Once-Promising Drug Ofev Fails in Mesothelioma Clinical Trial
July 30, 2019
The search for a cure of mesothelioma hit another roadblock recently when a once-promising immunotherapy drug, combined with standard chemotherapy, failed to slow disease progression in a phase III study.
The multicenter study covering 27 countries involved Ofev (nintedanib), a small-molecule enzyme inhibitor drug that had shown considerable potential in earlier studies.
Lancet Respiratory Medicine published the trial results, signaling another setback for the highly anticipated use of certain immunotherapy drugs to treat mesothelioma.
“Making significant improvements in systemic therapy for malignant pleural mesothelioma has proven to be quite challenging,” lead researcher Dr. Giorgio Scagliotti, University of Turin, San Luigi Hospital in Italy, wrote. “Despite promising data from the phase II part of the study, the primary endpoint [progression-free survival] was not met in the phase III part.”
Ofev Doesn’t Help with Chemotherapy
The recent trial included 458 patients randomly assigned to pemetrexed and cisplatin chemotherapy, plus either Ofev or a placebo.
Unfortunately, Ofev provided no advantage. Median progression-free survival was 6.8 months for patients assigned Ofev, compared with seven months for those with the placebo.
Median overall survival was 14.4 months in the Ofev group and 16.1 months in the placebo group.
A secondary measure of health-related quality of life and average symptom burden index scores only slightly favored the Ofev group.
Serious side effects occurred in 44% of patients receiving Ofev. A third of those receiving Ofev required dose reduction in subsequent treatments.
Based on the results, the study of Ofev was stopped.
Earlier Trials with Ofev Looked Promising
The outcome was especially disappointing because of earlier successes with the drug.
Doctors in the United Kingdom and the United States have been using it in combination with chemotherapy to treat certain lung cancers.
The U.S. Food and Drug Administration in 2017 granted Ofev an orphan drug designation for mesothelioma, encouraging its use without officially approving it.
The phase II portion of this latest clinical trial using Ofev with chemotherapy reported a progression-free survival of 9.4 months, compared to just 4.7 months for chemotherapy alone.
Overall survival was 18.3 months, compared to just 14.2 months.
This was not the first time a highly touted immunotherapy drug failed to live up to expectations.
Tremelimumab, which also had received orphan drug designation by the FDA for use with mesothelioma, failed an effectiveness test in 2017 as a stand-alone, second-line immunotherapy treatment.
Anetumab ravtansine, which combines immunotherapy with cytotoxic therapy, also failed to show effectiveness in stand-alone clinical trials.
Both drugs, though, are still being tested as part of drug combination treatments.
Ofev, in earlier trials, had shown effectiveness in slowing tumor growth. With lung cancer, it worked well in relieving breathing problems by softening the lungs.
The FDA already has approved it for pulmonary fibrosis.
More Trial Results Coming Soon
The Barbara Ann Karmanos Cancer Institute at Wayne State University in Detroit is nearing completion of a phase II clinical trial using Ofev alone in patients with recurrent pleural mesothelioma. Those results are expected to be announced soon.
Although this recent study showed no improvement with chemotherapy, researchers did see survival benefit for patients with a higher platelet count, compared to those with a lower platelet count.
The study, though, was not designed to analyze that variable.
Ofev and other anti-angiogenetic drugs are a different type of immunotherapy than Keytruda and Opdivo, which are known as immune checkpoint inhibitors and have shown considerable promise with a small percentage of patients with mesothelioma.
Those drugs use a different molecular target to spark their effectiveness.
“This latest failure of an anti-angiogenetic drug in patients with mesothelioma fosters consistent doubts and skepticism and raises questions of whether we should drop this approach after so many failures,” wrote Dr. Michele Maio, University Hospital of Siena in Italy, in an editorial accompanying the study results. “Whether targeting immune checkpoints will be the beginning of a new era in mesothelioma therapy remains to be established.”