The second day of the J.P. Morgan Healthcare Conference, much like the first, didn’t include the type of market-moving acquisitions or announcements that might break the biopharmaceutical sector out of its slump.

But anticipation for such a move is high, with nearly every large drugmaker fielding questions from analysts and investors about what they aim to do with all the cash at their disposal.

Executives didn’t give much away, but their answers reflect how biotech has changed in recent years, with an explosion of new companies giving big pharma more opportunities to spread their bets.

Read on for details on what they said, as well as for some other notable updates from the meeting:

How big is a bolt-on deal?

The stars seem aligned for a year of dealmaking. Biotech company valuations have plummeted amid a sector-wide slump, and top drugmakers are sitting on large piles of cash. Industry watchers, like investment bank SVB Leerink, characterized 2021’s pattern of acquisitions, with many “small tuck-in deals,” as more an anomaly than a trend.

But top drugmaker executives, for the most part, don’t appear to have changed their tune much, with several emphasizing “bolt-on” acquisitions instead of the large-scale buyouts that some expect.

While Merck & Co. CEO Rob Davis said his company is open to deals that are “larger than we have done,” Bristol Myers CEO Giovanni Caforio expressed a preference for “early science” and “mid-sized bolt-on deals.” (At the conference’s start, Bristol Myers announced accelerated plans to buy back $5 billion in shares this quarter).

Others appear to share Bristol-Myers’ thinking. Large, “transformative acquisitions” are “very disruptive” and aren’t “really our thing,” said Roche CEO Bill Anderson. “We don’t believe in big M&A,” added top Novartis executive Vas Narasimhan, noting the company aims to spend about 5% of its market capitalization, or about $10 billion on deals each year. It was the same story for GlaxoSmithKline, whose CEO, Emma Walmsley, said the British company is focused on bolt-on acquisitions and licensing deals.

The seeming, or at least stated, reluctance to pursue megadeals may also reflect the sheer number of smaller biotechs that now exist, compared to years ago. “There are a number of us that are looking,” said Amgen CEO Bob Bradway. But “the number of targets that we’re looking at is vast, and that plays into the transaction dynamic.”

Can Roche beat Merck and Bristol Myers?

It’s not a stretch to say Roche, the biggest cancer drugmaker in the world by sales, has been surpassed by some of its rivals in the fast-moving immunotherapy field. Revenue for its top cancer immunotherapy, Tecentriq, is dwarfed by the billions of dollars generated by Merck and Bristol Myers’ similar medicines. Merck’s Keytruda, in particular, has become a standard treatment in many tumor types.

“We were really late to the game,” Roche’s Anderson conceded on Tuesday. But the company believes it will close the gap this year, thanks to the edge it currently has on others in developing a new type of immunotherapy aimed at the protein TIGIT.

The drug, tiragolumab, is part of a group of TIGIT-blocking drugs from Merck, Bristol Myers, Gilead and several other companies. These medicines have become some of the most closely watched research programs in oncology, propelled by early results showing they may boost the effects of drugs like Tecentriq and Keytruda, which don’t work for everyone.

Data Roche presented from a small study in December showed a particularly significant survival benefit for advanced lung cancer patients whose tumors express high levels of the protein PD-L1, more than half of whom were alive at least three years after starting treatment. “That’s phenomenal in lung cancer,” he said.

Though promising immunotherapy combinations have disappointed before, Roche is betting TIGIT will be different. The company has launched nine pivotal trials — four of which, in tumors of the lung, esophagus and cervix, should produce results this year.

“We said there were going to be three waves” in cancer immunotherapy, Anderson said. And the third, built on immunotherapy combinations, has the “ability for us to reclaim a leadership position.”

A head-to-head study with big implications

Merck’s Keytruda was approved in the U.S. just over seven years ago. Since then, six other drugs that work like it have won FDA clearances and a seventh is currently under regulatory review.

The drugs, known as checkpoint inhibitors and targeting proteins called PD-1 or PD-L1, have become widely used and changed how some cancers are treated. But very little is known about how they compare to one another in tumor types for which several are approved. That’s mostly because their makers, as is typical in the industry, are reluctant to run head-to-head trials for fear their medicine may prove less effective.

This has frustrated the FDA. “Sponsors making claims about developing ‘a better’ checkpoint inhibitor should directly compare their agent with those that are already approved; unfortunately, there is no evidence that such randomized trials are under way,” Richard Pazdur, one of the agency’s top cancer drug evaluators, wrote in a recent editorial.

That may change soon. EQRx, a richly funded biotech with grand plans to change how drugmakers do business, plans to run a head-to-head study comparing a checkpoint inhibitor it licensed from China’s CStone Pharmaceutical directly against approved PD-1 or PD-L1 blockers.

The study will be randomized and span multiple trial sites, at least some of which will be based in the U.S., according to Melanie Nallicheri, EQRx’s CEO. “This is additional evidence that we believe our health community wants to see,” she said in a presentation Monday.

Nellacheri offered few other details, but said EQRx would start the study this year. The results could be instructive and, if favoring EQRx’s medicine, boost the company’s plan to challenge market incumbents.

Vir’s omicron moment

Vir Biotechnology’s COVID-19 antibody drug sotrovimab was initially an afterthought when it was first authorized in May, after similar treatments from Eli Lilly and Regeneron had already reached market. But it’s now become one of the best tools available against the omicron variant, which is able to evade Lilly’s and Regeneron’s medicines. That’s made for a “pivotal moment” for Vir, said CEO George Scangos.

A little-known, privately held biotech only a few years ago, Vir is now racing to boost supply of a drug the world is clamoring to receive as quickly as possible. The company and partner GSK “accelerated everything that we have” to be able to make about 2 million doses in the first half of 2022, he said.

But those supplies are quickly getting bought up. The U.S. government contracted for 600,000 more doses of sotrovimab Tuesday, adding to a $1 billion order in November. All told, Vir has secured orders for about 1.7 million doses globally, and more requests are coming in “from other countries around the world,” Scangos said.

“We are contracting for additional manufacturing capacity,” Scangos added. “We’re being as aggressive as we can.”