#ESMO22: ‘End of the beginning’: As PD-(L)1s press on, how far can combo therapies take immuno-oncology?

PARIS — It’s no secret that anti-PD-(L)1 drugs have drastically changed immuno-oncology over the last decade or so. Merck’s market-leading Keytruda and Bristol Myers Squibb’s Opdivo are highly effective across a wide range of cancers, helping millions of patients around the world and racking up billions in sales along the way.

But 2022 has proven relatively bumpy for the class, with more than a handful of trial failures as researchers try to move the drugs into more challenging tumor settings and earlier treatment lines. And a slate of mixed results at this year’s ESMO conference, combined with increased scrutiny in Washington over accelerated approvals and renewed debate over pricing, raise the question of whether anti-PD-(L)1s are approaching a ceiling.

One need not look past Keytruda, the fourth-highest grossing drug in the world last year, and second-highest behind AbbVie’s Humira when excluding the two mRNA-based Covid-19 vaccines. Already in 2022’s first half, Merck’s megablockbuster has reeled in more than $10 billion, a number that could easily continue growing thanks to Keytruda’s jaw-dropping eight approvals a year ago.

Given Merck’s comfortable pole position, no one would blame execs for showing off a little. Indeed, the New Jersey-based company’s booth on the ESMO exhibition floor featured an ostentatious 12-foot statue of a spinning letter “Y” colored on one side with the Keytruda logo and on the other with faux shrubbery.

Big Pharma companies like to keep the spotlight away from their giant piles of cash, however, and instead on patients. At a press event Saturday evening, Merck presenters summarized several positive studies in different cancer settings, largely focusing on long-term overall survival data but also touting newer neoadjuvant data in melanoma.

But this weekend most outside observers’ attention centered around a Phase III liver cancer study, in which Merck and Eisai announced last month a Keytruda and Lenvima combo failed to show survival benefits compared to Lenvima alone. The duo revealed the full data this weekend, reporting a 21.2-month median OS in the combo compared to 19 months for Lenvima.

Progression-free survival came in almost numerically identical: 8.2 months for Keytruda and Lenvima together versus 8 months for Lenvima on its own. On top of that, Merck outlined another previously reported flop at ESMO in head and neck cancer, detailing how Keytruda plus chemo didn’t significantly affect event-free survival.

Keytruda wasn’t the only anti-PD-(L)1 drug to return negative results at ESMO, as Opdivo and Roche’s Tecentriq both elaborated on previously known flops. Bristol Myers’ Opdivo plus Yervoy combo and Tecentriq both failed to achieve significant survival benefit in renal cell carcinoma for patients whose kidneys were removed.

Meanwhile, fuller data for Opdivo in combination with Nektar’s IL-2 therapy showed the BMS drug performed better on its own, shedding light on how hopes for a $3.6 billion deal fell apart.

Ironically, the kidney cancer failures effectively handed Merck a monopoly, following a Keytruda approval here last November. But none of these datasets landed in a vacuum. The liver and head and neck cancer misses came after Keytruda had already whiffed in prostate cancer earlier this year, both in combination with Lynparza and chemotherapy.

They also come amid an increasingly aggressive FDA that’s willing to go over “dangling” accelerated approvals where confirmatory benefits are fuzzy — at best. Within the last 18 months, Merck has pulled Keytruda indications in small cell lung cancer and stomach cancer, the latter following a marathon two-day ODAC hearing where panelists debated the merits of keeping dangling green lights on the market for Merck, Roche and BMS.

That’s to say nothing of FDA officials lambasting Eli Lilly and Innovent at a February adcomm for what could have been the eighth PD-(L)1 approval, when Oncology Center of Excellence director Rick Pazdur and his deputies said the pair’s application suffered from data integrity issues and accused the companies of misrepresenting their actions with regulators. At one point, division of oncology 2 director Harpreet Singh threatened to release all private communications into the public domain.

Eli Lilly had tried to hype up the drug as potentially a lower-cost therapy in a market that’s seen no price movement in eight years (every approved PD-(L)1 therapy costs about $150,000 per year). But Pazdur repeatedly said in February’s hearing that the FDA does not take pricing into account.

Eliav Barr

What does this all mean for the field’s leaders? Asked about how Merck’s two misses fit into the context of the potential PD-(L)1 ceiling at Saturday’s event, newly appointed chief medical officer Eliav Barr sidestepped the question, saying the expectation of some failure is baked into any clinical trial program.

