Limited Benefit from the Addition of Immunotherapy to Chemotherapy in TKI-Refractory EGFR-Mutant Lung Adenocarcinoma

SIMPLE SUMMARY: Although it is known that anti-PD1/L1 monotherapy does not render significant benefit in patients with EGFR-mutant lung adenocarcinoma, whether the addition of anti-PD1/L1 therapy to chemotherapy can enhance chemotherapy efficacy for TKI-refractory EGFR-mutant lung adenocarcinoma patients is not clear. To address this question, we retrospectively analyzed a cohort of 178 EGFR-mutant lung adenocarcinoma patients who had progressed on EGFR TKIs and received subsequent non-TKI systemic therapy to determine whether the addition of immunotherapy to chemotherapy truly improves clinical outcomes. We found that the addition of anti-PD1 immunotherapy did not add benefit to the platinum-based chemotherapy at the time of TKI progression for EGFR-mutant LUAD. Although underpowered, the anti-VEGF therapy demonstrated a trend towards adding benefit. As ongoing clinical trials with newer agents or combinations demonstrate preliminary efficacy in TKI-resistant EGFR-mutant LUAD patients, the ideal choice for post-TKI treatment is still being evaluated. ABSTRACT: Background: The benefit of chemotherapy combined with immunotherapy in EGFR-mutant lung adenocarcinoma (LUAD) patients whose tumor developed resistance to EGFR tyrosine kinase inhibitors (TKIs) is not thoroughly investigated. The goal of this retrospective cohort study is to assess the clinical efficiency of immunotherapy alone or in combination with chemotherapy in a real-world setting. Methods: This retrospective cohort study enrolled LUAD patients with EGFR sensitive mutations whose tumor had acquired resistance to EGFR TKIs and received systemic treatment with chemotherapy (chemo; n = 84), chemotherapy combined with immunotherapy (chemoIO; n = 30), chemotherapy plus bevacizumab with or without IO (withBev; n = 42), and IO monotherapy (IO-mono; n = 22). Clinical progression-free survival (PFS) and overall survival (OS) were evaluated. Associations of clinical characteristics with outcomes were assessed using univariable and multi-covariate Cox Proportional Hazards regression models. Results: A total of 178 patients (median age = 63.3; 57.9% females) with a median follow-up time of 42.0 (Interquartile range: 22.9–67.8) months were enrolled. There was no significant difference in PFS between chemoIO vs. chemo groups (5.3 vs. 4.8 months, p = 0.8). Compared to the chemo group, patients who received withBev therapy trended towards better PFS (6.1 months vs. 4.8; p = 0.3; HR 0.79; 95% CI: 0.52–1.20), while patients treated with IO-mono had inferior PFS (2.2 months; p = 0.001; HR 2.22; 95% CI: 1.37–3.59). Furthermore, PD-L1 level was not associated with PFS benefit in the chemoIO group. Patients with EGFR-mutant LUAD with high PD-L1 (≥50%) had shorter PFS (5.8 months) than non-EGFR/ALK LUAD patients who received chemoIO (12.8 months, p = 0.002; HR 0.22; 95% CI: 0.08–0.56) as first-line treatment. Chemotherapy-based therapy rendered similar benefit to patients with either EGFR exon19 deletion vs. L858R in the LUAD. Conclusions: This retrospective analysis revealed that immunotherapy provided limited additional benefit to chemotherapy in TKI-refractory EGFR-mutant LUAD. Chemotherapy alone or combined with bevacizumab remain good choices for patients with actionable EGFR mutations.