Antibody-drug conjugates

The Food and Drug Administration in January expanded use of AstraZeneca and Daiichi Sankyo’s Enhertu, allowing the drug to be given earlier and more broadly in people with an aggressive form of breast cancer.

Since 2022, Enhertu has been approved in the U.S. to treat advanced breast tumors expressing “low,” but still detectable, levels of the HER2 protein. With its new decision, the agency widened Enhertu’s availability to include treatment of tumors with “ultralow” HER2 expression. HER2 protein levels must be determined by an FDA-approved test, AstraZeneca and Daiichi said.

The new approval positions Enhertu, an antibody-drug conjugate, or ADC, to be used before chemotherapy in people with low HER2-expressing tumors. Until now, Enhertu was available only for people whose cancer had progressed despite one or more hormone therapies as well as chemo. (The drug is also approved for use after HER2-targeted treatment in people with classically HER2 positive tumors.)

The approval “represents another paradigm shift in how certain breast cancers can be treated,” said Ken Keller, Daiichi Sankyo’s president and CEO, in a statement.

Enhertu, which delivers a toxin to tumor cells expressing HER2, has secured a series of approvals since AstraZeneca and Daiichi began collaborating five years ago. U.S. regulators have cleared it for use in breast, lung and gastric tumors. And it became the first ADC to win a pan-tumor OK, having been approved last year for use treating any solid tumor expressing HER2.

The approvals for HER2-low and, now, HER2-ultralow breast cancers are changing clinical practice, making it important for doctors to view expression beyond binary positive or negative terms.

For example, AstraZeneca estimates that as many as two-thirds of hormone receptor-positive breast cancers typically classified as negative for HER2 actually have low levels of the protein. The company has said another 20% to 25% may have “ultralow” HER2 expression.

“It is critical for patients to understand the HER2 status of their metastatic breast cancer to help them make informed treatment decisions,” said Krissa Smith, the vice president of education at the nonprofit group Susan G. Komen, in the statement provided by AstraZeneca and Daiichi.

Enhertu is part of AstraZeneca and Daiichi’s plan to prove ADCs can replace chemo in many tumor types. The company has six ADCs in clinical development, among them Datroway, which produced mixed results in testing but won its first U.S. approval in breast cancer in January

“The key goal from this trial is to show the power of ADCs in truly replacing chemotherapy,” said Mohit Manrao, the senior vice president of AstraZeneca’s U.S. oncology division, in an interview last year. “We are seeing with this therapy, we can displace traditional chemotherapy and bring it earlier to the patients.”

Enhertu’s clearance was based on study results, published in The New England Journal of Medicine last September, showing that Enhertu delayed cancer progression or death by a median of 13.2 months, versus 8.1 months among those who received chemo. That equated to a 36% reduction in the risk of cancer progression for study participants treated with Enhertu.

Nearly identical results were observed in the smaller group of people with ultralow HER2 levels, though the study wasn’t powered to detect a statistical difference on that measure.

The study hasn’t run for long enough to prove whether Enhertu extends survival. At the time of data cut-off last year, treatment was associated with a roughly 17% reduction in the risk of death, which was not statistically significant. There were also higher rates of serious drug-related side effects in people who received Enhertu, among them a kind of lung scarring called interstitial lung disease. Although this side effect wasn’t serious in most, three patients died, study results showed.

AstraZeneca and Daiichi are evaluating Enhertu even earlier in HER2-positive breast cancer, with Phase 3 tests ongoing in the first-line setting as well as before or after surgical removal of a tumor. Results from all three trials are expected later this year.

The Food and Drug Administration in January approved AstraZeneca and Daiichi Sankyo’s Datroway for use in people with a common type of breast cancer that has advanced despite two earlier lines of treatment.

Datroway, previously known as datopotamab deruxtecan or dato dxd, is cleared for people whose breast tumors are HR-positive and HER2-negative, where in testing it was associated with a 37% reduction in the risk of progression or death compared to chemotherapy. Datroway will compete in that setting with Gilead Sciences’ Trodelvy, which gained a similar approval in 2023.

A targeted type of cancer medicine called an antibody-drug conjugate, Datroway has struggled to show a clear benefit in lung cancer and, in breast tumors, hasn’t yet proven it can help people live longer. Nonetheless, AstraZeneca is still optimistic about Datroway’s potential, featuring Datroway among 20 drugs that can help the company achieve $80 billion in annual sales.

