Pointed Progress in Second-Line Advanced Non-Small-Cell Lung Cancer: The Rapidly Evolving Field of Checkpoint
Barbara Melosky1, Quincy Chu2, Rosalyn Juergens2
1Barbara Melosky, British Columbia Cancer Agency, Vancouver Centre, Vancouver, British Columbia; Quincy Chu, Cross Cancer Institute and University of Alberta, Edmonton, Alberta; Rosalyn Juergens, McMaster University, Juravinski Cancer Centre, Hamilton; Natasha Leighl, Princess Margaret Hospital and University of Toronto; Deanna McLeod, Kaleidoscope Strategic, Toronto, Ontario; and Vera Hirsh, Montreal General Hospital, Royal Victoria Hospital, and McGill University, Montreal, Quebec, Canada. bmelosky@bccancer.bc.ca.
Purpose:
Non-small-cell lung cancer (NSCLC) is globally prevalent and associated with high rates of mortality. Immune checkpoint pathways are often exploited by tumors to evade immunity-mediated destruction, and checkpoint inhibitors can reactivate tumor-related immune responses. This review considers available clinical evidence for the use of checkpoint inhibitors in the treatment of second-line advanced NSCLC.
Methods:
Our systematic search revealed 20 clinical trials evaluating checkpoint inhibitors in the second-line setting, three of which were randomized trials comparing programmed cell death protein 1 and programmed death ligand 1 (PD-L1) inhibitors to docetaxel, the current standard of care in this setting.
Results:
A randomized phase II trial comparing the PD-L1 inhibitor atezolizumab to docetaxel did not demonstrate improved survival for atezolizumab in patients overall, although a trend toward improved survival with increased PD-L1 expression was apparent. Twin phase III trials showed significantly improved survival for the programmed cell death protein 1 inhibitor nivolumab compared with docetaxel in patients with both squamous and nonsquamous disease. PD-L1 expression correlated with improved survival in patients with nonsquamous disease, and patients with low levels of PD-L1 expression (< 10%) and those with EGFR mutations are unlikely to benefit. Checkpoint inhibitor therapy is generally well tolerated and associated with low rates of grade 3 or 4 adverse events compared with standard care.
Conclusion:
Level 1 evidence exists to support the use of nivolumab as second-line treatment of patients with squamous advanced NSCLC, as well as in select patients with nonsquamous disease. Benefits remain unknown in patients with targetable driver mutations, and use of PD-L1 expression to guide therapy remains controversial. Results from ongoing randomized trials evaluating biomarkers and other checkpoint inhibitors will further our understanding of this rapidly evolving area of oncology.
Insights
Nivolumab improves survival in second-line advanced non-small-cell lung cancer (NSCLC). Programmed cell death protein 1 (PD-1) inhibitors offer a well-tolerated option for select NSCLC patients, but PD-L1 expression and mutations impact efficacy.
Area of Science:
- Oncology
- Immunotherapy
- Clinical Trials
Background:
- Non-small-cell lung cancer (NSCLC) presents a significant global health challenge with high mortality rates.
- Tumors often evade immune surveillance through immune checkpoint pathways.
- Immune checkpoint inhibitors (ICIs) offer a strategy to restore anti-tumor immunity.
Purpose of the Study:
- To review clinical evidence for ICI use in second-line advanced NSCLC.
- To evaluate the efficacy and safety of PD-1 and PD-L1 inhibitors compared to docetaxel.
Main Methods:
- Systematic search of 20 clinical trials in the second-line NSCLC setting.
- Focus on three randomized trials comparing ICIs (nivolumab, atezolizumab) to docetaxel.
Main Results:
- Nivolumab demonstrated significantly improved survival versus docetaxel in both squamous and nonsquamous NSCLC.
- Atezolizumab did not show overall survival benefit, but a trend was observed with higher PD-L1 expression.
- PD-L1 expression correlated with survival in nonsquamous NSCLC; low PD-L1 (<10%) and EGFR mutations predicted poor response.
- ICI therapy was generally well-tolerated with fewer severe adverse events than docetaxel.
Conclusions:
- Nivolumab is supported by Level 1 evidence for second-line advanced NSCLC, particularly squamous histology and select nonsquamous cases.
- Efficacy in patients with targetable driver mutations requires further investigation.
- The role of PD-L1 expression in guiding therapy remains under evaluation, with ongoing trials expected to clarify its utility.
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