Oncology's research boom

Merck & Co.’s cancer immunotherapy Keytruda is one of the pharmaceutical industry’s biggest successes. The drug's arrival in 2014 introduced a new way of treating cancer and, over time, it became standard therapy for a panoply of different tumors. Clinical achievements brought about commercial performance, making Keytruda the world's best-selling medicine.

After the repeated failure of past attempts to improve on Keytruda, a new class of drugs might finally offer a better backbone for immunotherapy's next decade.

In September 2024, biotechnology companies Summit Therapeutics and Akeso revealed clinical trial results showing one of these drugs significantly outperformed Keytruda. Called ivonescimab, it cut the risk of lung cancer progression in half compared to Keytruda in a Phase 3 study — a result so striking it sparked a wave of investment in oncology research practically overnight.

“This really was a ‘black swan’ event,” said Allen Yang, Summit’s chief medical officer. “It’s clearly what everybody’s been looking for.”

In the wake of Summit’s results, drugs like ivonescimab, which block cell signaling via proteins called PD-1 and VEGF, have become the “new shiny object” in cancer research, according to analysts with the investment bank William Blair. More than a dozen companies, from pharmaceutical giants to newly formed biotech startups, are now developing them.

Proponents see these “PD-1/VEGF inhibitors” as building upon Keytruda and drugs like it, such as Bristol Myers Squibb’s Opdivo. The hope, some say, is they’ll improve response rates, shrink tumors their predecessors can’t and become cornerstone cancer treatments of the future.

“These drugs are going to work,” said David Epstein, the former CEO of Seagen and head of Ottimo Pharma, a startup developing a PD-1/VEGF inhibitor. “The question is, how big is the order of magnitude going to be, and across how many different tumor types?”

Many aren’t as convinced as Epstein. Ivonescimab hasn’t shown it can extend overall survival by more than Keytruda. It wasn’t tested against the Keytruda-chemotherapy combination that’s standard of care in most lung cancers. And the trial demonstrating ivonescimab’s superiority to Keytruda took place only in China, leaving it unclear whether a similar benefit will be observed in broader testing. Those questions hang over not only Summit, but others working on PD-1/VEGF inhibitors, too.

“The jury is out,” said Samit Hirawat, the chief medical officer of Bristol Myers Squibb.

What are PD-1/VEGF inhibitors and how do they work?

Cancer cells are survivalists. They’re adept at siphoning the body’s resources to fuel their rampant growth, and skilled at slipping past immune defenses evolved to stop them. Even when beat back by drug therapies, malignant cells can acquire new abilities to thwart treatment.

Drugmakers and researchers have spent enormous effort studying cancer’s weaponry, uncovering along the way many tools that have improved care. Two breakthroughs from the 1990s helped researchers design protein drugs that can pinch off a tumor’s supply chains and, years later, unleash the immune system against cancerous growth.

In the former case, antibodies that block VEGF, such as Avastin, can stop tumors from forming new blood vessels. The latter kind of antibodies, which are called PD-1 or PD-L1 inhibitors for the proteins that they block, prevent cancer cells from shutting down powerful defenders known as T cells. Keytruda is the most famous example.

Both classes of medicines are now used to treat dozens of tumor types. PD-1 and PD-L1 immunotherapies, also called “checkpoint” inhibitors, are sometimes a patient’s first line of defense after a tumor is surgically removed — or even before.

Developers like Akeso and Summit aim to combine the power of both types of drugs into a single, multi-pronged antibody, typically termed “bispecific” or “bifunctional.” These medicines can interfere with PD-1 and VEGF signaling in ways their makers contend will maximize the benefits and minimize the flaws of their predecessors.

Akeso designed ivonescimab to have a “tetravalent” structure, in theory giving it better binding to PD-1 and to VEGF. Yang, Summit’s CMO, says the simultaneous targeting of both proteins helps increase the affinity the drug has for each.

“We believe that those two features make ivonescimab, and the whole class of PD-1/VEGFs, unique,” he added. “Now people seem to believe us.”

Others have different twists on the concept. BNT327, a drug acquired by German biotech BioNTech, binds to the ligand PD-L1 instead of the PD-1 receptor. A drug licensed by Merck consists of an anti-VEGF antibody fused to two PD-1-targeting antibodies, while Ottimo’s lead program, jankistomig, specifically targets a related protein called VEGF receptor 2.

Crescent Biopharma has a drug its CEO, Jonathan Violin, said on a conference call in October 2024 was “purpose-built” to mimic the pharmacology of ivonescimab while enhancing its “stability and manufacturability.”

They’re joined by other companies pursuing more variations, such as drugs that block three proteins or use different strategies to block VEGF.

The glut of similar drugs means “many or most of the resulting companies seem unlikely to succeed,” wrote Paul Rennert, the head of consulting firm Sugarcone Biotech, in a February report. Still, Epstein, Ottimo’s CEO, said the sheer size of the commercial opportunity leaves ample room for many to prosper.

“How many PD-1s and PD-L1s are there? How big is the market currently? And how big is it going to be if people live twice as long, or at least twice as long before their cancer progresses?” Epstein said.

What are the advantages over drugs like Keytruda?

Keytruda and other checkpoint inhibitors like it are the standard choice for many tumor types because trial data has shown they can extend lives to degrees that weren’t possible with other cancer medicines.

There’s no better example than in lung cancer. Some studies have shown that, in the years before cancer immunotherapy, the average five-year survival rate for people with metastatic non-small cell lung cancer was around 5%. That rate has climbed since the arrival of Keytruda and its cousins. In Phase 3 testing, around 20% of people given a Keytruda-chemotherapy combination survived at least five years.

Yet that statistic also shows checkpoint inhibitors aren’t panaceas. In lung cancer and other malignancies, they still don’t work well for a good portion of people — particularly those whose tumors express little of the PD-L1 protein that’s linked to an immunotherapy response. They also struggle against so-called cold tumors that don’t tend to provoke as strong immune reactions.

In response, drugmakers have searched for more than a decade to find new immunotherapies that work better, but the hunt has yielded far more failures than successes.

“It’s been one disappointment, honestly, after another,” said Srini Akkaraju, a founder and managing general partner of Samsara BioCapital, and an investor in Ottimo.

Among the approaches tested, with mixed results, were combinations of PD-1 inhibitors together with anti-VEGF drugs. Roche found that pairing Avastin with its immunotherapy Tecentriq improved survival in liver cancer and won an approval in that tumor type as well as lung cancer. Further testing showed a limited survival benefit as well as significant side effects, however. And the combination hasn’t been as broadly successful as hoped.

Merck has had a similarly uneven experience. It has gained clearances of regimens involving Keytruda and the VEGF-inhibiting drugs Lenvima and Inlyta in a few tumors, but these combinations have fallen short in others.

“You see, in many cases, clear evidence of [delaying tumor progression]. But then as we go longer out, we're not able to hit [on survival] as often as we wish to,” said Merck research chief Dean Li, during a conference presentation last January.

At least so far, ivonescimab seems to work more effectively than delivering two separate drugs together. The initial evidence “raises the possibility that there may be some true synergy when the two are combined with a single molecule,” John Heymach, chair of thoracic, head and neck oncology at the MD Anderson Cancer Center, said in a September interview.

Supporters say that will play out with further testing. If they’re right, the “emerging blue sky story” is that these drugs might make immunotherapy useful to more people and against more tumors, wrote Stifel analyst Bradley Canino in a note in 2024.

More data could burst those expectations, too, though. Bristol Myers’ CMO Hirawat noted how ivonescimab hasn’t yet been proven to extend survival. Moreover, its advantage over Keytruda on tumor progression appeared to shrink after six months. And for earlier-stage drugs also targeting the PD-1 and VEGF pathways, promise in single-arm studies will need to be replicated in more rigorous tests.

“There is some level of additional data that is required,” Hirawat said. “We'll keep an eye on it and continue to look for what the right opportunities are from a scientific perspective, and what we need to continue to learn.”

In their report, William Blair analysts had a similarly skeptical take. Citing the multiple “disappointing datasets” with checkpoint inhibitor and Avastin combinations, they wrote that developers need more results from global studies and a clear survival advantage to prove these drugs can become “a new standard of care.”

Safety is also a concern. VEGF-blocking drugs are associated with sometimes severe side effects like high blood pressure, bleeding or protein in the urine. In clinical practice, doctors can stop treatment when these instances occur. With a combined therapy, though, “if we see [concerning] proteinuria, then we have to hold the whole drug,” Jyoti Malhotra, director of thoracic medical oncology at City of Hope Orange County, said.

Which companies are developing PD-1/VEGF inhibitors?

More than a dozen companies are developing dual-targeting antibodies that block PD-1 or PD-L1 and VEGF in one way or another.

Akeso, a Guangdong, China-based cancer drug developer, originally discovered ivonescimab. Summit got involved in 2022 when it paid Akeso $500 million upfront. In February, Pfizer and Summit agreed to test ivonescimab alongside some of Pfizer’s targeted cancer medicines in the hopes of finding yet more powerful drug combinations.

