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Comparative effectiveness and safety of systemic therapies for treatment-naïve, PD-L1 expression <1% advanced NSCLC:

Mengyun Zhou1,2, Junfang Huang1, Zhou Jin1

  • 1Department of Respiratory and Critical Care Medicine, Peking University First Hospital, Beijing, China.

Translational Lung Cancer Research
|December 10, 2025
PubMed
Abstract

Insights

For advanced non-small cell lung cancer (NSCLC) with low PD-L1 expression, histology-based first-line treatments are recommended. Pembrolizumab plus chemotherapy and nivolumab plus chemotherapy plus bevacizumab are optimal for non-squamous NSCLC, while nivolumab plus ipilimumab plus chemotherapy is best for squamous NSCLC.

Area of Science:

  • Oncology
  • Immunotherapy
  • Clinical Trials

Background:

  • Advanced non-small cell lung cancer (NSCLC) with programmed cell death ligand 1 (PD-L1) expression <1% and no actionable mutations typically receives pembrolizumab plus chemotherapy (Pembro-chemo) as standard care.
  • Emerging therapeutic combinations and trial data suggest potential alternatives that may challenge the current standard, especially across different NSCLC histologic types.

Purpose of the Study:

  • To evaluate the efficacy and safety of first-line treatments for advanced NSCLC with PD-L1 <1%, specifically comparing non-squamous and squamous subtypes.
  • To identify optimal treatment strategies beyond the current standard of care for this patient population.

Main Methods:

  • A systematic literature search of phase III randomized controlled trials (RCTs) was conducted across PubMed, Ovid Medline, Cochrane Library, and Embase up to August 15, 2025.
  • Included RCTs focused on treatment-naïve advanced NSCLC with PD-L1 <1% and no EGFR/ALK alterations, reporting efficacy outcomes like overall survival (OS), progression-free survival (PFS), and objective response rate (ORR).
  • Surface Under the Cumulative Ranking Value (SUCRA) was used for therapy ranking, and risk of bias was assessed using the Cochrane Risk of Bias 2 tool.

Main Results:

  • Twenty-five phase III RCTs with 5,815 participants identified 21 first-line treatments.
  • For overall survival (OS), pembrolizumab + chemotherapy + canakinumab showed potential (SUCRA=0.90), followed by nivolumab + ipilimumab (SUCRA=0.78), with both demonstrating non-significant superiority over Pembro-chemo.
  • Optimal progression-free survival (PFS) regimens included nivolumab + chemotherapy + bevacizumab (SUCRA=0.88) and serplulimab + chemotherapy (SUCRA=0.87). For non-squamous NSCLC, Pembro-chemo was optimal for OS (SUCRA=0.90), while nivolumab + chemotherapy + bevacizumab optimized PFS (HR=0.52). For squamous NSCLC, nivolumab + ipilimumab ± chemotherapy led in OS, and serplulimab + chemotherapy in PFS.

Conclusions:

  • First-line treatment for advanced NSCLC with PD-L1 <1% should be personalized based on histology, balancing efficacy and toxicity.
  • Pembrolizumab + chemotherapy and nivolumab + chemotherapy + bevacizumab are recommended as optimal first-line options for non-squamous NSCLC.
  • Nivolumab + ipilimumab ± chemotherapy is recommended as the optimal first-line treatment for squamous NSCLC.
Keywords:
Advanced non-small cell lung cancer (advanced NSCLC)first-line treatmentprogrammed cell death ligand 1 negative (PD-L1 negative)

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