Optimal Management of Patients with Advanced NSCLC Harboring High PD-L1 Expression and Driver Mutations
Justin A Chen1, Jonathan W Riess2
1Department of Internal Medicine, Division of Hematology and Oncology, UC Davis Comprehensive Cancer Center, 4501 X St, Suite 3016, Sacramento, CA, 95817, USA. jachen@ucdavis.edu.
Opinion Statement:
Patients with stage IV or recurrent/metastatic non-small cell lung cancer (NSCLC) whose tumors harbor high PD-L1 expression and driver mutations with approved targeted treatments (EGFR, ALK, BRAFV600E, ROS1) should receive initial therapy with targeted therapy based on impressive clinical activity. PD-(L)1 inhibitors have demonstrated minimal activity in many driver mutation subsets including EGFR and ALK and appears to have more benefit in smoking-associated oncogenic drivers (KRAS, BRAF). For KRAS-driven tumors, co-mutations such as STK11/LKB1 are negative predictive markers of immunotherapy with or without chemotherapy. Therefore, driver mutations need to be evaluated before pursuing immunotherapy independent of PD-L1 expression level. Caution should be used with TKIs following or concurrent with immunotherapy owing to potentially increased toxicity. New immunotherapy combinations are needed especially for oncogene-driven tumors associated with never or light smoking history.
Insights
For advanced non-small cell lung cancer (NSCLC), targeted therapy is recommended over immunotherapy for tumors with specific driver mutations like EGFR or ALK. Evaluating driver mutations before immunotherapy is crucial for treatment decisions.
Area of Science:
- Oncology
- Medical Oncology
- Translational Research
Background:
- Advanced non-small cell lung cancer (NSCLC) treatment landscape involves targeted therapies and immunotherapies.
- Tumor driver mutations and PD-L1 expression are key biomarkers for treatment selection.
- Optimal sequencing and combination strategies remain an area of active investigation.
Purpose of the Study:
- To provide an opinion statement on the optimal initial treatment strategy for patients with stage IV or recurrent/metastatic NSCLC.
- To evaluate the role of targeted therapy versus immunotherapy based on tumor driver mutations and PD-L1 expression.
- To highlight considerations for combining targeted therapies and immunotherapies.
Main Methods:
- Review of current clinical evidence and treatment guidelines for NSCLC.
- Analysis of the efficacy of targeted therapies and PD-(L)1 inhibitors in different molecular subsets.
- Consideration of predictive and prognostic markers for immunotherapy response.
Main Results:
- Targeted therapy is recommended for NSCLC with high PD-L1 and actionable driver mutations (EGFR, ALK, BRAF, ROS1).
- PD-(L)1 inhibitors show limited activity in EGFR/ALK-mutated NSCLC but may benefit KRAS/BRAF-driven tumors.
- STK11/LKB1 co-mutations are negative predictors for immunotherapy in KRAS-driven NSCLC.
- Driver mutation status should guide immunotherapy decisions, irrespective of PD-L1 levels.
- Concurrent or sequential use of TKIs and immunotherapy may increase toxicity.
Conclusions:
- Initial treatment for NSCLC with driver mutations and high PD-L1 should prioritize targeted therapy.
- Comprehensive genomic profiling is essential for guiding treatment selection in NSCLC.
- Further research is needed for novel immunotherapy combinations, particularly for oncogene-driven NSCLC in never/light smokers.
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