BioNTech is best known for successfully developing a COVID vaccine with Pfizer. But the company’s initial focus was in cancer. It bought into PD-L1/VEGF drug development first by partnering with and then in 2024 acquiring Biotheus, a cancer biotech based in Zhuhai, China.

Ottimo Pharma was formed in 2020 by U.K. venture firm Medicxi and prolific biotech founder and former Pfizer researcher Jonny Finlay. The company emerged from stealth in October with Epstein, a former Seagen and Novartis executive, as its CEO and raised $140 million in Series A funding two months later. Ottimo’s lead prospect is a bifunctional antibody, meaning its “arms” can interact with both of its targets.

Crescent Biopharma spun out of Paragon Therapeutics in 2024 armed with a PD-1/VEGF prospect and two other medicines. In October, it merged with struggling drug developer GlycoMimetics, giving the company enough cash to fund operations into 2027.

Merck in November 2024 paid $588 million for worldwide rights to a PD-1/VEGF drug discovered by Shanghai-based LaNova Medicines.

Joining them are at least 12 more companies, many of which of are based in China, reflecting a fast-advancing biotech sector there that’s created a broad pipeline of drug candidates in competitive areas of pharmaceutical research.

“They all have little variations. They all have a reason to be best in class,” said Yang, Summit’s CMO, of the medicines following ivonescimab. “But we think ours has all the features that are important, and that have been proven to be important.”

Gwendolyn Wu, Jonathan Gardner and Ned Pagliarulo contributed reporting.

Nine years ago, Lisa Haines got news no one wants to hear. Her doctors said her lung cancer, which chemotherapy had earlier arrested, was growing again.

The Massachusetts resident began planning for family events she thought would be her last, like her son’s wedding and a Thanksgiving trip. Her doctor didn’t give up, however. She recommended Haines try an immunotherapy called Opdivo, one of what was then a new class of drugs that works by enlisting the body’s immune system to fight cancer.

In December 2015, Haines became the first patient at Addison Gilbert Hospital in Gloucester, Mass., to receive Opdivo. The following August, lung inflammation prompted her doctors to stop treatment. But by then, scans showed her disease was stable. Most of what remained was scar tissue. Nearly a decade later, she has no detectable disease.

“I’m alive today because of those drugs,” Haines said. “They’re miraculous when they work.”

Developed by Bristol Myers Squibb, Opdivo was the second so-called PD1 inhibitor to be approved in the U.S. The first, Merck & Co.’s Keytruda, won Food and Drug Administration clearance on Sept. 4, 2014.

Keytruda’s initial U.S. approval, which preceded Opdivo’s by a few months, was niche, reserved for people with inoperable melanoma or whose disease had spread and couldn’t be controlled with other medicines. Today, Keytruda is on track to become one of the highest selling pharmaceutical products of all time, supported by approvals for 20 different types of cancer.

In addition to Keytruda and Opdivo, seven other drugs that block the PD1 pathway have reached market. They’ve been used to treat millions of people with cancer.

Along the way, they have reshaped patient and doctor expectations of what cancer treatment can accomplish. In lung cancer like Haines’, the spread of deadly nodules is now most commonly contained with Keytruda-based combinations. In melanoma, metastatic skin lesions are often held in check with Opdivo and another immunotherapy called Yervoy. And facing tumors of the kidney, liver, stomach, breast and lymph system, doctors can choose immunotherapy options instead of older interventions that may be less effective or more toxic.

“I stand at a podium now and talk about curing 50% of patients,” said Hussein Tawbi, an oncologist at MD Anderson Cancer Center who specializes in treating melanoma.

The success of PD1 immunotherapies has also set a high standard for treatment — one that, in the years since, drugmakers and researchers have spent billions of dollars trying unsuccessfully to top. Since the arrival of PD1 drugs, only one new type of these “checkpoint inhibitors” has won approval, defying expectations they’d lead to a new armamentarium of immune-boosting cancer medicines. Now, even Merck is turning more of its research focus to other types of cancer treatment.

“We thought we had enough scientific understanding to unlock the biology,” said Caroline Loew, formerly Bristol Myers’ R&D strategy and planning chief and now CEO of Mural Oncology. “We didn’t; we weren’t quite there.”

Coley’s toxins

For decades, the main prescription for cancer was chemotherapy, which stops tumor growth by essentially poisoning cells that divide rapidly. But chemo affects healthy cells, too, leading to side effects like hair loss and nerve damage.

A huge step forward came in the 1990s and 2000s, when more precise therapies arrived. Herceptin, an antibody drug, changed the way doctors thought about a protein known as HER2 and its role in breast cancer. Gleevec, a chemical medicine, vastly improved the outlook for people with a type of leukemia. While these targeted treatments can be less toxic than chemo, they are usually limited in which cancers they treat.

Immunotherapies work differently. Keytruda, Opdivo and their cousins help circumvent the ways tumor cells evade detection and destruction by the immune system, specifically infection-fighting T cells. Another type of immunotherapy, known as CTLA4 inhibitors, makes T cells work harder to find and eliminate tumor cells.

But the path to understanding the immune system’s role in cancer was long. More than a century ago, scientists were able to guess at a relationship. Most famously, in the 1890s, a surgeon named William Coley noticed how some people with cancer who experienced a bacterial infection unexpectedly had their tumors shrink.

At a time when X-rays were seen as the best way to treat cancer, Coley instead tried injecting bacteria into the tumors of people with cancer. “What he found was that the patient would have an enormous inflammatory response. And then within a couple of days, the tumor would simply melt away,” said Robert Schreiber, a pathology and immunology professor at Washington University who has studied how cancer and the immune system interact.

Scientists of Coley’s time didn’t have the means to tease out the immune system’s role. Only over time did they gain the right tools so that, by the 1960s and 1970s, they could try new experiments with immunocompromised mice.

Unfortunately, the experiments, which involved injecting carcinogens into these mice and into others with healthy immune systems, failed to show any meaningful result. The setback slowed the field’s development for decades.

Schreiber was one of the scientists who began building the foundations that would later enable immunotherapy’s breakout. His experiments, an offshoot of studies into an immune-signaling chemical called gamma interferon, involved mice bred without a certain gene that’s expressed on T cells.

His research found the specially bred mice developed more cancers and did so more rapidly. “We didn't believe it,” Schreiber said. “So we did it over and over and over again, and got the same answer.”

In essence, he was able to show what previous experiments couldn’t: Mice with weakened immune systems weren’t able to fight cancer as well. His lab’s discoveries led to the theory of cancer “immunoediting,” which proposed that, although the immune system could destroy tumor cells, in some cases the response is only powerful enough to keep cancer in check for a short time. During that time, variations can develop that help tumors “escape” immune attack.

‘No tumors anywhere’

Schreiber’s work helped inform researchers elsewhere. Among them was James Allison, who, with Japanese researcher Tasuku Honjo, eventually won a Nobel Prize for discovering how cancer cells shield themselves from the immune system.

Allison, at MD Anderson, along with researchers at the University of Chicago, found the CTLA4 molecule regulates T cells’ response to tumors. Certain proteins expressed on cancer cells use CTLA4 to essentially tell those T cells to stand down, leading to tumor escape.

This and other molecules became known as immune “checkpoints,” which check, or brake, the body’s immune response. Japanese researchers led by Honjo separately discovered another checkpoint, called PD1, that eventually became the target of Keytruda and Opdivo.

Allison first presented data on CTLA4 in 1995, but found almost no one willing to help him translate his work into drugs that could be tested in humans. One big obstacle was that, at the time, many of the world’s most powerful drug companies considered cancer immunotherapy a dead end. Prior attempts to create a therapeutic cancer “vaccine” had flamed out.

“A lot of the companies I approached said, ‘Immunotherapy has never worked. It's never going to work,’” Allison said.

Complicating matters further, Bristol Myers held intellectual property rights to a drug that targeted CTLA4, making companies wary of licensing Allison’s science.

Eventually, through some of his academic connections, Allison was able to forge a deal with a company called Medarex, which took his findings forward into clinical research.

Medarex was in a hurry. After using Allison’s science to design an antibody that blocked CTLA4, the company took just 466 days to move from a key first step in the laboratory to testing it in humans. That speed has only recently been beaten by Regeneron Pharmaceuticals in its development of a COVID antibody, according to Nils Lonberg, who helped shepherd immunotherapy research while at Medarex and later Bristol Myers.

“We didn’t know if the project was going to work or not,” Lonberg said. “If it didn’t work out, we didn’t want to spend any time or money on this.”

But it worked. The second patient tested with Medarex’s drug was a young woman whose relapsed melanoma got so severe that a metastasized tumor collapsed her lung. She was about to be sent into hospice care. After one treatment with Medarex’s drug, though, her tumor shrank enough doctors could remove it surgically.