“If you don’t have studies that are bold, like science-based but with various degrees of a likelihood of success, what we’ll end up with is 100% efficacious trials but a lot of patients who never would know they could take Keytruda,” Barr said. “So the point is that we look at a very, very large set of studies, because we wanted to make sure we leave no patients behind.

“We’ll find some negative trials but a lot of our track record is pretty good, and I think it’s going to continue to be that way,” he added.

Bristol Myers declined to make an executive available for an interview, and emailed questions to a company spokesperson went unanswered.

Rob Davis

Seemingly foremost in analysts’ minds, though, is Keytruda’s looming patent expiration in 2028, when Merck will lose the drug’s exclusivity rights. That will sharply cut into the company’s revenues, and though Merck has remained busy on the M&A and licensing sides, CEO Rob Davis stressed during its full-year 2021 earnings call that “we need to do more.”

As the aggressive pipeline reinvigoration comes ahead of the 2028 deadline, Barr emphasized Saturday that Merck isn’t “putting all of its eggs in one basket,” pursuing a wide variety of potential combinations across different immune system pathways and touting July’s $290 million upfront deal with Orion.

It’s this strategy of combinations that appears to be how Merck, Bristol Myers and other PD-(L)1 players are attempting to tackle the immune system’s next frontier. BMS already has Yervoy, the only approved anti-CTLA-4 therapy, to pair with Opdivo in cancers where it can’t reach its full potential, but its competitors are not sitting idly by.

Israel Lowy

Regeneron, the sixth of seven entrants to the field that developed Libtayo with Sanofi, only has three PD-1 approvals in four years, but its efforts have been about finding the right combinations from the beginning, SVP of oncology translational science Israel Lowy told Endpoints News. Libtayo, Lowy says, is aimed at being the foundation of a whole toolkit of immuno-oncology programs and “not just another PD-1 — but a damn good one.”

The big biotech is confident that despite getting its first Libtayo approval in 2018, the drug can play a prominent role in the field, evident by its move to acquire all rights from Sanofi for $900 million upfront a few months ago. And Lowy noted Regeneron has the luxury of not relying solely on Libtayo for revenue given the blockbuster status of two other drugs, Eylea and Dupixent.

“We’re not under any illusions that we’re going to make everybody switch from Keytruda to Libtayo,” Lowy said. “But we think physicians and patients like choice, and we think that they’re sacrificing nothing by using Libtayo.”

Susan Galbraith

Others are furiously trying to develop more potential combination therapies as well. Not content with just the Yervoy add-on, Bristol Myers also secured approval for Opdualag, a combo of Opdivo and the LAG-3 inhibitor relatlimab, in advanced melanoma earlier this year. BMS also has an Opdivo plus Empliciti regimen in Phase II studies for multiple myeloma.

AstraZeneca, meanwhile, is on the doorstep of an FDA approval for its own anti-CTLA-4 drug, tremelimumab, to rival Yervoy and pair with the PD-L1 therapy Imfinzi. The company announced the drug candidate received priority review in April and that the PDUFA would come in the fourth quarter — likely October, marking the end of the 6-month accelerated review period. AstraZeneca cancer R&D chief Susan Galbraith told Endpoints only that discussions with the FDA are ongoing.

And Merck, for its part, highlighted five Phase III programs it’s working on to pair with Keytruda, including its own LAG-3 inhibitor and anti-TIGIT candidate. Barr pointed toward data pairing Keytruda with Seagen and Astellas’ Padcev and alluded to a broader combo strategy in his Saturday presentation, describing Keytruda-related efforts going forward as “the end of the beginning.”

Eric Rubin

Eric Rubin, Merck’s head of oncology early development, also noted the company is researching other approaches rather than just checkpoint inhibitors, highlighting antibody-drug conjugates and Dragonfly’s TriNKETs as other areas of promise. But Rubin also tells Endpoints it’s difficult to know if there’s another Keytruda out there — a lightning-in-a-bottle blockbuster that’s extremely effective across so many cancer types.

The best thing Merck can do until, or if, it finds one is to keep plugging away at the combination strategy and hoping some of them work out.

“Some of the combinations have the potential to be active across multiple cancer types. We’ve seen that for some of them already,” Rubin said. “Although, you know, some of these don’t seem to work in every cancer type. So we’ll have to just study it and identify the winners. Hopefully we can continue to make a difference.”

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