Positive results have been reported from a crucial immunotherapy trial that used a combination of two Bristol-Myers Squibb (BMS) drugs, nivolumab (Opdivo) and ipilimumab (Yervoy), to treat patients with a specific type of non–small-cell lung cancer patients. But previously undisclosed changes BMS made to the study, known as Checkmate-227, are raising questions about the validity and strength of the results, according to a STAT report.
The outcome of Checkmate-227 is important to BMS as it tries to catch up to Merck and other pharmaceutical companies in the lucrative lung cancer immunotherapy market. Billions of dollars in revenue are at stake, and Merck is in the lead, already having secured regulatory approval to treat newly diagnosed lung cancer patients with its checkpoint inhibitor pembrolizumab (Keytruda) combined with chemotherapy, STAT said.
Details from BMS were sparse, but the company said its combination of nivolumab and ipilimumab delayed the progression of tumors more than chemotherapy, meeting one of the coprimary endpoints of the study. The patients had newly diagnosed lung cancer with a biomarker known as high tumor mutation burden (TMB), based on a diagnostic test.
The study will continue to determine if the nivolumab/ipilimumab combination will help patients live longer than chemotherapy.
“TMB has emerged as an important biomarker for the activity of immunotherapy,” Matthew Hellman, the study investigator, said in a statement provided by BMS.
TMB measures the total number of mutations in tumor cells, and that biomarker may be a way to predict the degree to which a patient will respond to immunotherapies. If tumor cells have a high TMB, they have higher levels of neoantigens, which are thought to stimulate an increased immune response.
But BMS’s use of TMB as the biomarker, which determined victory in Checkmate-227, is stirring controversy, STAT reported. As originally designed, the primary analysis of the Checkmate-227 study was not supposed to parse lung cancer patients based on TMB status.
On a conference call, BMS’s chief scientific officer, Tom Lynch, said that the study’s design and statistical plan were changed based on “evolving science” of lung cancer and that this was done after consultation with the FDA.
Other companies, including Merck, have used a different biomarker known as programmed death ligand-1 (PD-L1) in their immunotherapy lung cancer trials. BMS originally set out to use PD-L1, too, until it was dropped in favor of the TMB biomarker after the study was nearly finished.
Checkmate-227 was an open-label study, meaning patients and doctors were not blinded to which treatment they were receiving. However, BMS’s Lynch said the study design was altered without knowledge of the results.
Patients with lung cancer containing high levels of TMB represented about 45% of the Checkmate-227 population, BMS says. The magnitude of the benefit derived from treatment with nivolumab and ipilimumab won’t be known until the company presents the study results at a medical meeting. Without those details, it’s not known how nivolumab/ipilimumab compares to Merck’s pembrolizumab/chemotherapy regimen.
The validation and comparison of the competing biomarkers—PD-L1 and TMB—is also a new and complicating factor. BMS said it plans to discuss the Checkmate-227 data with regulators with the aim of submitting for approvals.
Source: STAT; February 5, 2018.