Bristol-Myers withdraws Opdivo/Yervoy lung cancer EU application — but others are incoming
Early in 2019, Bristol-Myers Squibb rescinded an FDA application to market its checkpoint inhibitor Opdivo in combination with its CTLA-4 therapy Yervoy for frontline use in patients with the most common form of lung cancer. One year later — the company is taking the same step with the European regulator.
Despite a head start, when Bristol-Myers’ and its pioneering checkpoint inhibitor Opdivo suffered a key lung cancer setback in 2016 — they found themselves relegated to the backseat as Merck’s Keytruda seized the wheel on the road to immunotherapy stardom. The drugmaker has since suffered a series of blows in its quest to take a big slice of the lucrative market, peppered with some successes.
This Opdivo/Yervoy combo was meant to claw back some of that lost ground. Originally filed in 2018, the EU application was designed to allow the use of the Opdivo/Yervoy as a first-line regimen in patients with non-small cell lung cancer (NSCLC) with high tumor mutational burden (TMB) on the basis of the CheckMate-227 study.
In one arm of the trial, which compared the combo to chemotherapy, researchers said they had observed a “highly” significant progression-free survival rate in patients with high TMB, regardless of PD-L1 expression. The high TMB group accounts for 45% of all frontline patients, the company estimated at the time. Bristol-Myers had redesigned the study to focus on TMB after stumbling on a pivotal trial that involved a broader patient population.
Overall survival data, posted months later, showed that the hazard ratio in patients getting the Opdivo/Yervoy combo was comparable whether they were high or low TMB patients. However, the median overall survival in patients with high TMB was 23.03 months on the Opdivo/Yervoy arm, versus 16.72 months in the chemotherapy group. In the low TMB group, the median OS was 16.20 months and was 12.42 months on the combination and chemotherapy arms, respectively.
Since the OS data came later, the EU application was amended accordingly. A full assessment of the application by the EU regulator was not possible following multiple protocol changes the company made, Bristol-Myers’ said, citing its response from the EU agency.
The company — which withdrew a similar US application in January 2019 after it was unable to convince the FDA of the connection between TMB and PD-L1 — has no plans to refile this application in the EU, it said on Friday.
Instead, Bristol-Myers has taken a slightly different approach. Last month, the FDA granted the company’s application for the Opdivo/Yervoy combo for the first-line treatment of patients with metastatic or recurrent NSCLC with no EGFR or ALK genomic tumor aberrations priority review, on the basis of the same CheckMate-227 study.
In addition, Bristol-Myers plans to file applications across the Atlantic following the results of a Phase III open-label study — CheckMate -9LA — which evaluated the impact of Opdivo/Yervoy administered concomitantly with a limited course of chemotherapy for the first-line treatment of NSCLC.
Lung cancer is the most lucrative oncology market — and as such, checkpoint inhibitors of all hues have been scrambling to gain ground in the field. For now, Merck’s Keytruda remains way in front. According to 2024 projections compiled by Cowen analysts, Opdivo is expected to generate a meaty $12.4 billion that year, while king Keytruda is expected to reap a hefty $20.6 billion.
Bristol-Myers hunt for adoption in the smaller small cell lung cancer (SCLC) market has also been punctuated with failure. 2018 saw an Opdivo/Yervoy combo miss the primary endpoint for overall survival in the CheckMate-451 study, where the Bristol-Myers drugs were being evaluated as maintenance therapy for SCLC, following an initial round of chemotherapy. The results came just over a month after the drugmaker unveiled an Opdivo flop in the CheckMate-331 study, which tested the immunotherapy against the second-line SCLC standard-of-care.
Still, over the years, Opdivo has seen some lung cancer success — including the approval of the drug in squamous NSCLC patients whose cancer has progressed despite platinum-based chemotherapy as well as patients with metastatic SCLC, whose cancer has progressed after platinum-based chemotherapy and at least one other line of therapy.