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EGFR mutations and ALK rearrangements are associated with low response rates to PD-1 pathway blockade in non-small cell lung cancer: A retrospective analysis

Gainor, J.F., Shaw, A.T., Sequist, L.V., (...), Engelman, J.A., Mino-Kenudson, M.

Clinical Cancer Research, 2016 Sep 15;22(18):4585-93

Commentary by Tom Stinchcombe

In subset analyses of phase 3 clinical trials, patients with a known EGFR mutation have experienced similar benefit from immunotherapy compared to chemotherapy. Patients who are never-smokers have been observed to have a lower response rate compared to ever smokers presumably due to a lower tumor mutational load. This retrospective study identified 58 patients treated with PD-1/PD-L1 inhibitors, and the objective response rate observed in patients with an EGFR mutant or ALK rearrangement compared to EGFR wild-type or ALK-negative was 3.6% and 23.3% (P=0.053). The objective response rate in patients with a history of never or light-smoking and heavy smoking was 4.2% and 20.6% (P=0.123) Among patients with EGFR mutant NSCLC (N=57) the PD-L1 expression levels changed after the development resistance in 16 patients (28%). Concurrent PD-L1 expression (≥5%) and high levels of tumor infiltrating cells were observed in only 1 pretreatment (2.1%) and 5 resistant (11.6%) EGFR mutant specimens. This study is small but corroborates other studies which have shown less benefit from immunotherapy in patients with EGFR mutant or ALK positive NSCLC, and a lower rate of PD-L1 expression or immune activation is the best hypothesis for the reduced activity in patients. The number of patients who had a change in the PD-L1 status raises concerns if the PD-L1 status is tested on archival tissue it may not reflect the current PD-L1 status.

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