Distinct survival, optimal combination strategy of immunotherapy, and immunophenotype in uncommon and 20ins EGFR-mut lung adenocarcinoma: a multi-center study

The efficiency and optimal combination strategies of immune checkpoint inhibitors (ICI) in lung adenocarcinoma (LUAD) patients with epidermal growth factor receptor (EGFR) other mutations apart from 19del/L858R (classical), which account for up to 20% EGFR mutations, remains unclear. In this retrospective multi-center study, a total of 656 EGFR-mut patients receiving ICI alone or with other therapies from several centers were integrated as three independent cohorts and divided into uncommon, classical, and 20ins groups. In all three cohorts, patients in the EGFR uncommon group had longer median progression-free survival (mPFS) than classical or 20ins groups, and longer median overall survival (mOS) than classical group, which were more significant in programmed cell death-ligand 1 (PD-L1) ≥ 1% subgroup. For uncommon group, the mPFS and mOS of ICI alone were similar to ICI plus chemotherapy, but longer than chemotherapy. For 20ins group, the mPFS of ICI plus chemotherapy was longer than ICI alone or chemotherapy. For classical group, ICI plus chemotherapy and anti-angiogenic therapies or plus chemotherapy were found to prolong mPFS than chemotherapy. The tumor mutation burden (TMB) of the uncommon group was relatively higher than classical or 20ins group, with similar PD-L1 expression across them. Uncommon group had more M1 macrophages, less Tregs and M2 macrophages infiltrations than classical or 20ins group. Conclusively, LUAD patients with different EGFR mutations responded to ICI diversely, deserving customed stratification of ICI-based therapies according to specific mutations. EGFR uncommon mutations were linked to relatively higher TMB and heterogeneous immune cell infiltrations.