Her response was so profound it took her physicians by surprise. At a follow-up imaging scan, Allison recalls the radiologist saying, “There's some mistake here, because there are no tumors anywhere anymore, so it's got to be the wrong patient.”

That patient is still alive in 2024.

In 2004, Bristol Myers partnered with Medarex to work on immunotherapy research that years later would lead to Yervoy and Opdivo. The pharma company followed up five years later by buying its partner for $2.4 billion.

As Bristol Myers moved deeper into testing, results began exciting melanoma specialists who were used to new drug treatments disappointing. Tawbi remembers how, for many doctors then, the first step they would recommend for metastatic melanoma was a clinical trial. Melanoma was “the place where all good drugs go to die.”

“We could give people chemotherapy. Sometimes — rarely — that helped. But there was almost never a durable response,” said Jedd Wolchok, a Weill Cornell Medicine oncologist who ran some of the first clinical trials of checkpoint inhibitors.

The most important data for Yervoy came in 2010, at a plenary session of the American Society of Clinical Oncology’s annual meeting. They showed the drug helped people with melanoma live longer when compared to an experimental vaccine for the cancer.

“I remember sitting in the audience. We actually gasped,” Tawbi said. “I got back to the clinic and used it as soon as I could.”

The FDA approved Yervoy in 2011. But Yervoy’s substantial side effects on the intestines, liver, kidneys and other organs proved difficult to tolerate. And early on, doctors were reluctant to use the steroids that later proved effective in managing the drug’s toxicity.

With Yervoy’s use constrained by side effects, researchers hunted for another immunotherapy that would be as effective in stopping melanoma, but easier for patients to take.

An acquisition afterthought

In the early 2010s, Merck primarily sold cardiovascular and respiratory disease drugs. The company faced a big patent “cliff,” when top-sellers like its asthma medicine Singulair were set to lose market exclusivity.

Merck was also digesting what was then one of the largest pharma acquisitions, a $41 billion takeout of Schering-Plough in 2009.

Two years earlier, Schering-Plough had purchased a company called Organon BioSciences, the human and animal health division of a Netherlands chemical company. At the time, Schering-Plough was excited about Organon’s products in central nervous system diseases and women’s health. But within its labs Organon had developed a little-noticed PD1-targeting antibody it called lambrolizumab.

By the time Merck absorbed Organon, lambrolizumab wasn’t a high priority and, according to reports, was even marked for sale. Right around then, though, Bristol Myers advanced Yervoy into late-stage studies, catching the attention of Merck’s scientists.

“At the time, the whole immuno-oncology space was in its infancy, other than [Yervoy],” said Roy Baynes, Merck’s former chief medical officer. “What really re-energized Merck to develop this was a growing awareness that PD1 looked as though it was going to be important.”

In response, Merck dusted off lambrolizumab, renamed it pembrolizumab and thrust it into clinical trials. Because of its Medarex buyout, Bristol Myers had its own PD1 blocker in Opdivo, and the two companies became locked in a race to get the drugs into the clinic and approved.

The annual ASCO meeting in 2013 provided an early forum for both companies to present initial data from trial volunteers with melanoma. Baynes, who had previously worked with Merck research chief Roger Perlmutter at Amgen, was in attendance.

“Roger sought me out,” Baynes recalled. “He said, ‘What do you think of these data?’ And I said, ‘Well, they look pretty darn good.’ He said, ‘Well, why don't you come and help me develop it?’”

Perlmutter, Baynes and the Merck R&D team were widely viewed by Wall Street as playing catch-up to Bristol Myers. But Merck made up ground with a nimble strategy centered on a large Phase 1 trial that transformed from initial dose testing to fuller evaluations of safety and efficacy.

Merck beat Bristol Myers to market with that strategy, gaining an accelerated approval in melanoma for pembrolizumab, or Keytruda, on Sept. 4, 2014, more than three months ahead of Opdivo.

The PD1 drugs offered significant advantages over CTLA4 and Yervoy. Tawbi describes PD1s as “nine times better” than Yervoy — “three times more effective and three times less toxic.” And treatment began changing the lives of patients. “We started being able to sit down with patients and say, ‘You’ve got melanoma, but there’s a 42% chance of a cure,’” he said.

While the two companies worked to shore up those first approvals in melanoma, a second prize awaited in a common form lung cancer.

Once again, Merck got there first, winning U.S. approval a week before Bristol Myers in October 2015 to treat people whose disease worsened following chemotherapy. The approvals came with an important difference, however. To be eligible for Keytruda, people with lung cancer had to test positive for PDL1, the protein to which PD1 receptors bind, while Opdivo’s use wasn’t restricted.

But Bristol Myers’ “all comers” approach eventually led to one of the company’s largest setbacks. In a first-line trial, Merck enrolled people who were positive for PDL1 on at least 50% of their tested tumor cells, while Bristol Myers’ competing trial set the enrollment threshold at 5%. Moreover, Merck designed its trial with more opportunities for Keytruda to succeed, enrolling many more patients and following them for longer.

Merck’s trial succeeded in showing a survival benefit compared to chemotherapy, while Bristol Myers’ failed, an event so momentous Bristol Myers lost billions of dollars in market value.

“It destroyed BMS,” said Lonberg. “We had huge pressure from investors. It radically changed the company. It was just one bad trial design. But there was no clawing our way back.”

As the two companies competed for primacy, they sought to combine their drugs with others to improve on the survival benefit. Merck focused largely on pairing Keytruda with chemotherapy while Bristol Myers tested Opdivo both with Yervoy and with chemotherapy.

More recently, the two companies have focused on earlier-stage disease. Studies have shown immunotherapy can help reduce the size of tumors early so they are small enough to be removed with surgery. The drugs are also now used as follow-up treatment to prevent cancer from returning.

Over the course of the past decade, Merck and Bristol Myers also added approvals in numerous cancer types, including a “tissue agnostic” approval for Keytruda in people with a certain type of genetic mutation. These successes sparked a gold rush among other large pharma companies; First there was Roche with Tecentriq, and then followed drugs developed by Merck KGaA, AstraZeneca, Regeneron, GSK and others.

Merck and Bristol Myers also became the partner of choice for companies seeking to develop new cancer drugs, with hundreds of combination trials launched over the past 10-plus years.

Doctors have now used Keytruda to treat 2.5 million people, and the drug is currently in 1,600 studies, according to Merck’s own tally. During the 2024 ASCO meeting, Merck CEO Robert Davis said the company has spent $46 billion developing Keytruda and expects to invest another $20 billion by 2030.

By comparison, Opdivo has been used to treat 1.8 million people and tested in 500 clinical trials, according to Bristol Myers.

‘I hope to get a postcard from you’

For patients, it’s hard to understate the impact of immunotherapy. Haines, the lung cancer survivor, has been disease-free since ending Opdivo treatment in 2016. “They won’t say if it’s curative for some people but it’s pretty darn close,” she said. “I still get nervous whenever I get a scan. My oncologist says, ‘You’re good.’”

Heidi Nafman-Onda learned she had Stage 3A lung cancer from a scan following treatment for an ovarian cyst. At an initial consultation with a pulmonologist, she was told her tumor was inoperable. They said, “your prognosis is poor, you have four to six months left and you should get your affairs in order,” Onda recalled.

However, she was surprised by an oncologist in a follow-up visit. “He walked into the office all chipper and smiling. I wondered what he was smiling about,” Onda said. He told her an AstraZeneca immunotherapy called Imfinzi had been approved and that it could cure many patients with her diagnosis. “He said, ‘I hope to get a postcard from you in 10 years from some exotic vacation you’ve been on.’”

When she was about to begin treatment, her care team gave her extensive information about side effects. “I said, ‘I don’t want to look at it.’ This was my only option. It was either that or die soon.”

Her one year of Imfinzi treatment ended January 2020. “To this day I have no evidence of disease. They can’t see any trace,” said Onda, who co-founded the White Ribbon Project to raise awareness of lung cancer.

Pamela Berryhill, who had difficult with the side effects of Imfinzi and other drugs prescribed to treat her lung cancer, has found a tolerable regimen in Keytruda and the chemotherapy Alimta.

“They are telling me that this will be my lifetime treatment,” said Berryhill. “I can see myself being on this happily for the rest of my life because the side effects that I get are minimal and bearable — just giving myself a little bit of grace after the treatment to deal with the fatigue and fuzzy head feeling.”

For doctors who’ve been treating lung cancer for years, this is a remarkable turn of events. “I was in medical school in the ‘90s and medical oncology residency in the early 2000s. We had old platinum-based chemotherapy, and really not much more,” said Tina Cascone, a thoracic, head and neck cancer specialist at MD Anderson.

Now, there are a “plethora” of agents to use to improve survival. “We are able to tell our patients more and more there is no evidence of disease, that they’re cancer free, and they can go on with their life,” she said.

