Challenges and Emerging Strategies in Overcoming Resistance in EGFR-Mutant NSCLC

Despite promising early results, adding immunotherapy to standard chemotherapy does not significantly improve outcomes for patients with EGFR-mutant non-small cell lung cancer (NSCLC) who have progressed after initial targeted therapy, according to an article published in the Journal of Clinical Oncology.

The KEYNOTE-789 phase III trial, which tested the addition of the immunotherapy drug pembrolizumab to platinum-based chemotherapy in patients with EGFR-mutant NSCLC who had progressed on prior EGFR tyrosine kinase inhibitors (TKIs), failed to meet its primary endpoints of improved progression-free survival (PFS) and overall survival (OS). This result aligns with the similarly designed but smaller CheckMate 722 trial, which also showed no significant benefit from adding the immunotherapy nivolumab to chemotherapy in this patient population.

These findings highlight the ongoing challenge of treating EGFR-mutant NSCLC after resistance develops to initial targeted therapies. While EGFR TKIs like osimertinib have become standard first-line treatment, options remain limited once these drugs stop working. The immunotherapy approach was hoped to provide a new option, but appears to have only modest activity in this setting.

However, some promise remains for combining immunotherapy with anti-angiogenic therapy (which targets blood vessel growth) alongside chemotherapy. The IMpower150 trial showed a potential survival benefit for adding both atezolizumab (immunotherapy) and bevacizumab (anti-angiogenic) to chemotherapy in EGFR-mutant patients. Two other trials, ORIENT-31 and ATTLAS, have also shown improved PFS with similar combinations.

Researchers are now focusing on identifying biomarkers that could help select which patients are most likely to benefit from immunotherapy approaches. They are also exploring novel combination strategies and new targeted therapies like amivantamab.

“Combination [checkpoint inhibitor] with VEGF inhibition has been shown to synergize in other tumor types such as hepatocellular carcinoma and renal cell carcinoma, and may play an important role in EGFR-mutant NSCLC by promoting dendritic cell maturation, blocking recruitment of immune-suppressive Treg cells and tumor-associated macrophages, and inducing PD-L1 expression,” explained Thanika Ketpueak, MD, Lung Unit, Royal Marsden Hospital in London, United Kingdom, Division of Oncology, Department of Internal Medicine, Chiang Mai University in Chiang Mai, Thailand, and coauthors.

Reference

Ketpueak T, Tan DSW, Popat S. Immunotherapy in EGFR-mutant non-small cell lung cancer: end of the road or the first chapter? J Clin Oncol. Published online August 26, 2024. doi:10.1200/JCO.24.00829