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

Chen Lin; Xun Shi; Jun Zhao; Qiong He; Yun Fan; Weizhen Xu; Yang Shao; Xinmin Yu; Ying Jin

doi:10.3389/fonc.2020.00480

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

Front Oncol. 2020 Apr 29:10:480. doi: 10.3389/fonc.2020.00480. eCollection 2020.

Authors

Chen Lin^{1

2

3}, Xun Shi^{1

2

3}, Jun Zhao^{1

2

3}, Qiong He^{1

2

3}, Yun Fan^{1

2

3}, Weizhen Xu^{1

4}, Yang Shao⁵, Xinmin Yu^{1

2

3

6}, Ying Jin^{1

2

3

7}

Affiliations

¹ Institute of Cancer and Basic Medicine (ICBM), Chinese Academy of Sciences, Hangzhou, China.
² Department of Medical Oncology, Cancer Hospital of the University of Chinese Academy of Sciences, Hangzhou, China.
³ Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, China.
⁴ Clinical Trials Center, Zhejiang Cancer Hospital, Hangzhou, China.
⁵ Nanjing Geneseeq Technology Inc., Nangjing, China.
⁶ Zhejiang Key Laboratory of Diagnosis and Treatment Technology of Thoracic Oncology, Hangzhou, China.
⁷ Zhejiang Key Laboratory of Radiation Oncology, Hangzhou, China.

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).