Still, PD1 drugs are not panaceas. While in many cancers they work better than alternative treatments, the majority, or even sometimes most, of treated patients don’t respond fully. Testing for certain biomarkers can help identify patients most likely to respond to treatment, but isn’t a guarantee. So far, too, deadly cancers of the brain, ovaries, prostate and blood have proven harder to treat with immunotherapy, for reasons that drugmakers are still sorting out.

“Not all patients benefit from these treatments,” Cascone said. “Some patients still will experience severe side effects [that] impact the quality of life.” She said more research needs to be done to identify which patients will benefit and how immunotherapy can be better tailored.

The me-too trap

PD1 drugs have undoubtedly improved cancer treatment. Yet, despite much trying in the decade since they’ve launched, pharma companies haven’t been able to replicate their success.

New targeted treatments such as Tagrisso and Ibrance have helped people with certain solid tumors, while, in the field of immunotherapy, engineered cell therapies like Kymriah can produce durable survival benefits for people with blood cancers. But their reach is more limited than Keytruda’s or Opdivo’s. And while Bristol Myers has had success exploring a new immune checkpoint called LAG3, others’ attempts to rewire the immune system against cancer have mostly met with failure.

For its part, Merck doesn’t see its future in new cancer immunotherapies. Instead it’s leaning into targeted treatments. “We're not out there saying, ‘Let's find the next Keytruda.’ That was lightning in a bottle,” Davis said at the ASCO 2024 press conference. “Most of what we're looking at are therapies that are very specific.”

According to Weill Cornell’s Wolchok, one reason for the slow progress is that pharma companies and academics spent too much time and money trying to develop new PD1s or to combine new agents with PD1s in hopes of finding an additive benefit.

“There's no reason why we need the number of PD1-blocking drugs that we have,” he said. “What if we [had] tried to uncover another foundational checkpoint rather than making additional copies of similar drugs?”

The checkpoint inhibitors tested after PD1 weren’t particularly effective on their own. Nonetheless companies pushed them into expensive combination trials, lured by the financial promise of finding the next immunotherapy.

“What we've learned is single agent activity is really important,” he said. “What we call IO-IO combinations, that is two checkpoints put together, have been really underwhelming.”

However, Allison argues, other checkpoint inhibitors haven't been evaluated correctly yet. “We’ve got to change the way we think about testing,” he added. His laboratory is currently working on iterative small trials that can help tease out the benefit of targeting other checkpoints. And he notes how some immune checkpoints don’t seem to emerge until tumor cells are first exposed to PD1- or CTLA4-blocking drugs

Bristol Myers still sees its immunotherapies as backbone treatments, but is extending the combination to emerging drug classes like precisely targeted radiotherapies and chemotherapies. “It really does start with harnessing your own immune system to fight cancer and that gives us the ability to have that durable, long-term survival impact,” said Adam Lenkowsky, Bristol Myers’ chief commercial officer.

Even so, disappointment has been felt throughout the field.

“Combination development naturally becomes very complicated,” said Loew, of Mural Oncology. “All of that work, in the end, didn't result in anything except with LAG3.”

Loew claims cancer immunotherapy research is following a fairly typical pattern, though. Generally, drug development occurs in 10-year cycles, she said, and in immunotherapy, “we’re about to see another evolution, another step change.”

Lonberg, who’s now an executive-in-residence at the venture capital firm Canaan Partners, is also optimistic. Still, he concedes investment may flow away from some biotechnology companies as the field evolves.

“The more sophisticated players are going to survive and thrive,” he said, “and there will be renewed interest in immunotherapy because of that.”

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• Meanwhile, RWE contextualizes these findings, validating biomarkers, modeling outcomes and revealing how therapies perform beyond controlled trial settings.
• AI can be used with RWE to make large datasets more manageable, supporting RWE collection and analysis.

Together, these tools enable personalized medicine at scale—offering researchers and clinicians a continuous stream of actionable insights that extend far beyond traditional data collection methods.

A Rapidly Evolving Regulatory Landscape

Regulators worldwide are advancing frameworks to guide the use of AI and real‑world evidence (RWE). The FDA’s Advancing RWE Program supports high‑quality RWE for labeling changes and post‑approval requirements, while EMA and the European Medicines Regulatory Network are building standards for RWE across regulatory decisions. Canada’s CADTH and Health Canada issued reporting guidance to strengthen RWE quality, and the UK MHRA’s 2024–2027 Data Strategy prioritizes data, digital innovation and patient safety. In parallel, the FDA created the CDER AI Council and issued 2025 draft guidance on AI in regulatory decision‑making, alongside internal tools like ELSA.[i] Globally, initiatives such as the EU AI Act and national RWE and AI guidances reflect growing regulatory acceptance. However, to ensure reliability, reproducibility and patient safety, AI use remains highly scrutinized.

Clinical Applications Driving Real-World Impact

Digital Pathology

The use of AI and RWE in digital pathology highlights three main categories of impact:

• Prognostic: Better patient risk stratification
• Predictive: Forecast treatment benefit
• Practical Impact: More personalized, less toxic, cost-effective

Digital pathology exemplifies how AI is already reshaping oncology practice. By applying machine learning to pathology images, AI enhances biomarker scoring accuracy, detects subtle histologic patterns and accelerates turnaround times.

In prostate cancer, the Artera AI model integrated pathology and clinical data from the CHAARTED study to stratify patients into high-, intermediate- and low-risk groups revealing clear differences in five-year overall survival. Such stratification allows clinicians to tailor therapy intensity, minimize unnecessary toxicity and monitor high-risk patients more closely.[ii]

Beyond prognosis, AI is correlating image-based biomarkers with molecular alterations like PD-L1 expression and MSI status, supporting more precise, personalized therapy selection without additional invasive testing.

Patient Recruitment and Trial Optimization

Recruitment remains one of the most persistent challenges in oncology. AI tools such as Tempus and IBM Watson Health are helping overcome this by scanning electronic health records, pathology reports and genomic data to identify eligible patients in real time.

At ESMO 2024, the Tempus TIME Trial Network demonstrated how AI-driven matching for non-small cell lung and breast cancer improved referral and enrollment rates, particularly for patients with rare mutations. Integrated systems can now alert physicians when a patient qualifies for an active trial, reducing screening time and increasing trial accessibility for underrepresented groups.

Synthetic Control Arms

When randomized control trials are not feasible, synthetic control arms (SCAs) created from real-world data are emerging as a powerful alternative. AI analyzes RWE from cancer registries and EHRs to identify patients who match trial inclusion criteria and models outcomes for comparable cohorts.

This approach not only accelerates timelines but also reduces patient burden and strengthens the ethical foundation of oncology studies. The FDA has already accepted RWE as supportive evidence in dozens of oncology submissions, several of which resulted in approvals with RWE included directly in product labeling.

Navigating AI Integration Responsibly

Safe adoption of AI in oncology research requires governance rooted in transparency, accountability and human oversight. Teams must understand how algorithms are trained, validated and monitored over time to prevent bias and maintain data integrity. Because AI systems evolve as they learn, continuous validation and expert review are essential to ensure accuracy and trust.

At the same time, ethical and practical challenges must be addressed early:

• Transparency: Many AI systems function as “black boxes,” making it difficult to interpret outputs.
• Accountability: The question of who bears responsibility—clinician, institution or developer—remains unsettled.
• Data Privacy and Security: As datasets grow, robust de-identification and governance frameworks are essential.
• Bias and Representation: Underrepresentation of minority populations in training data risks perpetuating inequities.

Asking questions such as What data trained this model? or How was bias assessed? reinforces accountability and ensures responsible use. The goal is not to replace human judgment but to enhance it with stronger evidence, clearer insight and more equitable outcomes.

Engaging Regulators Early and Often

Early FDA engagement is essential for sponsors developing AI-enabled models. Pre‑IND and IND discussions help align on credibility frameworks, validation needs and context of use. The FDA encourages risk‑based performance evaluation and iterative planning. Programs like the Center for Clinical Trial Innovation and CID offer structured pathways to discuss AI-driven trial designs and model qualification. Early collaboration helps set expectations, address challenges and reduce development risk, improving the likelihood of regulatory acceptance.

Charting the Next Phase of Oncology Research

AI and RWE are no longer experimental—they are integral to the evolution of oncology research, helping improve prognostic precision, optimize treatment selection, reduce toxicity and increase trial efficiency.

Their success, however, depends on responsible adoption. Data standardization, validation, transparency and ethical oversight will determine how fully AI and RWE can transform patient outcomes. Collaboration among regulators, sponsors, CROs and healthcare systems remains essential to ensure innovations translate into real-world benefit.

