Publication-only abstracts (abstract number preceded by an "e"), published in conjunction with the 2019 ASCO Annual Meeting but not presented at the Meeting, can be found online only.
Comprehensive genomic profiling identifies novel genetic predictors of response to anti-PD-(L)1 therapies in NSCLC.
Metastatic Non-Small Cell Lung Cancer
Lung Cancer—Non-Small Cell Metastatic
2019 ASCO Annual Meeting
J Clin Oncol 37, 2019 (suppl; abstr e20536)
Author(s): Wenfeng Fang, Yuxiang Ma, Jiani Yin, Shaodong Hong, Huaqiang Zhou, Ao Wang, Fufeng Wang, Hua Bao, Xue Wu, Yunpeng Yang, Yan Huang, Hongyun Zhao, Yang Shao, Li Zhang; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Sun Yat-Sen University Cancer Center, Guangzhou, China; Nanjing Geneseeq Technology Inc., Nanjing, China; Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China; Translational Medicine Research Institute, Geneseeq Technology Inc., Toronto, ON, Canada; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Sun Yat-sen University Cancer Center, Guangzhou, China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
Background: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of many different cancer types, including non-small-cell lung cancer (NSCLC). However, our understandings of the molecular and immunologic determinants of response to ICIs remain incomplete. Methods: We performed whole-exon sequencing (WES) in 73 patients with advanced NSCLC who underwent anti-PD-(L)1 therapies to further explore predictive biomarkers for treatment efficacy. Novel somatic mutations and copy number alterations were identified to be predictive of response or resistance to anti-PD-(L)1 therapies. Results: We confirmed that high tumor mutation burden (TMB) was associated with improved clinical outcomes. Quantification of TMB by targeted next-generation sequencing using a customized panel including 422 cancer-relevant genes (Geneseeq) was strongly correlated with WES results (Spearman's Rho = 0.81, p< 0.001). Patients whose tumour harbored FAT1 mutant had higher durable clinical response (DCB) and objective response rate (ORR) compared with wild-type (62.5% vs 20%, p = 0.02, and 50% vs 12.3%, p = 0.02, respectively), whereas patients with activating mutations in EGFR or ERBB2 had significantly shorter mPFS compared with other patients (51 vs 70.5 days, p = 0.0037, HR = 2.47 [95% CI, 1.33-4.62]). Furthermore, We found copy number loss in specific 3p segments (mPFS, 61.5 vs 65 days; survival rates at 6 months, 0% vs 31%, p = 0.012, HR = 2.08 [95% CI, 1.09-4.00]), which contain the tumor suppressor ITGA9 (mPFS, 36.5 vs 64 days, p< 0.0001, HR = 9.09 [95% CI, 2.91-27.78]) and several chemokine receptor pathway genes, were highly predictive of poor clinical outcome. These findings were further validated in two independently published datasets comprising multiple cancer types. Conclusions: Our findings suggest that comprehensive profiling of TMB and the aforementioned novel genetic alterations could result in greater predictive power of response in NSCLC patients treated with ICI therapies.