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Updated: Oct 9, 2025
Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
Immunotherapy in Non-Small Cell Lung Cancer With Actionable Mutations Other Than EGFR
Karan Seegobin1, Umair Majeed1, Nathaniel Wiest2
1Division of Hematology and Oncology, Mayo Clinic, Jacksonville, FL, United States.
Abstract:
While first line targeted therapies are the current standard of care treatment for non-small cell lung cancer (NSCLC) with actionable mutations, the cancer cells inevitably acquire resistance to these agents over time. Immune check-point inhibitors (ICIs) have improved the outcomes of metastatic NSCLC, however, its efficacy in those with targetable drivers is largely unknown. In this manuscript, we reviewed the published data on ICI therapies in NSCLC with ALK, ROS1, BRAF, c-MET, RET, NTRK, KRAS, and HER2 (ERBB2) alterations. We found that the objective response rates (ORRs) associated with ICI treatments in lung cancers harboring the BRAF (0-54%), c-MET (12-49%), and KRAS (18.7-66.7%) alterations were comparable to non-mutant NSCLC, whereas the ORRs in RET fusion NSCLC (less than10% in all studies but one) and ALK fusion NSCLC (0%) were relatively low. The ORRs reported in small numbers of patients and studies of ROS1 fusion, NTRK fusion, and HER 2 mutant NSCLC were 0-17%, 50% and 7-23%, respectively, making the efficacy of ICIs in these groups of patients less clear. In most studies, no significant correlation between treatment outcome and PD-L1 expression or tumor mutation burden (TMB) was identified, and how to select patients with NSCLC harboring actionable mutations who will likely benefit from ICI treatment remains unknown.
Insights
Immune checkpoint inhibitors show variable efficacy in non-small cell lung cancer (NSCLC) with specific mutations. Response rates differ significantly across driver alterations, and patient selection for these therapies remains challenging.
Area of Science:
- Oncology
- Immunotherapy
- Genomics
Background:
- Targeted therapies are standard for NSCLC with actionable mutations but resistance develops.
- Immune checkpoint inhibitors (ICIs) have improved outcomes in metastatic NSCLC.
- ICI efficacy in NSCLC with targetable drivers is not well understood.
Purpose of the Study:
- To review published data on ICI therapies in NSCLC with specific driver alterations.
- To evaluate the objective response rates (ORRs) of ICIs in NSCLC harboring ALK, ROS1, BRAF, c-MET, RET, NTRK, KRAS, and HER2 alterations.
Main Methods:
- Systematic review of published studies on ICI treatment for NSCLC with actionable mutations.
- Analysis of objective response rates (ORRs) reported in the literature.
- Assessment of correlation between treatment outcomes and PD-L1 expression or tumor mutation burden (TMB).
Main Results:
- ICI ORRs in BRAF, c-MET, and KRAS-altered NSCLC were comparable to non-mutant NSCLC.
- Low ORRs were observed in RET and ALK fusion NSCLC.
- Efficacy of ICIs in ROS1, NTRK, and HER2 altered NSCLC remains unclear due to limited data.
- No significant correlation found between PD-L1 expression/TMB and treatment outcomes.
Conclusions:
- ICI efficacy varies considerably across different actionable driver alterations in NSCLC.
- Current biomarkers like PD-L1 and TMB do not reliably predict ICI response in these patients.
- Further research is needed to identify predictive biomarkers and optimize ICI selection for NSCLC with targetable drivers.
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