---

References:
^[i] United States Food and Drug Administration. (2025, January). Considerations for the use of artificial intelligence to support regulatory decision-making for drug and biological products: Guidance for industry and other interested parties (Draft — Not for Implementation). U.S. Department of Health and Human Services. https://www.fda.gov/media/184830/download

^[ii] Prognostic validation of a digital pathology-based multi-modal artificial intelligence (MMAI) biomarker in patients with metastatic hormone-sensitive prostate cancer (mHSPC) from the CHAARTED trial (ECOG-ACRIN EA3805) [Abstract 5077]. Journal of Clinical Oncology, 42(16_suppl), Abstract 5077. https://doi.org/10.1200/JCO.2024.42.16_suppl.5077

Soon after starting a new biotechnology company, David Li realized he needed to rethink his strategy. 

Li had been conducting the competitive research biotech entrepreneurs typically undertake before soliciting investment. He drew up a list of drug targets that his startup, Meliora Therapeutics, could pursue and checked them against the potential competition. 

Li quickly found that biotechs in China were already working on many of the targets he had on his list. Curious, he visited Shanghai and Suzhou and witnessed a buzzing scene of startups set frenetically to task. 

“They're not really thinking about the U.S. at all. They're just trying to create more value and stay alive to differentiate themselves from the next guy in China,” he said. “They're moving quick. There are a lot of them and they're just quite competitive.”

Li’s experience is illustrative of a trend that could pressure biotech companies in the U.S. and alter their drug development strategies. More and more, large pharmaceutical companies are licensing experimental drugs from China. Venture companies are testing similar tactics by launching new U.S. startups around compounds sourced from China’s laboratories. This shift has been sudden, with licensing deals ramping rapidly over the past two years. And it is occurring even as the shadow of U.S.-China competition within biotech grows longer. 

Executives and investors interviewed by BioPharma Dive at the J.P. Morgan Healthcare Conference in January 2025 shared Li’s outlook. They expect such deals will accelerate and, in the process, force U.S. biotechs to work harder to stand out. 

“We’ve been warning people for a while, we're losing our edge,” said Paul Hastings, CEO of cell therapy maker Nkarta and former chair of the U.S. lobbying group the Biotechnology Innovation Organization. “Innovation is now showing up on our doorstep.”

There’s perhaps no clearer example of this than ivonescimab, a drug developed by China-based Akeso Therapeutics and licensed by U.S.-based Summit Therapeutics. Results from a lung cancer study run in China showed ivonescimab outperformed Keytruda, Merck’s dominant immunotherapy and currently the pharmaceutical industry’s most lucrative single product. 

The finding “put a huge focus on what’s happening in China,” said Boris Zaïtra, head of business development at Roche, which sells a rival to Keytruda. 

Fast-moving research

Today’s deal boom has roots in efforts by the Chinese government to upgrade the country’s biotech capabilities by upping investment in technological innovation. In the life sciences, the initiative provided funding, discounted or even free laboratory space and grants to support what Li described as a “robust ecosystem” of biotechs. 

The results are clear. Places like Shanghai and Suzhou are home to a skilled workforce of scientists and hundreds of homegrown companies that employ them. Science parks akin to the U.S. biotech hubs of Cambridge, Massachusetts and San Francisco have sprouted up. 

Chinese companies generally can move faster, and at a lower cost, than their U.S. counterparts. Startups can go from launch to clinical trials in 18 months or less, compared to a few years in the U.S., Li estimated. Clinical trial enrollment is speedy, while staffing and supply chain costs are lower, helping companies move drugs along more cost effectively. 

“If you're a national company within China running a trial, just by virtue of the networks that you work within, you pay a fraction of what we pay, and the access to patients is enough that you can go really fast,” said Andy Plump, head of research at Takeda Pharmaceutical. “All of those are enablers.” 

And what they’ve enabled is a large and growing stockpile of drug prospects, many of which are designed as “me too better” versions of existing medicines, analysts at the investment bank Jefferies wrote in a December report. Initially focused in oncology, China-based companies are now churning out high-quality compounds across multiple therapeutic areas, including autoimmune conditions and obesity. 

“There was a huge boom of investment in China, cost of capital was very low, and all these companies blew out huge pipelines,” said Alexis Borisy, a biotech investor and founder of venture capital firm Curie.Bio. ”Anything that anybody was doing in the biotech and pharmaceutical industry, you could probably find 10 to 50 versions of it across the China ecosystem.”

Me-toos become me-betters

For years now, Western biopharma executives have scouted the pipelines of China’s biotech laboratories — exploration that yielded a smattering of licensing deals and research collaborations. Borisy was among them, starting in 2020 a company called EQRx that sought to bring Chinese versions of already-approved drugs to the U.S. and sell them for less. EQRx’s plan backfired amid scrutiny by the U.S. Food and Drug Administration of medicines tested only in people from a single country.

Now, however, the pace of deals has accelerated rapidly. There are a few reasons for this. According to Plump, one is the improving quality of the drug compounds being developed. The “me toos” are becoming “me betters” that could surpass available therapies and earn significant revenue for companies — like BeiGene’s blood cancer drug Brukinsa, which, in new prescriptions for the treatment of leukemia, overtook two established medicines of the same type in 2024. 

Another reason, Plump said, is that China-based companies are becoming more innovative, studying drug targets that might not have yet yielded marketed medicines, or for which the most advanced competition is in early testing. Li notes how Chinese companies are going after harder “engineering problems,” like making complex, multifunctional antibody drugs, or antibody-drug conjugates. 

“There are so many [companies] that the new assets are going to keep coming,” Li said. 

Much as in the U.S., China-based biotechs are also fighting for funding, pushing them to consider licensing deals with multinational pharma companies. At the same time, these pharmas are hunting for cheap medicines they can plug into their pipelines ahead of looming patent cliffs. The two trends are “colliding,” said Kristina Burow, a managing director with Arch Venture Partners. “I don’t see an end to that.”

The statistics bear Burow’s view out. According to Jefferies, the number and average value of deals for China-developed drugs reached record levels in 2024. Another report, from Stifel’s Tim Opler, showed that pharma companies now source about one-third of their in-licensed molecules from China, up from around 10% to 12% between 2020 and 2022. 

“I see huge opportunities for us to partner and work together with Chinese companies,” said Plump, of Takeda. 

Several venture-backed startups have been built around China-originated drugs, too, among them Kailera Therapeutics, Verdiva Bio, Candid Therapeutics and Ouro Medicines, all of which launched with nine-figure funding rounds. 

“There's been a lot of really good, high quality molecules and data that have emerged from China over the last couple of years,” said Robert Plenge, the head of research at Bristol Myers Squibb. “It's also no longer just simply repeating what's been done with the exact same type of molecule.”

Geopolitical risks

These deals are happening against an uncertain backdrop. U.S. Congress has spent considerable time kicking around iterations of the Biosecure Act, a bill that would restrict U.S. biotechs from working with certain China-based drug contractors. A committee in the House of Representatives called for new limits on clinical trials that involve Chinese military hospitals. And the Trump administration has reportedly considered restrictions on the kinds of licensing deals that have recently proliferated.

“We don’t know what this ... administration is going to do,” said Jon Norris, a managing director at HSBC Innovation Banking.

The Biosecure Act “keeps going sideways,” added Hastings, who believes that any impact from the legislation, if passed, would be minimal. Instead, Hastings wonders if tariffs may be more problematic. “There will be tariffs on other goods coming from China. Does that include raw materials and innovation? It’s hard to imagine that it won’t,” he said. 

But executives and investors expect deals to continue, meaning U.S. biotechs will have to do more to compete. 

“U.S. companies will need to figure out what it is they’re able to bring to the table that others can’t,” said Burow, of Arch. 

Borisy said startups working on first-of-their-kind drugs need to be more secretive than ever. “Do not publish. Do not present at a scientific meeting. Do not put out a poster. Try to make your initial patent filing as obtuse as possible,” he cautioned. 

“The second that paper comes out, or poster at any scientific meeting, or talk or patent, assume it has launched a thousand ships.”

Those that are further along should assume companies in China will be quick on their heels with potentially superior drugs. “The day when you could come out with a bad molecule and open up a field is over,” he said. 

Greater competition isn’t necessarily a bad thing, according to Neil Kumar, CEO of BridgeBio Pharma. Drug development could become more efficient as pharmas acquire medicines from a “cheaper” starting point and advance them more quickly. 

Venture dollars could be directed towards newer ideas, rather than standing up a host of similar companies.“If all of a sudden this makes us less ‘lemming-like,’” Kumar said, “I have no problem with that.”

Li similarly argues that, going forward, U.S. companies need to focus on “novelty and innovation.” At his own company, Li is now working on things “we felt others were not able to access.”

“The game has always been the same. Bring something super differentiated to market,” he said. But “the bar has risen.” 

Gwendolyn Wu and Jacob Bell contributed reporting. 

ORLANDO – A regimen involving Johnson & Johnson’s dual-acting drug Tecvayli could be curative when used early in the disease course of people with multiple myeloma, according to data disclosed in December.

Released at the annual meeting of the American Society of Hematology in Orlando, the results come from a trial called MajesTEC-3. J&J had earlier claimed early success for the study, which evaluated Tecvayli alongside another J&J drug called Darzalex, against Darzalex and a standard combination in people whose disease had advanced after one to three treatment lines. But it didn’t provide specific details, saving them for a spotlighted presentation at ASH.

