Keytruda taught Merck how to build a blockbuster. But manufacturing a 2nd lightning bolt is easier said than done

On the second night of the largest annual European cancer conference, some 100 Merck scientists packed into Champeaux, a classic French restaurant, to break bread and share clinical wisdom.  

It was less of a ceremonious affair and more of a team bonding event. At least, that was the hope, says Eliav Barr, M.D., Merck’s chief medical officer, who attended the dinner.  

“I feel like good ideas are generated through interaction of people who you didn't expect to meet with,” he told Fierce Biotech on the sidelines of this year’s European Society for Medical Oncology (ESMO) congress.  

The dinner also served as a metaphor. Champeaux is situated blocks away from the Louvre, the famed Paris museum that houses arguably the most recognizable painting ever, Leonardo da Vinci’s "Mona Lisa." And, in the pharma world, you could make the case that Merck has a "Mona Lisa" of its own. 

But unlike da Vinci’s classic work of art, Merck’s medical masterpiece Keytruda isn’t guaranteed to hang on the walls forever. The drug’s patent expires in 2028—a nearing time bomb of revenue depletion—and there has been a slew of recent trial failures.  

That spotlight on Merck’s drive to diversify was the context that loomed over this dinner—and Barr—as the team convened. Merck’s group of oncology investigators is now roughly 170-people strong, with about 100 at the dinner. There were some members of the regulatory team there, as well.  

Corralling so many people into one place may also be emblematic of Merck’s larger clinical strategy.  

In drug development, throwing clinical paint at a canvas to see what takes shape is not likely how a company would describe its work. There are a number of reasons for this, most importantly that your canvas is human life, and there needs to be a sound hypothesis that a clinical examination could reap some benefit. Still, for some of the sickest patients, particularly with cancer, risks are taken. It’s simply a function of progress.  

 Merck, in some respects, is leaning into risk-taking. And the dinner represented the all-hands-on-deck effort to develop the next generation of cancer therapies that will puncture the status quo, just like Keytruda has.

'Perfectly comfortable' with negative studies

To Barr, and by extension Merck, failure is merely the cost of doing business when you’re looking to pave new ground.   

“We’re perfectly comfortable with the fact that some studies are going to be negative,” he said. 

Barr compared drug development to a professional baseball batting average. “If you've got a batting average of 1.000, it means that … you're really omniscient or you've been very timid, and you've only taken the very low-hanging fruit.”   

Keytruda is certainly established as one of the most formidable cancer therapies, setting an exceptionally high bar. Launching in 2014, the drug raked in a mind-boggling $42.65 billion (PDF) from 2019 through 2021. The explosive revenue is due in part to the expansion of its use over the years, with the drug now approved to treat more than a dozen cancers.  

That prowess makes Keytruda’s recent string of failures more noteworthy. Just in the last three months, there have been three significant flops. A trial testing Keytruda in combination with Eisai-partnered Lenvima in front-line liver cancer came up short. The immuno-oncology asset alongside chemotherapy also failed in metastatic castration-resistant prostate cancer. And Keytruda missed its goal in a head and neck cancer study.  

That dichotomy between Keytruda’s multibillion-dollar status and signs of deficiencies put an emphasis on the company’s ambitions. For now, the plan is twofold: Get Keytruda, a PD-1 checkpoint inhibitor, into earlier lines of treatment and continue to pursue a variety of combinations. 

Merck is designing new checkpoint inhibitors to mix and match with Keytruda, including TIGIT and CTLA4 inhibitors that are in phase 3.  

When asked at a press briefing whether the company had concerns in light of Roche’s failures with its TIGIT, Merck’s primary investigator, Marina Garassino, M.D., said too many conclusions were coming from that company’s interim analysis and that it’s too early to make conclusions about the target. 

As for CTLA4—validated in the form of Bristol Myers Squibb approved cancer drug Yervoy but a target that’s marred by high toxicity rates—Eric Rubin, M.D., senior vice president of oncology early development, said the company was very careful in its dose-finding study.  

Merck also plans to narrow the cancer types that it tests the combination on. CTLA4 inhibitors generally don’t have a large effect as a monotherapy, so the strategy is to focus on those cancers where these assets have shown single-agent efficacy, like in renal cell carcinoma, Rubin explained.

The search for another Keytruda 

As much as Merck’s leaders are projecting confidence about its ability to extend Keytruda’s life through combinations, it's not putting all its eggs in that basket. The company outlined its cancer pipeline at ESMO, and the largest bet outside of checkpoint inhibitors is in antibody-drug conjugates (ADCs). As a dual-faceted class of cancer therapy that combines a monoclonal antibody with cancer- cell killing chemicals using a linker, the hope is that ADCs add critical firepower to a cancer regimen.  

Rubin agreed “in some sense” with the notion that ADCs were a focal point of the company’s pipeline, given picking out the most important assets is the drug development equivalent of choosing your favorite child.  

Merck is looking to take ADCs to new heights. “The technologies [are] advanced there, where the sophistication for selecting tumor-specific targets has gotten better. The linker chemistry has gotten better,” he said. 

Merck has three ADCs, all in phase 2. Merck has full control of only one, zilovertamab vedotin, which is being developed for diffuse large B-cell lymphoma, hematologic malignancies and advanced solid tumors. The other two assets, ladiratuzumab vedotin and MK-2870, are being positioned against various solid tumors including breast and non-small cell lung cancers.  

Rubin underscored MK-2870’s target, TROP2. Because it’s expressed in several tumors, “you've got the potential of having something like Keytruda that's active across many different cancer types,” he explained. 

The dive into ADCs is not stopping Merck from dipping its toes into still other modalities, however. The company is investing in immune agonists, cancer vaccines and cell therapies. Addressing cell therapies, both of which are in preclinical testing, Barr said cost and scalability remain hinderances to further investment. 

In talking about the patient-specific, or autologous approach, taken by companies with marketed cell therapies, Barr said, “We decided consciously not to be ... a Novartis or Kite/Gilead or BMS." Rather, Merck's preference is to focus on the so-called off-the-shelf, or allogeneic, technique. 

Taking a 10,000-foot view on Merck’s larger ambitions, Barr said Keytruda taught the company to bust open the development gates when the evidence suggests that an asset is effective. “I think Keytruda taught us a lot of really important things from our point of view, which is when you have something that looks incredibly good, don't mess around, just blow it out,” he said. 

Naturally, this strategy extends into the other disease areas that Merck focuses on. In other words, the next Keytruda may not even be a cancer treatment.  

Barr noted his own excitement for the company’s recently acquired pulmonary arterial hypertension (PAH) med. Merck got hold of sotatercept when it bought Acceleron for $11.5 billion in 2021.  

Pulmonary hypertension, a larger condition than PAH that affects millions of patients, could be where the company takes sotatercept next, Barr teased. Analysts project peak sales could hit $2 billion. 

Barr described sotatercept as a “Keytruda-like” drug, saying that the company is now testing the asset in every stage of the disease. “And so you look at that, and you come to realize that when you have something that's unique, and really different … that's when you go big or go home.”