Here we describe two patients with RET-positive advanced NSCLC with PD-L1 expression ≥ 50% who developed progressive disease during first-line treatment with the anti-PD-1 agent pembrolizumab. In particular, while patient 2 was immediately switched to treatment with a selective RET inhibitor within the setting of a clinical trial, patient 1 responded to cytotoxic chemotherapy delivered at the time of progression while on pembrolizumab.