Purpose: 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