Efficacy of ICIs vs. Chemotherapy in NSCLC

What is the effectiveness and safety of first-line immune checkpoint inhibitors (ICIs), as monotherapy or in combination, compared to platinum-based chemotherapy, with or without bevacizumab for people with advanced NSCLC, according to the level of PD-L1 expression

In advanced NSCLC patients with high PD-L1 expression, ICI monotherapy outperforms platinum-based chemotherapy for survival outcomes, though combination ICI regimens offer no additional advantage and safety profiles are similar.

Abstract

Immune checkpoint inhibitors yielded a survival benefit over platinum‐based chemotherapy primarily in patients with high PD-L1 expression. In one trial, pembrolizumab monotherapy in patients with a tumor proportion score of ≥50% achieved a median overall survival of 20.0 months compared with 12.2 months with chemotherapy (p = 0.0003). Two separate trials of durvalumab monotherapy in high PD-L1 populations reported median overall survival improvements of 1.8 to 3.4 months (p = 0.037 and p = 0.036, respectively). In contrast, combination regimens—such as durvalumab plus tremelimumab and sitravatinib plus nivolumab—did not consistently yield statistically significant overall survival benefits when compared with chemotherapy or monotherapy.

Reported safety outcomes were sparse. One study noted 0–1 dose‐limiting toxicities in a pembrolizumab plus chemotherapy regimen, and no study reported marked differences in grade 3–4 adverse events, treatment discontinuation, or treatment‐related deaths. Together, these findings indicate that first‐line immune checkpoint inhibitor monotherapy, especially with pembrolizumab or durvalumab, appears effective in extending overall survival among patients with high PD-L1 advanced non‐small cell lung cancer, whereas combination regimens have not demonstrated clear added benefit.

Methods

We analyzed 9 sources from an initial pool of 75, using 8 screening criteria. Each paper was reviewed for 6 key aspects that mattered most to the research question.

Screening

We screened in sources based on their abstracts that met these criteria:

• Population - Age and Stage: Does the study focus exclusively on adult patients (≥18 years) with advanced/metastatic NSCLC?
• Treatment Line: Is the study conducted in a first-line treatment setting?
• Intervention: Does the study evaluate approved immune checkpoint inhibitors as monotherapy or in combination?
• Comparator: Does the study include a platinum-based chemotherapy (with or without bevacizumab) control arm?
• PD-L1 Data: Does the study report PD-L1 expression levels?
• Study Design: Is the study either a randomized controlled trial (RCT) or a systematic review/meta-analysis of RCTs?
• Outcomes: Does the study report at least one efficacy outcome (overall survival, progression-free survival, or response rates) OR safety outcome (adverse events or treatment discontinuation)?
• Study Quality: Is the study design something other than a case report, case series, non-comparative observational study, or Phase I trial?

We considered all screening questions together and made a holistic judgement about whether to screen in each paper.

Results

Characteristics of Included Studies

Study

• Study Design: Phase 3 randomized controlled trial (open-label, multicenter, terminated early)
  • Advanced squamous or non-squamous non-small cell lung cancer (programmed death-ligand 1
  • sample size = 5
• Treatment Arms: Cemiplimab plus ipilimumab; Pembrolizumab
• Primary Endpoints: Progression-free survival (not assessed)

Efficacy by PD-L1 Expression Levels

Safety Findings

• In the Novartis Pharmaceuticals, 2024 study, 0–1 dose-limiting toxicities were mentioned in the safety run-in for pembrolizumab plus chemotherapy with or without canakinumab.
• There was no mention of grade 3-4 adverse events or treatment discontinuation in any of the other studies.

Limitations:

• Early termination and sample size: Several studies were terminated early or had small sample sizes, which limits interpretability.
• Incomplete safety reporting: Most studies did not provide safety and adverse event data, limiting assessment of tolerability.