Rearranged during transfection (RET) gene rearrangements are found in approximately 2% of patients with non-small cell lung cancer (NSCLC). Importantly, the presence of these rearrangements predicts patient response to treatment with selective RET inhibitors.

The efficacy of immune checkpoint inhibitors in RET-positive NSCLC, however, has not yet been sufficiently established.

We describe two patients with RET-positive advanced NSCLC with anti-programmed cell death-ligand 1 (PD-L1) ≥ 50% who experienced progressive disease on first-line immunotherapy with pembrolizumab.

Our data, together with data reported in the literature, suggest that patients with RET-positive NSCLC are unlikely to benefit from immunotherapy.

Rather, selective RET inhibitors (if available) or cytotoxic chemotherapy (with or without immunotherapy) should be considered as the preferred treatment option in this context, regardless of the PD-L1 status of the tumor.