Patients with Mesothelioma See No Survival Benefit With Defactinib Maintenance Therapy

Maintenance therapy with defactinib failed to improve survival following front-line chemotherapy in patients with merlin-low malignant pleural mesothelioma, according to results from the phase 2 COMMAND trial.

“Defactinib cannot be recommended as maintenance therapy for advanced (malignant pleural mesothelioma),” the researchers wrote.

With limited treatment options for malignant pleural mesothelioma — an incurable cancer that is a consequence of asbestos exposure – combined pemetrexed with cisplatin is the only current first-line therapy for these patients. However, efficacy with the chemotherapy regimen is limited and there are no approved maintenance treatments or a therapy approved for when disease progression occurs.

As precision medicine and targeted therapies continue to flourish in the treatment landscape of various cancer types, it is “underexplored” among those with malignant pleural mesothelioma, according to the researchers.

Merlin-low is a type of expression found in malignant pleural mesothelioma that is associated with an increased sensitivity to FAK inhibitors, such as defactinib.

Therefore, the researchers conducted the global, double-blind, randomized, placebo-controlled COMMAND (Control Of Mesothelioma with MAiNtenance Defactinib) trial to evaluate the efficacy of defactinib in 344 patients with merlin-low malignant pleural mesothelioma as maintenance therapy after at least four cycles of standard first-line chemotherapy.

Progression-free survival — or the time from treatment to disease worsening – and overall survival served as the study’s co-primary endpoints, while quality of life was also evaluated.

Patients were randomized 1:1 to receive either oral defactinib (173 patients) or placebo (171 patients) until disease progression, unacceptable toxicity or withdrawal occurred. Seventy-two patients in the defactinib arm and 71 in the placebo arm were considered merlin-low.

The majority of patients were men (84%) and the median age was 68 years.

The median progression-free survival was just 4.1 months with defactinib, compared with 4.0 months with placebo, and was 4.5 and 2.8 months for patients who had merlin-high and merlin-low disease, respectively, in the treatment arm.

Meanwhile, overall survival was better among patients who received the placebo compared with the FAK inhibitor (13.6 months vs. 12.7 months). Similarly, in those who had merlin-low disease, the median overall survival was 9.0 months in the defactinib group and 9.5 months in the placebo group.

Overall, there was no statistical significance observed between arms in regards to response rate, progression-free survival, overall survival and quality of life in those with merlin-low malignant pleural mesothelioma.

The most common reason for termination of study drug was disease progression (62%). The study was closed after the first interim analysis by the drug safety monitoring board.

The most common serious side effects were nausea, diarrhea, fatigue, dyspnea and decreased appetite.

A variety of clinical studies are ongoing to continue to evaluate treatment options for these patients. “Molecularly stratified therapy for mesothelioma is a potentially promising approach to improve outcomes for this aggressive cancer, but the approach is currently in its infancy,” the researchers wrote.