According to those results, the Tecvayli-Darzalex combination cut the relative risk of disease progression or death by 83% when compared to Darzalex and other therapies. Progression was also uncommon for treatment recipients who went six months without relapsing. According to J&J, 90% of those enrollees were still progression-free three years after the study’s start, leading researchers to suggest the combination could have curative potential.

“The efficacy is truly remarkable with this combination,” said Surbhi Sidana, an associate medical professor at Stanford University and a trial investigator. “We can see a light at the end of our tunnel with all of these therapies for our patients, having maybe a functional cure in the future.”

Tecvayli is one of four so-called bispecific antibodies available for multiple myeloma. All are cleared under “conditional” approvals, though, and only available for patients who’ve previously received at least four lines of treatment. 

The MajesTEC-3 results show the potentially dramatic benefits of moving these drugs into earlier lines of care and combining them with other treatments, said one expert.

“What it does is prove two things. One is clearly that when you give bispecific antibodies earlier in the disease course they work better,” said Amrita Krishnan, executive medical director for hematology at City of Hope Orange County, in an interview. The other is that Darzalex “further augments the efficacy of [Tecvayli], and one would assume the same for other bispecifics,” added Krishnan, who wasn’t involved with the trial. 

If approved for earlier use, Tecvayli would provide a more convenient, and potentially more broadly used alternative to the CAR-T cancer cell therapy Carvykti, she said. Carvykti, with J&J also markets, is made from a patient’s own cells. It is administered most often in a limited number of highly specialized cancer centers and less so in the community oncology practices that treat many patients.

“There are patients at early relapse who we do not want to [give] CAR-T, and a preference would be to give them a bispecific antibody,” she said. But bispecifics have only been available to patients much later on in their disease course, so “we’ve had to wait to be able to do that.”

Widening use of bispecifics in multiple myeloma has been one of J&J’s major objectives, said Imran Khan, its vice president of hematology medical affairs. “Up to 50% of patients are in the community. We want to ensure that every single patient has the opportunity to get the option that is best for them where they are in their treatment journey,” he said.

But broader use could bring new safety considerations, too. The presentation showed that 13 people in the Tecvayli-Darzalex group died from infections, and treatment recipients were more likely to contract COVID-19 and related pneumonia, as well as upper respiratory tract infections and other viral conditions. By comparison, patients who receive CAR-T therapies are closely monitored and even kept in hospitals to quickly receive care for side effects like infections.

MajesTEC-3 trial investigators changed medication protocols during the study to allow for immunoglobulin replacement therapy and antimicrobial prevention.

“Infection risk can be mitigated, but still, patients do get some infections,” Sidana said. “We have to be very, very vigilant, especially as we transition these drugs to the community, where doctors are treating many different diseases and they may not be so on top of things.”

J&J enrolled 587 people and randomized roughly half to the Tecvayli-Darzalex combination, with the rest receiving Darzalex, a commonly used steroid and either Velcade or Pomalyst. The study’s main objective was improving progression-free survival. Response rates, overall survival and achieving undetectable disease were considered secondary endpoints.

The Tecvayli-Darzalex combination induced a complete response, meaning patients had no trace of disease, in 82% of people who received it, compared with 32% of people who got the alternative combinations. The combination also reduced the relative risk of death by 54%.

Additionally, 83% percent of people who got Tecvayli were still alive three years after entering the trial, compared with 65% of people who got the other regimens.

An experimental drug from Terns Pharmaceuticals is showing it may emerge as a threat to multiple established medicines for a slow-growing blood malignancy known as chronic myeloid leukemia. 

According to results presented at the American Society of Hematology in December, Terns’ drug, codenamed TERN-701, helped a majority of study participants with CML who had received previous treatments significantly reduce the number of diseased white blood cells in their bloodstream. The findings suggest the drug, a type of targeted, oral treatment, may eventually be competitive with widely used medicines like Novartis’ Scemblix, which is expected to generate more than $4 billion in peak yearly sales. 

Terns first announced a small cut of data from the trial in early November, claiming at the time that the efficacy findings were “unprecedented” among marketed and experimental treatments for CML. Company shares have more than tripled since then, heightening anticipation for the detailed results being presented at ASH. TERN-701 “could potentially upend Scemblix dominance” in CML, wrote William Blair analyst Andy Hsieh, in a research note in November.  

The study, called CARDINAL, is primarily evaluating the safety of TERN-701 in people who’ve received prior treatments such as Scemblix or another Novartis medicine, Gleevec, as well as determining which dose to advance into further testing. Nearly all of the study recruits joined the trial because their previous treatments stopped working or had too many side effects. 

But investigators also measured “molecular response,” or how much the drug reduces the share of cells containing the aberrant BCR-ABL gene that drives the disease. Molecular response rates are frequently used as a study endpoint for CML trials because it’s predictive of longer-term benefits, such as a reduced risk of disease progression.

Among 38 patients who were evaluable for efficacy, TERN-701 helped 74% attain a “major” molecular response — a 1,000-fold reduction in the percentage of white blood cells with the BCR-ABL gene —  by 24 weeks. Of those who weren’t classified as being in major molecular response at the study’s start, 64% achieved it afterwards. All patients at that level when the trial began maintained that status, too. 

In a similar study population, Scemblix helped 25% of trial volunteers achieve a major molecular response at 24 weeks. Cross-trial comparisons can be misleading, however, and the two drugs haven’t been tested head to head.

Still, “what it's telling us is that this is a better drug,” said Terns CEO Amy Burroughs, in an interview with BioPharma Dive. “This is going to raise the bar in efficacy.”

Updated data presented at ASH show that the occurrence of side effects and severe side effects remains low among TERN-701 recipients, with 32% of the 63 patients who entered the trial having a “Grade 3” adverse event. Only one patient dropped out of the study due to a severe side effect. No signs of high blood pressure or pancreatitis — side effects associated with Scemblix and another CML drug, Iclusig — have occurred. Iclusig also has a “black box” warning of blood clotting events that have included heart attacks and strokes.

Drugs like TERN-701 and others in its class work by blocking a signaling molecule that produces the diseased white blood cells in CML. Early drugs like Gleevec worked by blocking the active part of the molecule that prevents its signaling, while Scemblix and TERN-701 grab onto a site that changes the shape of the molecule. 

The latter approach reduces the number of “off-target” interactions that can trigger severe side effects, Burroughs said.

For AstraZeneca, a single mutation launched a blockbuster lung cancer franchise.

In 2003, the pharma giant began a complicated journey that was almost doomed from the outset. The lung cancer treatment Iressa, which targeted the mutation of the EGFR gene, was cleared by U.S. regulators but AstraZeneca later pulled it from the market due to low efficacy.

In the ensuing years, however, AstraZeneca learned more about the subset of people who did respond to its medication, and by 2015 Iressa was re-approved based on studies in patients with these so-called EGFR mutations. Shortly thereafter, the company brought to market an EGFR-targeting medicine called Tagrisso, which has since gone on to become a multibillion-dollar seller and the cornerstone of its lung cancer portfolio.

The drug’s success has been part of an ascension for AstraZeneca’s oncology business. In a final analysis from a late-stage study, a combination of Tagrisso and chemotherapy meaningfully extended survival in patients with EGFR-mutated non-small cell lung cancer. The recent approval of Datroway — though narrower than initially anticipated — could build on the company’s EGFR business and contribute to its lofty goal of treating more than half of all patients with lung cancer by 2030.

PharmaVoice spoke with Arun Krishna, the vice president and head of AstraZeneca’s lung cancer programs, about how the company’s strategy has evolved to embrace EGFR-targeting therapies. The following interview has been edited for brevity and style.

PHARMAVOICE: How did EGFR become such an important mutation to target?

ARUN KRISHNA: Most people associate lung cancer with a smoker's disease, but we know very clearly that 20% of people who get lung cancer have actually never smoked. So our journey started with the whole EGFR space because we understood from the science that if you have an oncogenic driver like EGFR, that’s something that leads to lung cancer in nonsmokers. Ten years ago, we got our first approval with Tagrisso in [specific EGFR mutation] T790M, so we started with a very small population in second line, and quickly moved to first line with the Flaura study that showed overall survival benefit. Since then, Tagrisso has been the standard of care in EGFR.

We’re moving to identify lung cancer earlier. We [now] have EGFR data not just in the metastatic setting, but also in the early stage. Tagrisso is the backbone treatment for all EGFR patients across all stages of their cancer. Twenty years ago, the only option patients had was chemo. The science has evolved tremendously.

AstraZeneca has a slate of lung cancer drugs, Datroway being one of the latest. Why have several drugs that target the same mutation?

KRISHNA: There are different patient types, all within the EGFR space. Some of them might benefit from monotherapy. Some might benefit with a combination of treatments, because ultimately, that is where the future is going. There's not one single modality that addresses a specific type of cancer, so we are looking at multiple ways to attack the cancer through combinations of treatment.

