Tumor Mutation Burden Correlates With Efficacy of Chemotherapy/Targeted Therapy in Advanced Non-Small Cell Lung Cancer

Abstract

Objectives: Accumulating evidence has illustrated greater benefit of immunotherapy in tumors with high tumor mutation burden (TMB), whereas its impact on targeted therapy or chemotherapy is undefined. Herein, we evaluated TMB outside of immuno-oncology in epidermal growth factor receptor (EGFR)-mutant patients and EGFR/ALK wild-type cohorts. Methods: In this retrospective study, we correlated TMB with response rate and progression-free survival (PFS) of patients who received EGFR-tyrosine kinase inhibitors (TKIs) or pemetrexed/platinum as first-line therapy. Tumor mutation burden was evaluated by targeted next-generation sequencing. Patients were divided into low (L)/intermediate (I)/high (H) TMB groups by tertiles. Results: In EGFR-mutant cohort, TMB-L patients had a massively improved PFS compared to TMB-I and TMB-H patients (16.4 vs. 9.0 vs. 7.4 months; log-rank p = 0.006) when treated with first-generation EGFR-TKIs. In EGFR/ALK wild-type cohorts who received pemetrexed/platinum regimen, the objective response rate (ORR) of TMB-L group was statistically superior than that of TMB-I and TMB-H groups (53.8% vs. 23% vs. 8.3%; log-rank p = 0.037), and patients with low TMB had a numerically but not significantly prolonged PFS (6.9 vs. 4.3 vs. 4.6 m; log-rank p = 0.22). Conclusion: Our data provide insights into the relevance between TMB and targeted/chemo therapy. Higher non-synonymous TMB correlates with inferior PFS for first-generation EGFR-TKIs in EGFR-driven patients and worse response to pemetrexed/platinum regimen in EGFR/ALK wild-type patients, which has potential clinical implications for cancer treatment but needs corroboration in larger studies.

Keywords: chemotherapy; clinical benefit; epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs); non–small cell lung cancer (NSCLC); tumor mutation burden (TMB).

Figure 1

The mutational gene profiles of all 198 patients with advanced non–small cell lung cancer.

Figure 2

The comparisons of TMB in different subgroups. (A) Tumor mutation burden comparison of EGFR-mutant, ALK-fusion, E/A-negative (EGFR/ALK–negative driver mutations, including BRAF/HER2/KRAS/NRAS/MET/ROS1/RET), and pan-negative (tumors that lack mutations in known targetable genes) groups. (B) The correlation between demographics or clinicopathologic features and TMB. (C) Tumor mutation burden comparison in DDR-positive group and DDR-negative group. (D) The proportion of DDR-positive and -negative patients in low (L)/intermediate (I)/high (H) TMB groups.

Figure 3

Tumor mutation burden and survival outcome in EGFR-mutant patients. (A) Progression-free survival of EGFR-mutant patients using first generation of EGFR-TKIs stratified by tertiles of TMB. (B) ORR of EGFR-TKIs in EGFR-mutant patients of TMB L/I/H groups. (C) Progression-free survival of EGFR-mutant patients divided by three mutational subtypes. (D) Progression-free survival of EGFR-mutant patients divided by DDR genes status. (E) Hazard ratio (Mantel–Haenszel method) and p-value (log-rank) for subgroups evaluating PFS of EGFR-TKIs in EGFR-mutant patients stratified by low vs. intermediate/high TMB.

Figure 4

Tumor mutation burden and survival outcome in patients receiving chemotherapy. (A) Progression-free survival of EGFR/ALK WT patients using pemetrexed/platinum stratified by tertiles of TMB. (B) ORR of pemetrexed/platinum chemotherapy in EGFR/ALK WT patients of TMB L/I/H groups. (C) Progression-free survival of EGFR/ALK WT patients divided by TP53 status. (D) The proportion of TP53 mutant or WT patients in TMB L/I/H groups. (E) Hazard ratio (Mantel–Haenszel method) and p-value (log-rank) for subgroups evaluating PFS of pemetrexed/platinum in EGFR/ALK WT patients stratified by low vs. intermediate/high TMB.