How would you approach first-line treatment in metastatic NSCLC for a patient with ALK-EML4 V3a/b variant and MSI-high status?

Both ALK and MSI-high status were noted on a liquid biopsy since there was not enough tissue available for molecular testing. Some reports suggest lower sensitivity to ALK inhibitors with variant 3a/b (at least 1st and 2nd generation). Would this change your choice of starting with an ALK TKI?

1 Answer

Mednet MemberInvited Expert

Medical Oncology · University of Colorado Anschutz Medical Center

Answered on · Updated on

It's a good question. I would first confirm the MSI-high status using tissue-based testing. I would recommend a pathology re-review in light of these molecular findings, and consider the possibility that this could be metastatic colorectal cancer. While EML4-ALK fusions are most common in NSCLC, they have also been seen in colorectal carcinomas [Lasota et al., PMID 32804454, Hu et al., PMID 38381603, Lin et al., PMID 19737969], especially given the concurrent finding of microsatellite instability, which is exceptionally rare in lung cancer. [Yang et al., PMID 37838086]

Regarding sequencing, I would still favor ALK TKIs (specifically lorlatinib) first and keep immune checkpoint inhibitors on reserve. The reason for this sequence is the higher rates of hepatotoxicity seen with ALK TKIs when patients have prior immunotherapy exposure. [Lin et al., PMID 30205166]