The safety and efficacy of anti-PD-1 inhibitor-based combinational therapy in non-small cell lung cancer patients with oncogenic alterations.

Background: The anti-programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) immunotherapy has been extensively used in patients with non-small cell lung cancer (NSCLC) in which the tumors are negative for oncogenic alterations. However, whether PD-1/PD-L1 blockade therapy could be applicable in patients harboring oncogenic mutations is largely unknown.

Methods: In this retrospective study, we analyzed the safety and efficacy of anti-PD-1 inhibitor-based combinational therapy in a NSCLC cohort of 84 patients who harbored oncogenic alterations in epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), k-Ras, RET, HER2 and BRAF. The patients were followed up till disease progression or death. The adverse effects associated with the treatment were carefully evaluated and timely interrupted.

Results: There were 50 patients harboring EGFR mutations, 17 patients with k-Ras mutation, 2 patients with ALK rearrangement, 6 patients with RET rearrangement, 6 patients with HER2 exon20 insertion and 3 patients with BRAF V600E mutation. About 58.8% of the k-Ras mutant patients responded to the combinational treatment. The median progression-free survival (mPFS) of the k-Ras cohort was 14 months, with the 12-month median overall survival (mOS) ratio and the 24-month OS ratio of 86.7% and 75.8%, respectively. Patients with mutation or RET rearrangement tended to have a more favorable response, while patients harboring ALK rearrangement, HER2 exon20 insertion and BRAF V600E mutation did not respond well to anti-PD-1 inhibitor-based combinational therapy. The incidence of treatment-related toxicity was 52.3% and the most common immune-related adverse events (irAEs) were PD-1 inhibitors-related hypothyroidism and pneumonitis. The PD-L1 status and lung immune prognostic index (LIPI) could be used as biomarkers dictating therapeutic outcomes of the combinational therapy.

Conclusions: The anti-PD-1 inhibitor-based combinational therapy elicited exciting anti-tumor efficacy and prolonged patient survival with manageable adverse effects in NSCLC patients harboring oncogenic alterations. The PD-L1 status and LIPI could be used as a biomarker predicting response to anti-PD-1 inhibitor-based combinational treatment in these patients.