms of an] improvement in median OS.”

She then summarized the results of several combination studies in the ES-SCLC setting, concluding that most did not show efficacy benefits with immunotherapy combination regimens vs single-agent immunotherapy. However, she spotlighted the biomarker-based phase 2 SWOG S1929 trial (NCT04334941), which evaluated maintenance atezolizumab alone vs in combination with talazoparib in patients with SLFN11-positive ES-SCLC. In this trial, the median PFS was 4.2 months (80% CI, 2.8-4.7) in the talazoparib arm (n = 54) vs 2.8 months (80% CI, 2.0-2.9) in the atezolizumab monotherapy arm (n = 52; HR, 0.70; 80% CI, 0.52-0.94; 1-sided log-rank stratified P = .056).7

“[It is] important to show that a biomarker-based study could be conducted in SCLC,” she noted.

Furthermore, Hann highlighted data from the phase 3 IMforte trial (NCT05091567) of first-line maintenance therapy with lurbinectedin (Zepzelca) plus atezolizumab that were presented at ASCO 2025. In this trial, patients with ES-SCLC who received the combination (n = 242) achieved a median PFS by independent review facility of 5.4 months (95% CI, 4.2-5.8) vs 2.1 months (95% CI, 1.6-2.7) with atezolizumab monotherapy (n = 241; stratified HR, 0.54; 95% CI, 0.43-0.67; 2-sided P< .0001).8 The median OS was 13.2 months (95% CI, 11.9-16.4) with the combination vs 10.6 months (95% CI, 9.5-12.2) with atezolizumab alone (stratified HR, 0.73; 95% CI, 0.57-0.95; 2-sided P = .0174).

Notably, these data supported the October 2025 FDA approval of lurbinectedin plus atezolizumab or atezolizumab and hyaluronidase-tqjs (Tecentriq Hybreza) as maintenance therapy for adult patients with ES-SCLC whose disease has not progressed after frontline induction therapy with atezolizumab or atezolizumab and hyaluronidase, carboplatin, and etoposide.9

“With these data, etoposide plus a PD-L1 inhibitor is standard frontline therapy,” Hann reported. “Lurbinectedin offers PFS and OS benefit when added to maintenance atezolizumab as an option for, I say, select [patients with SCLC]. They have to be pretty fit and technically [have] no brain metastases at presentation. Toxicities are predictable but can be significant.”

What may be the future role of biomarkers in SCLC?

Hann concluded her presentation by emphasizing the importance of finding predictive biomarkers to further refine the role of immunotherapy. Questions remain as to which patient populations would benefit most from immunotherapy as monotherapy vs part of combination regimens. Hann also noted the uncertainty around optimal treatment strategies for patients with small cell transformation from EGFR-mutant adenocarcinoma, acknowledging that although early data suggest that ICIs might not be the most effective in this population, other types of immunotherapies might provide better outcomes. She also emphasized the importance of developing therapies that are more effective than chemotherapy for patients who are not eligible to receive ICIs, including those with active autoimmune conditions, those who have undergone transplant, and those who have paraneoplastic syndrome.

References

  1. Hann CL. Immunotherapy in SCLC: when, what, and how much? Presented at: 20th Annual New York Lung Cancers Symposium; November 15, 2025; New York, New York.
  2. Spigel DR, Cheng Y, Cho BC, et al. ADRIATIC: durvalumab (D) as consolidation treatment (tx) for patients (pts) with limited-stage small-cell lung cancer (LS-SCLC). J Clin Oncol. 2024;42(suppl 17):LBA5. doi:10.1200/JCO.2024.42.17_suppl.LBA5
  3. FDA approves durvalumab for limited-stage small cell lung cancer. FDA. December 4, 2024. Accessed November 15, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-durvalumab-limited-stage-small-cell-lung-cancer
  4. NRG Oncology trial implies the addition of atezolizumab concurrently to standard of care does not improve survival in limited-stage small cell lung cancer. News release. NRG Oncology. September 30, 2024. Accessed November 15, 2025. https://www.nrgoncology.org/Home/News/Post/nrg-oncology-trial-implies-the-addition-of-atezolizumab-concurrently-to-standard-of-care-does-not-improve-survival-in-limited-stage-small-cell-lung-cancer
  5. Bradley JD, Sugawara S, Lee KHH, et al. Durvalumab in combination with chemoradiotherapy for patients with unresectable stage III NSCLC: final results from PACIFIC-2. ESMO Open. 2024;9(suppl 3):102986. doi:10.1016/j.esmoop.2024.102986
  6. Gronberg BH, Aanerud M, Dumoulin DW, et al. Randomized phase II trial investigating whether atezolizumab after chemoradiotherapy (CRT) prolongs survival in limited stage (LS) small cell lung cancer (SCLC). J Clin Oncol. 2025;43(suppl 17):LBA8005. doi:10.1200/JCO.2025.43.17_suppl.LBA8005
  7. Karim NFA, Miao J, Reckamp KL, et al. SWOG S1929: Phase II randomized study of maintenance atezolizumab (A) versus atezolizumab + talazoparib (AT) in patients with SLFN11 positive extensive stage small cell lung cancer (ES-SCLC). J Clin Oncol. 2023;41(suppl 16):8504. doi:10.1200/JCO.2023.41.16_suppl.8504
  8. Paz-Ares L, Borghaei H, Liu SV, et al. Lurbinectedin (lurbi) + atezolizumab (atezo) as first-line (1L) maintenance treatment (tx) in patients (pts) with extensive-stage small cell lung cancer (ES-SCLC): primary results of the phase 3 IMforte trial. J Clin Oncol. 2025;43(suppl 16):8006. doi:10.1200/JCO.2025.43.16_suppl.8006
  9. FDA approves lurbinectedin in combination with atezolizumab or atezolizumab and hyaluronidase-tqjs for extensive-stage small cell lung cancer. FDA. October 2, 2025. Accessed November 15, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-lurbinectedin-combination-atezolizumab-or-atezolizumab-and-hyaluronidase-tqjs-extensive?utm_medium=email&utm_source=govdelivery

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