AstraZeneca aims to treat more than half of all people with lung cancer with one or more of its drugs by 2030. How will you accomplish that?

KRISHNA: There's a [multi]-pronged approach to achieving this. One is through the medicines, making sure we are not just looking at single agents, but combinations. Secondly, we’re moving into the earlier part of the patient journey. But that isn't sufficient, because we know the rates of screening in lung cancer are very low, especially here in the U.S. There isn't a policy around screening for people who have never smoked. So one of our big goals in the next three to five years is to partner with health systems, partner with our clinical community, partner with patient advocacy groups to drive that awareness of screening. In addition, we’re working in collaboration with universities and academic centers to look at programs for nonsmokers so they can be detected earlier. It goes in tandem: You have the medicines that we’re discovering and moving into the clinic very quickly, but at the same time working in the environment to be able to rapidly drive the adoption of screening strategies in the population.

EGFR is now a well-established target, but that wasn’t always the case. Does the infrastructure still exist to make those kinds of leaps?

KRISHNA: We are on the cutting edge, and we're in the center of that explosion of science and technology. We're going to discover more subtypes and mutations. But there’s still a gap, and that’s what needs to be addressed. We’ve come leaps and bounds, but there’s still work to be done at the grassroots level, at the community level, to make sure that clinicians are aware, and that patients ask to be tested for their biomarker so they then get the right treatment at the right time, and have the best survival outcome possible.

Hiroyuki Okuzawa holds an enviable position. The veteran Daiichi Sankyo executive took over as the Japanese drugmaker’s new CEO in April and inherited a company whose cancer medicines have, over the past half-decade, won it three of the pharmaceutical industry’s largest licensing deals.

One of those medicines, the antibody-drug conjugate Enhertu, took the spotlight at the American Society of Clinical Oncology’s annual meeting on June 2, showing potential to become part of standard therapy for the frontline treatment of advanced breast cancer. It did the same in 2022 and 2024.

Okuzawa can point to Enhertu and four other antibody-drug conjugates Daiichi Sankyo’s developing with AstraZeneca and Merck & Co. as proof of the strength of its research laboratories. By 2030, the company plans to have these five “ADCs” approved across more than 30 tumor types, which would allow it to treat nearly 400,000 cancer patients each year.

“We’d like to become one of the most important players in oncology,” said Okuzawa, noting aspirations to crack the top 10 companies by cancer drug sales. “Our senior leaders are now talking about not only top 10, but maybe top 5. We’re very much confident in our ADCs.”

But, current success notwithstanding, the task ahead of Okuzawa is among the most difficult in corporate management. Daiichi Sankyo has one hit drug platform; he must figure out what comes next.

“In the coming five years, our growth will be driven by these five programs,” he said in an interview at ASCO. “But at the same time, we would like to establish the next growth driver.” Identifying that driver will be a big part of the company’s next five-year plan, which it will launch for the fiscal year beginning April 2026.

Daiichi Sankyo’s current ADCs are built around a technology known as DXd that the company’s scientists have fine-tuned since inventing it 15 years ago. It is the backbone for Enhertu, as well as the recently approved breast cancer medicine Datroway and three other ADCs that remain experimental.

ADCs like these contain three main components: a targeting antibody, a cancer-killing toxin and a linking molecule that can tightly hold onto the drug’s payload while it’s transiting through the body, but then release it upon arriving at the tumor. The concept is simple, but the details make the difference in balancing efficacy with safety.

Both AstraZeneca and Merck are convinced Daiichi Sankyo has struck the right balance. The former company gave Daiichi Sankyo $1.35 billion in 2019 to license rights to what became Enhertu and then one year later paid another $1 billion upfront for the drug the two companies now sell as Datroway. Then, in 2023, Merck bought rights to the three experimental ADCs for $5.5 billion in payments spread over two years.

Daiichi Sankyo’s next big thing might end up being more ADCs.

Okuzawa highlighted two as particularly promising. The first, dubbed DS-3939, combines an antibody licensed from Glycotope with the DXd backbone. It could be an opportunity for Daiichi Sankyo to take on independently, said Okuzawa. The other, DS-9606, uses a new payload technology Daiichi Sankyo hopes will yield other medicines in much the same way DXd has.

Yet Okuzawa, who has been at Daiichi Sankyo since 1986 and previously held several senior leadership positions, noted that the company’s research may take it in new directions, too.

“There are a lot of opportunities in the ADC space. On the other hand, [our scientists] are also pursuing discovery research outside of ADCs,” he said. “We have rich ideas for new modalities.”

In the meantime, Daiichi Sankyo needs to execute on the partnerships it already has in place with AstraZeneca and Merck. Combined, those deals promise up to $27 billion in conditional fees due upon Daiichi Sankyo’s medicines reaching certain regulatory and sales milestones. While some of those payments have already been made, the bulk remains unrealized.

Enhertu, which earned some $3.7 billion in sales last year, is well on track to meeting expectations. However, the path forward for Datroway and the lead program being developed with Merck may be steeper. While Datroway won an important U.S. approval in January 2025, AstraZeneca and Daiichi Sankyo have narrowed their development plans in lung cancer after obtaining mixed study results. And in late May, Merck and Daiichi Sankyo withdrew an approval application for another ADC in lung cancer after it failed to extend survival in a study they presented at ASCO in June

“Further biomarker analyses of the [study] are being conducted to determine if certain patient populations might differentially benefit as we explore the path forward for patritumab deruxtecan in lung cancer,” a spokesperson for Daiichi Sankyo confirmed by email, using the ADC’s generic name.

“However, we remain confident in the broad clinical development program of patritumab deruxtecan, which includes multiple clinical trials across 15 types of cancer.”

Development setbacks may be partly to blame for Daiichi Sankyo’s stock price, which in U.S. over-the-counter trading has fallen by one-quarter over the past year. Shares now trade at just under $21 apiece, about what they were worth at the start of the current five-year planning cycle in 2021.

The Food and Drug Administration in December granted a key approval for AstraZeneca and Daiichi Sankyo’s Enhertu, clearing a regimen involving the drug as an initial treatment for HER2-positive breast cancer. 

The approval came well ahead of the FDA’s decision deadline and greenlit a combination of Enhertu and Roche’s targeted therapy Perjeta for frontline use in people whose metastatic breast cancer is confirmed to be HER2-positive by an FDA-approved test. The clearance was based on results published in the New England Journal of Medicine last year, which showed the Enhertu-Perjeta regimen was more beneficial than the current first-line standard, a combination of chemotherapy and precision drugs that’s known as THP. 

“With this approval of Enhertu in the first-line HER2-positive metastatic setting, Enhertu once again offers significant improvements in progression-free survival and has practice-changing potential when used in combination with pertuzumab,” said Ken Keller, global head of oncology business and president and CEO of Daiichi Sankyo, in a statement, referring to Perjeta’s biological name.

Enhertu is an antibody drug conjugate that targets the HER2 protein, which is overexpressed on multiple tumor types including 15% to 20% of breast cancers. AstraZeneca and Daiichi Sankyo began co-developing the drug in 2019 as part of a multibillion-dollar alliance and, that year, saw Enhertu receive its first approval as a third-line treatment. Enhertu has since been cleared for a few different malignancies and become a mainstay in breast cancer care, changing the way certain tumors are characterized and in some cases supplanting chemotherapy. The drug generated almost $3.8 billion in sales for 2024 and was on track to surpass that total in 2025. 

The new approval could boost sales further still, as it positions Enhertu earlier in breast cancer care. According to AstraZeneca, about 10,000 patients in the U.S. are treated each year in the first-line setting. 

Study results supporting it showed that the Enhertu-Perjeta combination lowered the risk of disease progression or death by 44% compared to THP. The treatment held tumors in check for a median of almost 41 months, versus 27 months for those receiving THP. 

The side effects observed in testing were “consistent” with the profiles of the individual medicines, with “no new safety concerns identified,” AstraZeneca said in a statement. But among those side effects for Enhertu are potentially serious lung complications. Called interstitial lung disease and pneumonitis, they’re already part of a safety warning on Enhertu’s labeling and were observed in 46 treated participants — including two deaths — in AstraZeneca and Daiichi Sankyo’s study. Only four cases occurred in those who received THP. The Phase 3 study enrolled 1,157 participants. 

The Food and Drug Administration in September approved a new medicine for breast cancer, clearing Eli Lilly’s Inluriyo for people with a specific genetic mutation.

Previously known as imlunestrant, the drug was cleared for use in a subgroup of adults whose metastatic, estrogen receptor-positive, HER2-negative breast cancer has progressed after at least one hormone therapy. The approval made the treatment available specifically to people who fit that criteria and have mutations to a gene called ESR1 — an alteration Lilly believes to occur in about half of people with that form of the disease either during, or after, exposure to hormone therapy. 

