[Verzenio (abemaciclib), a drug that has proven effective in breast cancer,] showed preliminary activity in its first-ever clinical trial in mesothelioma.
The cyclin-dependent kinase (CDK) 4/6 inhibitor [Verzenio (abemaciclib)] achieved disease control at 12 weeks in 14 of 26 patients with progressive mesothelioma associated with a CDKN2A mutation and loss of the tumor suppressor p16ink4A. Grade ≥3 treatment-related adverse events occurred in three patients.
The MiST2 trial met the primary endpoint, and [Verzenio (abemaciclib)] earned consideration for further study in p16ink4A-negative mesothelioma, reported Dean Fennell, MD, PhD, of the Leicester Cancer Research Center in England, and co-authors in Lancet Oncology.
“A key pan-cancer study in Nature Communications last year showed that the mutation investigated in MiST2 is associated with lower response to immunotherapy,” Fennell told MedPage Today via email. “This has not yet been validated in mesothelioma, but suggests that [Verzenio (abemaciclib)] may be a suitable targeted therapy in this common subgroup.”
“Based on the results of MiST2, a randomised study to further evaluate CDK4/6 inhibition is certainly warranted,” he added.
Following recent advances in understanding of the molecular biology of cancer, immunotherapy has proven ability to extend survival in mesothelioma. Unfortunately, improved understanding of the genomic landscape of mesothelioma has not translated into effective targeted therapies, Fennell and co-authors noted in their introduction. A substantial unmet therapeutic need remains, particularly in the setting of relapse beyond second line.
Most mesotheliomas have copy number alterations in the short arm of chromosome 9 (9p21.3), which encompasses the tumor suppressor gene CDKN2A-MTAP that encodes for both CDK4 and the CDK6 inhibitor p16ink4A. Restoring p16ink4A leads to synthetic lethality in preclinical models of CDKN2A-negative mesothelioma.
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