Despite a head start, when Bristol-Myers Squibb 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. Bristol-Myers has since suffered blow after blow in its quest to take a big slice of the lucrative market, peppered with some small successes. On Tuesday, the New Jersey drugmaker touted positive data from a Phase III open-label study in a bid to carve itself a piece of the frontline lung cancer market.
The study, dubbed CheckMate -9LA, tested Bristol-Myers’ Opdivo in combination with its CTLA-4 Yervoy in addition to chemotherapy (two cycles) versus chemotherapy alone (up to four cycles followed by optional pemetrexed maintenance therapy if eligible) as a first-line treatment in patients with advanced non-small cell lung cancer (NSCLC) regardless of PD-L1 expression.
The PD-L1 drug met the main trial goal of superior overall survival at a prespecified interim analysis, the company said, adding that detailed data will be presented at a future medical conference. The company’s shares $BMY rose more than 5% to $55.94 in Tuesday premarket trading.
Secondary endpoints included progression-free survival, overall response rate, and efficacy measures according to biomarkers.
In January, the company rescinded its application to market the Opdivo/Yervoy combo in frontline NSCLC cases with high tumor mutational burden (TMB), after discussions with the agency suggested they needed more data to reinforce the connection between TMB and PD-L1.
The application was based on the CheckMate-227 study, in which 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, presented 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.
The results of CheckMate-227 suggested that Yervoy has activity in lung cancer when combined with Opdivo — but the data suggest that patients have to wait for some period of time for the benefit to manifest, Wolfe Research’s Tim Anderson wrote in a note.
“Chemotherapy, when given to lung cancer patients, often shows a fast initial response, but one that lacks durability. But by combining chemotherapy+Opdivo+Yervoy, BMY may have (finally) found a cocktail of drugs that delivers both near- and longer-term benefit, leading to an early response and improved long-term survival.”
However, Anderson was cautious about the cocktail’s safety profile in CheckMate -9LA.
“Opdivo+Yervoy by itself shows toxicity and adding chemotherapy into the mix will only increase this,” he said. “The commercial value of CM-9LA will, therefore, depend on the balance between the clinical benefit and the toxicity. It will only be once full results are presented that this risk:benefit assessment will be possible. Additionally, adding a third drug into the mix also raises the cost of therapy somewhat.”
Meanwhile, the company’s hunt for adoption in small cell lung cancer (SCLC) market has also been punctuated with failure.
Last year 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 a 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 small cell lung cancer 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 patients, whose cancer has progressed after platinum-based chemotherapy and at least one other line of therapy.
The results of CheckMate -9LA could have an impact on AstraZeneca, which is running the POSEIDON trial, Anderson added.
The trial is structurally similar to CM-9LA but with one key difference — instead of only giving a short course of chemotherapy in addition to its own checkpoint inhibitor Imfinzi and CTLA-4 tremelimumab, it gives chemotherapy continuously, he said.
“This may or may not be a good thing – it can be predicted that more chemotherapy likely yields more toxicity, but will it yield more benefit? Furthermore, AZN’s anti-CTLA4 therapy (tremelimumab) has yet to show it works in any tumor type (by contrast, BMY’s Yervoy is already approved in different settings) potentially reflective of the fact that it has slightly different properties versus Yervoy.”
Opdivo, which is also approved for use in a host of other cancers, generated about $3.6 billion in the first half of this year. By 2025, Opdivo is set to be the fourth best-selling drug in the world with annual sales forecasted to hit $12 billion. King Keytruda, however, is expected to take top spot and rake in more than $22 billion, according to GlobalData calculations