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


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

John V. Heymach, MD, PhD:
One challenge we face sometimes in the clinic is when patients have seen commercials for immunotherapy or read about immunotherapy, or a family friend or a loved one has read about immunotherapy, and they’re extremely enthusiastic about immunotherapy. The concept of stimulating your own immune system to fight tumors is certainly very appealing and scientifically sound. This is why it’s become part of our standard therapy for non–small cell lung cancer.

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.

Finally, a few studies have confirmed this finding. A meta-analysis showed that immunotherapy as a monotherapy doesn’t offer any OS [overall survival] benefit in EGFR-mutant non–small lung cancer. This was presented by [Chung Khoon] Lee and colleagues. There was an immunotherapy target analysis by [Robert] Motzer and colleagues in Annals of Oncology in 2019 that showed immunotherapy was less effective as frontline therapy for EGRF andALK fusions. As I noted before, there was publication by Gainor and colleagues for EGFRand ALK. Finally I’ll note a publication by [Marcelo] Negrao and colleagues in JITC, the Journal of Immunotherapy for Cancer, for patients with driver oncogenes: EGFR, ALK, HER2 [human epidermal growth factor receptor 2], RET, and so forth. Immunotherapy was also not highly effective as monotherapy.

Transcript edited for clarity.

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