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. 2025 Jul 20:17:17588359251356919.
doi: 10.1177/17588359251356919. eCollection 2025.

Impact of delayed addition of PD-1/PD-L1 inhibitors to chemotherapy on outcomes in patients with extensive-stage small cell lung cancer

Shuangqing Lu  1   2 , Chao Wang  3 , Xiaoyang Zhai  2 , Zhuoran Sun  2 , Ke Zhao  2 , Dawei Chen  4 , Hui Zhu  5
Affiliations

Impact of delayed addition of PD-1/PD-L1 inhibitors to chemotherapy on outcomes in patients with extensive-stage small cell lung cancer

Shuangqing Lu et al. Ther Adv Med Oncol. .

Abstract

Background: Immunotherapy combined with chemotherapy is the first-line treatment for extensive-stage small cell lung cancer (ES-SCLC). However, the effect of delayed initiation of immunotherapy on its efficacy remains unclear.

Objectives: This study aimed to investigate the impact of the delayed addition of programmed death receptor 1/programmed death ligand 1 (PD-1/PD-L1) inhibitors on treatment outcomes in patients with ES-SCLC.

Design: This retrospective cohort study used propensity score matching (PSM) to balance baseline characteristics.

Methods: This study included 416 patients with ES-SCLC who received first-line immunotherapy between January 2020 and December 2022. Patients were categorized into two groups: delayed-immunotherapy (IO) (PD-1/PD-L1 inhibitors initiated during the 2nd or 3rd chemotherapy cycle) and early-IO (immunotherapy initiated during the first cycle). A 1:1 PSM was performed to balance baseline characteristics. The primary endpoints were overall survival (OS) and progression-free survival (PFS), which were analyzed using the Kaplan-Meier method and compared using log-rank tests.

Results: Owing to the exclusion of PD-L1/PD-1 inhibitors from medical insurance, financial constraints, and poor physical condition of some patients, 72 patients were included in the delayed-IO group (second cycle: 41; third cycle: 31), while 344 were in the early-IO group. Before PSM, median OS and PFS in the delayed-IO group were 24.00 and 8.75 months, compared to 18.59 and 7.57 months in the early-IO group, with no significant differences (OS: HR 0.72, p = 0.054; PFS: HR 0.86, p = 0.281). After PSM (72 patients per group), the delayed-IO group showed significantly longer median OS (24.00 vs 18.79 months, HR 0.60, 95% CI 0.38-0.97, p = 0.037) and PFS (8.75 vs 6.49 months, HR 0.69, 95% CI 0.48-0.99, p = 0.044) compared to the early-IO group. These results suggest that, in specific patient populations, delayed immunotherapy may improve survival outcomes by optimizing patient condition or treatment response.

Conclusion: In patients with ES-SCLC, delayed administration of PD-1/PD-L1 inhibitors during the second to fourth chemotherapy cycles improves survival outcomes compared to concurrent administration during the first cycle, with a similar safety profile. These results suggest that, in specific patient populations, delayed immunotherapy may improve survival outcomes by optimizing patient condition or treatment response.

Keywords: chemotherapy; combined timing; extensive-stage small cell lung cancer (ES-SCLC); immune checkpoint inhibitor; propensity score-matched study.

Plain language summary

The impact of delayed immunotherapy on treatment outcomes in small-cell lung cancer This study looks at the best time to start immunotherapy for small-cell lung cancer, which is a very aggressive type of lung cancer often found in its advanced stage. The standard treatment now is to combine immunotherapy with chemotherapy. However, it’s unclear if when you start immunotherapy affects how well it works. The study included 416 patients divided into two groups: one group started immunotherapy during the 2nd or 3rd cycle of chemotherapy (delayed immunotherapy group), and the other group started it with the first cycle of chemotherapy (early immunotherapy group). After matching patients’ basic characteristics, the delayed group had longer survival (median overall survival of 24 months) compared to the early group (median overall survival of 18.8 months). The delayed group also had longer progression-free survival (median 8.75 months) compared to the early group (median 6.49 months). This suggests that starting immunotherapy later, during the 2nd to 4th chemotherapy cycles, may be more effective than starting it with the first cycle. Importantly, delayed immunotherapy did not increase safety concerns. This finding offers new insights for treating small-cell lung cancer, especially for patients who might face financial or health-related reasons for not starting immunotherapy immediately.

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Conflict of interest statement

The authors declare that there is no conflict of interest.

Figures

Flowchart of how patients diagnosed with es-sclc at shanghai cancer hospital and shanghai cancer institute who met the certain criteria were screened.
Figure 1.
Flowchart of the screening procedure. EP, etoposide + platinum; ES-SCLC, extensive-stage small cell lung cancer; IO, immunotherapy; PD-1, programmed death receptor 1; PD-L1, programmed death ligand 1.
Overall survival and progression-free survival of early and delayed PSM cohorts.
Figure 2.
In the overall population, OS and PFS before and after PSM. (a) PFS prior to PSM; (b) OS prior to PSM; (c) PFS following PSM; (d) OS following PSM. IO, immunotherapy; OS, overall survival; PFS, progression-free survival; PSM, propensity score matching.
The image presents a comparison of tumor responses to chemotherapy in patients receiving early initiation of immunotherapy (IO) and delayed initiation of IO after two and four chemotherapy cycles.
Figure 3.
Tumor response evaluation after two and four cycles of chemotherapy in the early-IO and delayed-IO groups. (a) early-IO after two cycles; (b) early-IO after four cycles; (c) delayed-IO after two cycles; (d) delayed-IO after four cycles. Tumor responses are categorized as complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD).
Study results show no significant differences in progression-free survival and overall survival rates between early vs delayed immunotherapy groups when stratified by different patient subgroups, such as age, gender, KPS, T stage, N stage, and metabolic disturbances.
Figure 4.
Subgroup analysis of PFS (a) and OS (b) after PSM. IO, immunotherapy; KPS, Karnofsky performance score; OS, overall survival; PFS, progression-free survival; PSM, propensity score matching.
Improved OS and PFS outcomes in ICBT and CCI treatments for different brain metastasis conditions in PSM studies.
Figure 5.
In the populations with and without brain metastases, OS and PFS after PSM. (a) PFS following PSM in the population with brain metastases; (b) OS following PSM in the population with brain metastases; (c) PFS following PSM in the population without brain metastases; (d) OS following PSM in the population without brain metastases. IO, immunotherapy; OS, overall survival; PFS, progression-free survival; PSM, propensity score matching.
Comparative immunotherapy drug survival analysis by PSM, focusing on PFS and OS for atezolizumab, durvalumab, and serplulimab in early and delayed treatments. Graphs depict time-to-event outcomes in weeks, with blue histograms showing estimated median PFS and OS; red curves illustrate cumulative event rates. Graph (a) compares atezolizumab PFS, (b) OS, (c) durvalumab PFS, (d) OS, (e) serplulimab PFS, and (f) OS, using early-to-no immunotherapy (early-IO) and delayed-to-immunotherapy (delayed-IO) groups.
Figure 6.
Subgroup survival analysis by immunotherapy drug (post-PSM). (a) PFS of atezolizumab in early-IO versus delayed-IO groups; (b) OS of atezolizumab in early-IO versus delayed-IO groups; (c) PFS of durvalumab in early-IO versus delayed-IO groups; (d) OS of durvalumab in early-IO versus delayed-IO groups; (e) PFS of serplulimab in early-IO versus delayed-IO groups; (f) OS of serplulimab in early-IO versus delayed-IO groups. IO: immunotherapy; OS, overall survival; PFS, progression-free survival; PSM, propensity score matching.
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