Drug Design, Development and Therapy (May 2019)
Frequency, clinical features and differential response to therapy of concurrent ALK/EGFR alterations in Chinese lung cancer patients
Abstract
Jixian Liu,1,* Zhimin Mu,1,* Li Liu,2 Kang Li,2 Richeng Jiang,3 Peng Chen,3 Qiang Zhou,4 Meiling Jin,5 Yuxiang Ma,6 Yuancai Xie,1 Jianxing Xiang,7 Bing Li,7 Yafeng Ma,7 Xinru Mao,7 Lu Zhang,7 Tengfei Zhang,7 Da Wu11Department of Thoracic Surgery, Peking University Shenzhen Hospital, Shenzhen 518035, People’s Republic of China; 2Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital, Affiliated Cancer Hospital of Xiangya School of Medicine, Changsha 410000, People’s Republic of China; 3Department of Thoracic Oncology, Tianjin Cancer Institute & Hospital, Tianjin Medical University, Tianjin 300000, People’s Republic of China; 4Department of Oncology I, Yueyang First People‘s Hospital, Yueyang 414000, People’s Republic of China; 5Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai 200000, People’s Republic of China; 6Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510000, People’s Republic of China; 7Burning Rock Biotech, Guangzhou 510000, People’s Republic of China*These authors contributed equally to this workPurpose: EGFR and anaplastic lymphoma kinase (ALK) alterations have been regarded as oncogenic drivers and incorporated into clinical practices to manage nonsmall cell lung cancer (NSCLC). Alterations of these two genes were traditionally considered to be mutually exclusive, but recent studies have suggested that they can occur concomitantly. Here, we investigated the prevalence, clinical features and outcomes in response to the treatment of NSCLC patients who harbor EGFR and ALK co-alterations.Methods: We reviewed the genomic profiles of 419 ALK-rearranged NSCLC patients with the intent of investigating the EGFR kinase domain (exon 18–21) and ALK co-alterations. The genomes of these patients were sequenced in a Clinical Laboratory Improvement Amendments-certified laboratory.Results: The overall frequency of concomitant EGFR (exon 18–21) and ALK alterations was 5.01% (21/419) in ALK-rearranged NSCLC patients. The concomitant rate of EGFR alterations in patients with EML4-ALK co-alterations (3.06%, 11/359) was dramatically lower than that in patients with non-EML4-ALK co-alterations (16.67%, 10/60, p<0.01). EML4-ALK/EGF R co-alterations were more prone to occur in females than in males, and non-EML4-ALK/EGFR co-alterations were more common in males than in females (p=0.02). Before the detection of EGFR-ALK co-alterations, some patients were treated with EGFR-TKIs (n=16) according to previously detected EGFR alterations; Kaplan–Meier analysis revealed that EML4-ALK/EGFR co-altered patients (n=7) had a significantly shorter progression-free survival (PFS) after EGFR-TKI treatment than that of non-EML4-ALK/EGFR co-altered patients (n=8; mPFS, 6.0 vs 15.0 months, p=0.046). In addition, we demonstrated the subsequent clinical outcomes of co-altered patients after previous EGFR-TKI treatment. Five EGFR/ALK co-altered patients treated with single TKIs (EGFR-TKIs or ALK-TKIs) displayed diverse clinical outcomes. Three patients who received dual-TKI treatment (EGFR-TKI plus ALK-TKI) all achieved a PFS of more than 5 months (8.4 months, 8.6 months, >5.2 months).Conclusion: EML4-ALK/EGFR and non-EML4-ALK/EGFR co-alterations displayed distinct clinical features and responses to EGFR-TKIs, suggesting that non-EML4-ALK co-alterations are likely to occur as a resistance mechanism to EGFR-TKI. In addition, dual-TKI therapy might be a better choice than single-TKI treatments for these co-altered patients. To the best of our knowledge, this is the largest dual-positive EGFR/ALK cohort study in People’s Republic of China.Keywords: EGFR alteration, ALK rearrangement, nonsmall cell lung cancer, EML4-ALK, tyrosine kinase inhibitor
