麻豆传媒

A drug that made its mark in breast cancer showed preliminary activity in its first-ever clinical trial in mesothelioma.

The cyclin-dependent kinase (CDK) 4/6 inhibitor abemaciclib (Verzenio) 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 trial met the primary endpoint, and 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 .

"A key pan-cancer study in last year showed that the mutation investigated in MiST2 is associated with lower response to immunotherapy," Fennell told 麻豆传媒 via email. "This has not yet been validated in mesothelioma, but suggests that 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 in preclinical models of CDKN2A-negative mesothelioma.

Fennell and colleagues hypothesized that inhibition of CDK4 and 6 would effectively target p16ink4A-deficient mesotheliomas. To test the hypothesis, they enrolled patients with progressive mesothelioma treated with one or more prior lines of therapy, which must have included standard first-line pemetrexed and either cisplatin or carboplatin. Patients were screened for p16ink4A, BAP1, BRCA1, and PD-L1.

Patients received standard-dose abemaciclib daily in 28-day cycles for 24 weeks. The primary endpoint was disease control (response or stable disease) at 12 weeks after receipt of at least one dose of abemaciclib. Secondary endpoints included safety and toxicity, 24-week disease control, and best objective response rate. The trial would be considered positive if at least 11 (42%) patients met the primary endpoint.

Investigators screened 30 patents, 26 of whom received abemaciclib. Subsequently, 14 of the 26 patients had CT scans at 12 weeks and seven had follow-up scans at 24 weeks. All 26 patients tested negative for p16.

The results showed a 12-week disease control rate (DCR) of 54%, and 16 of 20 (80%) evaluable patients had some degree of tumor reduction at 24 weeks. DCR included one partial response at 12 weeks and four at 24 weeks. Post hoc analyses showed a median progression-free survival of 128 days and median overall survival of 217 days.

A post hoc analysis showed loss of MTAP expression in 11 of 25 evaluable patients. MTAP-negative mesotheliomas had significantly greater reduction in tumor volume after treatment with abemaciclib (-18% vs 0% for MTAP-positive tumors), and patients with MTAP-negative tumors had disease progression as best response.

Five (19%) patients had grade 3 adverse events (AEs) consisting of one case each of diarrhea, dyspnea, vomiting, urinary tract infection, and ascites. Two (8%) had grade 4 AEs, consisting of one case of thrombocytopenia and one of increased alanine aminotransferase. One patient died of neutropenic sepsis.

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