Frequency, clinical features and differential response to therapy of concurrent ALK/EGFR alterations in Chinese lung cancer patients

Abstract

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

Acknowledgments

The authors wish to thank Burning Rock Biotech for their technical and writing assistance. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The abstract of this paper was presented at the 2018 World Conferences on Lung Cancer (Asia) as a poster presentation with interim findings. The poster’s abstract was published in “Poster Abstracts” in 2018 Journal of Thoracic Oncology (DOI: https://doi.org/10.1016/j.jtho.2018.10.035).

Disclosure

The authors report no conflicts of interest in this work.