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Is There a Role for PD-L1 Inhibitors in EGFR-Mutant or ALK-Rearranged NSCLC?

*June 2022*

John Heymach, MD, PhD, discusses the poor outcomes that have been observed with immunotherapy in patients with NSCLC and EGFR mutations or ALK rearrangements.

An important exception to the use of PD-L1inhibitors as first-line therapy is for patients with oncogenic drivers. This is most strongly the case with EGFR and ALK rearrangements. For patients with EGFR and ALK, immunotherapy shouldn’t be part of the first-line therapy, and we can say that strongly and unequivocally. In fact, the NCCN [National Comprehensive Cancer Network] Guidelines dictate that for patients with EGFR/ALK alterations, PD-1 inhibitors are contraindicated in the first-line setting. Why is that? First, for patients with EGFRor ALK, the same applies to other driver oncogenes as well. They don’t respond well to immunotherapy, they often have a lower tumor mutational burden, and they usually have lower PD-L1levels. Even if a patient with an EGFR/ALK mutation has high PD-L1 levels, you should still use a targeted therapy first.

This was well described by a publication by Justin Gainor and colleagues that we collaborated on, with patients with EGFR mutation who had a greater than 50% PD-L1 level. They still didn’t respond well to immunotherapy. As unequivocally as I can say it, first-line patients, no matter what their PD-L1 level is, if they have an EGFR/ALK alteration, they should get the appropriate targeted therapy first and not immunotherapy. In those cases, I save immunotherapy for second or third-line therapy after they’ve progressed on an EGFR or ALK inhibitor, depending on what they have and sometimes multiple TKIs [tyrosine kinase inhibitors] before we consider moving to immunotherapy. Read more.