The clearance was based on results published in the New England Journal of Medicine in 2024. Those findings, from a study called EMBER-3, showed that Inluriyo helped reduced the risk of disease progression or death among those with ESR1 mutations by 38% when compared to standard hormone-suppressing therapies. Inluriyo delayed tumor progression by a median of 5.5 months, or close to 2 months longer than those on typical drugs. 

The approval marked the latest advance for a new group of oral estrogen-degrading drugs known as “SERDs.” These drugs aim to supplant the decades-old therapy fulvestrant, an injectable medicine that’s been a mainstay of breast cancer care. The first, Menarini Group’s Orserdu, was approved in 2023. Inluriyo now joins it, while multiple others from Roche, AstraZeneca and a partnership between Arvinas and Pfizer are close behind. 

In a statement, Jacob Van Naarden, the executive vice president and head of Lilly’s oncology division, noted how the approval represents an “important step toward advancing innovative, all-oral treatment approaches” in breast cancer. Komal Jhaveri, a study investigator and clinical director of early drug development at Memorial Sloan Kettering Cancer Center added that ESR1 mutations often contribute to treatment resistance, making Inluriyo a “meaningful alternative treatment option.” 

Yet it’s unclear how big of an impact Inluriyo and other drugs like it will have on cancer care. At the American Society of Clinical Oncology meeting earlier this year, some doctors interviewed by BioPharma Dive cited some of the “unknowns” in the existing oral SERD results. The drugs also haven’t proven clearly effective in people without ESR1 mutations. Arvinas and Pfizer, for instance, whose competing medicine is under review for a similar population, recently decided to out-license their therapy because of the smaller-than-envisioned market it’ll command. 

Lilly could add to its drug’s sales potential, though. The company is studying Inluriyo in an “adjuvant” therapy in early breast cancer, where its goal is to prevent relapses. Initial results could come in 2027, according to a federal database. 

When the Food and Drug Administration approved a new prostate cancer drug in 2022, it validated a bet made by Novartis to acquire the drug’s maker, Endocyte. The decision was also another step forward for a long-studied research field that is finally coming of age.

The medicine, Pluvicto, is known as a “radiopharmaceutical.” Unlike the small molecule or biologic medicines drugmakers use to flip cellular switches on or off, radiopharmaceuticals are designed to precisely deliver radioactive material into the body. The result is a targeted punch of radiation that can knock out tumors in a way other drugs can’t.

However, since Pluvicto’s approval, Novartis has hit challenges meeting demand, highlighting one of the many issues that has slowed development of radiopharmaceuticals. They’re difficult to produce, distribute and administer. The earliest examples never lived up to commercial expectations, hamstrung by manufacturing problems, competition, high costs and safety concerns. GSK stopped making one, known as Bexxar, in 2014. Another, named Zevalin and originally developed by Idec Pharmaceuticals, never became a big seller.

A group of companies, from biotechnology startups to pharmaceutical giants, think they’ve solved these problems. Borrowing from progress in another cancer drug field, they’re leaning on technical advancements that have enabled researchers to design medicines capable of safely delivering a radioisotope to just the right spot.

Novartis is the most invested, having spent $6 billion on acquisitions of Endocyte, Advanced Accelerator Applications and Mariana Oncology. Right alongside Novartis is Bayer, which has also brought a radiopharmaceutical to market and is testing others. Eli Lilly, Bristol Myers Squibb and AstraZeneca have all bought into the field.

Behind them are a handful of publicly traded companies and at least a dozen biotech startups, making radiopharmaceuticals a hotly competitive area of drug research. Here’s where things stand:

What are radiopharmaceuticals, and how do they work?

Born shortly after the discovery of the X-ray, radiation therapy has more than a century of history in cancer treatment. It’s a way of using high-energy particles or waves to damage the DNA of cancer cells, preventing division and growth.

Along with surgery, radiation therapy is a mainstay of cancer care, used to treat or prevent the recurrence of tumors in more than half of people with the disease, according to the American Cancer Society.

But radiation therapy is a blunt force. Rays beamed from outside the body can damage healthy tissue, while a more targeted, inside-the-body approach is costly and complex.

By comparison, radiopharmaceuticals can deliver the destructive power of radiation directly into tumors. They are akin to microscopic smart bombs — radioactive material guided by a molecular courier to cells with specific protein flags.

With Novartis’ drug Pluvicto, a radioisotope known as lutetium is chemically fused to a small molecule that binds to PSMA, a protein overexpressed in most prostate cancers. Novartis’ other radiopharmaceutical, Lutathera, delivers radioactive lutetium to SSTR, a target found on certain neuroendocrine tumors.

The drugs are complex, made of hand-picked parts. Different radioactive materials may weigh more or less, last longer or pack a bigger punch. Some radiopharmaceuticals may require a “chelator,” a molecule that keeps the radioactive material intact as it’s carried through the body.

Drugmakers also have to design chemical “linkers” that hold their therapies together, but don’t stick around too long after reaching their target. A molecular guide that seeks out malignant cells is another necessary component.

Once designed, radiopharmaceuticals are tricky to produce at scale. Supplies of radioactive materials are limited, and their transport is controlled. The drugs must be made and delivered quickly, before the radioactive components decay too much.

Why are radiopharmaceuticals a hot area of investment?

Interest in radiopharmaceuticals mirrors the ascent of another class of targeted cancer medicines, known as antibody-drug conjugates, or ADCs.

Like radiopharmaceuticals, ADCs deliver a toxic substance, usually a chemical, directly to a tumor. After years of slow progress, they’ve undergone a renaissance catalyzed by technical advances, regulatory approvals and interest from large drugmakers. Venture investors are in turn backing new startups.

Radiopharmaceuticals are now in the spotlight, too. Despite the poor sales of the field’s first medicines, newer drugs are performing better. Studies supporting some, like Pluvicto, have shown radiopharmaceutical drugs can extend survival and, in some cases, outperform other types of treatments.

Radiopharmaceutical drugs are “now being recognized as an effective, safe, and economically and logistically viable treatment modality,” wrote physicians from Johns Hopkins University School of Medicine and Memorial Sloan Kettering Cancer Center, in a 2020 article in Nature Reviews Drug Discovery.

As is often the case, large pharma investment is sparking a chain reaction of activity. Novartis’ acquisitions of Advanced Accelerator and Endocyte yielded Lutathera and Pluvicto, which, despite production challenges, are seeing strong demand. Bayer reached close to $500 million in peak yearly sales with its radiopharmaceutical Xofigo; it’s now working on newer medicines and, in 2021, acquired two startups.

Diagnostics company Lantheus Holdings bought the maker of Azedra, another radiopharmaceutical recently approved by the FDA for rare neuroendocrine tumors.

Those deals, along with radiochemistry advances and a “greater ability to innovate in ‘complex’ therapeutic modalities,” have spurred a wave of investments in new radiopharmaceutical companies, wrote Faisal Khurshid, an analyst with Leerink Partners, in a 2023 report.

Some, like Fusion Pharmaceuticals and RayzeBio, are going after the same targets as Pluvicto and Lutathera, but with different radioactive components or guiding molecules. Both were recently acquired, by AstraZeneca and Bristol Myers, respectively. 

Others are pursuing different cancer-associated proteins. The startup Abdera Therapeutics has a program in development aimed at DLL3, a long-studied target in a tough-to-treat form of lung cancer. Belgian biotech Precirix is evaluating a radiopharmaceutical for tumors driven to growth by HER2, a well-known cancer gene.

Which companies are working on it, and who is backing them?

More than a dozen radiopharmaceutical startups have launched in recent years. Many have pulled in sizable funding rounds, sometimes with overlapping investor groups.

In April, Abdera debuted with $142 million in funding and backers led by venBio and Versant Ventures. Those two investors also launched RayzeBio, which raised $418 million before its buyout.

Convergent Therapeutics launched in May with $90 million from RA Capital Management and OrbiMed. RA Capital also helped incubate Mariana Oncology alongside Atlas Venture and Access Biotechnology.

Aktis Oncology has secured $161 million in funding from Novartis, Merck & Co. and Bristol Myers Squibb, among others, since arriving in 2021.

Precirix is backed by Forbion and Jeito Capital and has raised 117 million euros since 2018. Germany-based Isotope Technologies Munich, or ITM, in June secured 255 million euros in a large funding round for a European biotech.

Artbio debuted in June with seed funding from Omega Funds and F-Prime Capital. It’s run by Emanuele Ostuni, the former head of Novartis Oncology’s cell and gene therapy operations in Europe, and was founded by the inventors of Xofigo.

Other firms in the mix include France’s Atonco Pharma, Australia’s GlyTherix, China-based Ablaze Pharmaceuticals, University of Connecticut spinout Nami Therapeutics and Boston-based Ratio Therapeutics.

These young companies join a handful of publicly traded biotechs as well as initiatives started by diagnostics firms or suppliers of nuclear material.