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PD-(L)1 containing rechallenge strategies in patients with advanced NSCLC previously treated with immunotherapy: A
Daniele Marinelli1, Fabrizio Citarella2, Andrea Torchia3
1Department of Experimental Medicine, Sapienza University, Rome, Italy; Department of Medical Oncology 2, IRCCS "Regina Elena" National Cancer Institute, Rome, Italy.
Introduction:
Even though PD-(L)1 inhibitors have dramatically changed the prognosis of patients with advanced non-small-cell lung cancer (NSCLC), resistance to treatment remains common. Rechallenge with PD-(L)1 based regimens has been explored in this context, but clinical benefit remains uncertain.
Methods:
Two independent reviewer teams performed parallel searches of MEDLINE and EMBASE from 2019 to 2025 to identify clinical trials evaluating PD-(L)1 inhibitor based rechallenge strategies in patients with advanced NSCLC previously treated with PD-(L)1-based regimens. Randomised controlled trials (RCTs) were included in quantitative meta-analysis, while non-randomised single-arm studies were synthesised descriptively. The primary endpoint was overall survival (OS). Sensitivity analyses examined outcomes according to resistance pattern. All analyses used fixed-effects models.
Findings:
A total of 10 RCTs (n = 3,081) and 106 non-randomised interventional trials were included. Across RCTs, PD-(L)1 based rechallenge strategies yielded modest improvements in both OS (HR 0.91, 95%CI: 0.82-0.99) and PFS (HR 0.89, 95%CI: 0.81-0.99) compared with the control arms, with no improvement in objective response rate (ORR). In sensitivity analyses, no benefit was observed in patients with primary resistance, whereas those with acquired resistance features (i.e., clinical benefit to prior immunotherapy) demonstrated a more favourable effect for OS (HR 0.86, 95%CI: 0.77-0.97). A more restrictive analysis excluding patients with < 3 months of prior PD-(L)1 exposure confirmed this pattern. Across the 106 single-arm trials, ORR varied widely, with only speculative signals of higher activity in regimens incorporating VEGF-targeting or chemotherapy.
Conclusions:
In the largest synthesis of rechallenge strategies to date, PD-(L)1 rechallenge produced statistically significant but clinically marginal improvements in OS and PFS compared with standard treatments, with no benefit in patients with primary resistance. A signal of benefit was observed in patients with acquired resistance to prior immunotherapy although this exploratory analysis was limited by heterogeneous resistance definitions across trials and a non-significant interaction test.
Insights
Rechallenging patients with advanced non-small-cell lung cancer (NSCLC) using PD-(L)1 inhibitors offers modest survival benefits, particularly for those with acquired resistance. However, no benefit is seen in primary resistance cases.
Area of Science:
- Oncology
- Immunotherapy
- Clinical Trials
Background:
- Programmed death (PD)-1/ligand (L)1 inhibitors revolutionized advanced non-small-cell lung cancer (NSCLC) treatment.
- Treatment resistance remains a significant challenge in advanced NSCLC.
- Rechallenge strategies with PD-(L)1 inhibitors are being explored, but their clinical utility is uncertain.
Purpose of the Study:
- To evaluate the efficacy of PD-(L)1 inhibitor rechallenge strategies in advanced NSCLC patients.
- To compare rechallenge outcomes based on resistance patterns (primary vs. acquired).
Main Methods:
- Systematic literature search of MEDLINE and EMBASE (2019-2025).
- Included 10 randomized controlled trials (RCTs) for meta-analysis and 106 non-randomized trials for descriptive synthesis.
- Primary endpoint was overall survival (OS); sensitivity analyses explored outcomes by resistance pattern.
Main Results:
- PD-(L)1 rechallenge showed modest improvements in OS (HR 0.91) and progression-free survival (PFS, HR 0.89) in RCTs.
- No benefit was observed in patients with primary resistance.
- Patients with acquired resistance demonstrated a favorable OS effect (HR 0.86).
Conclusions:
- PD-(L)1 rechallenge offers statistically significant but clinically marginal OS and PFS improvements in advanced NSCLC.
- Efficacy is dependent on resistance patterns, with no benefit in primary resistance.
- A potential benefit in acquired resistance warrants further investigation despite study limitations.