Datroway’s clearance has come in the most common form of breast cancer, which has historically been initially treated with hormone-blocking treatments and chemotherapy but, in recent years, has become a setting for more precise medicines like CDK 4/6 inhibitors and ADCs. Under the FDA approval, Datroway will be used in the third-line setting, following hormone drugs and chemotherapy.

The drug has a list price of about $4,891 per vial, according to an AstraZeneca spokesperson. It’s administered once every three weeks, though the dose given depends on a patient’s weight.  

The clearance finally enables Datroway to break into the U.S. market, despite questions about its sales potential. Already, mixed study results have led AstraZeneca and Daiichi to narrow their approval plans in lung cancer, one of the most lucrative markets in oncology. Now, the lack of a clear survival benefit in the drug’s prescribing information and the occurrence of a type of treatment-related lung scarring may give Gilead’s Trodelvy a few advantages, wrote RBC Capital Markets analyst Brian Abrahams. 

Additionally, the evolving treatment landscape in HR-positive breast cancer could relegate Datroway to the “third line and beyond,” as even the second-line setting is becoming increasingly segmented into tumors with specific genetic alterations, wrote Leerink Partners analyst Andrew Berens. Berens expects the drug to generate about $540 million in peak annual sales through its current indication. 

A bigger market opportunity may await in more aggressive “triple negative” tumors, for which clinical results are expected around the middle of the year. There, Datroway could end up competing with Trodelvy as well.

Pharmaceutical companies employ many different strategies when building their cancer drug pipelines, but one recent commonality among them is a belief in the future of targeted therapies known as antibody-drug conjugates.

Many of the leading cancer drugmakers have at least one or two antibody-drug conjugates, or ADCs, in development. Others, such as Pfizer, Johnson & Johnson and Merck & Co., have used buyouts or partnerships to build an ADC portfolio.

One of the best-selling ADCs on the market is AstraZeneca and Daiichi Sankyo’s Enhertu, which brought in combined sales of $3.7 billion in 2024. The two companies formed a $7 billion alliance around Enhertu in 2019 and since then, the drug has secured multiple approvals and changed the way some breast cancers are treated.

Over that time, AstraZeneca has made ADCs a more substantial part of its overall pipeline alongside radiopharmaceuticals and immunotherapies, giving the company many potential combinations to work with, said Carlos Doti, vice president and head of medical affairs for its U.S. oncology division.

“We started our ADC journey with the Daiichi partnership, and now we’re bringing seven or eight different molecules from our own platform,” Doti said.

Since the approval of the first ADC, Mylotarg, in 2000, researchers have improved the drugs’ capabilities by trying different components and changing the way they are linked together. As a result, newer ADCs could be used for more tumor types, and alongside other therapies, such as drugs that spur the immune system to fight cancer.

“ADCs can sort of be like a choose-your-own-adventure — you have all these different [tools] available to you, and now you can identify where there’s unmet need,” Doti said. “What was clear from [the American Society of Clinical Oncology’s annual meeting this year], the combination of ADCs and [immunotherapies] will change the first line of treatment by combining that immune system enhancement and directed therapy together.”

AstraZeneca study results, for example, have shown Enhertu can be used ahead of chemotherapy in a common type of advanced breast cancer, and in a broader group of patients. That finding is a step forward in a broader strategy by the company to use ADCs to supplant chemo in many tumor types.

But AstraZeneca is advancing other ADCs as well. The company has prospects in early clinical studies for lymphoma, leukemia, multiple myeloma and other malignancies. It is also aligned with Daiichi on Datroway, which was approved in January for a form of lung cancer.

ADCs, which chemically link a targeting antibody to a tumor-killing toxin, were originally seen as a way to more precisely deliver chemotherapies. But AstraZeneca and its peers are moving beyond chemo to transport other payloads, Doti said.

“We’re improving our technology, and getting better antibodies to direct where it needs to go, and using linkers that only release the payload at the point of delivery,” Doti said. “So if you see a lot of things going on for us and others, it’s that we're not just working on delivering chemotherapy in the payload anymore.”

AbbVie’s oncology pivot

AbbVie’s cancer drug portfolio is headlined by treatments for blood malignancies. Recently, though, the big drugmaker has made solid tumors a focus, and ADCs are a key part of its plan. In late 2023, the company spent $10 billion on ADC developer ImmunoGen, giving it an ovarian cancer drug, Elahere, as well as a group of experimental medicines that complemented its internal ADC research.

“We’ve been working in the hematological space, but solid tumors have a larger unmet need in oncology, and so it was a natural next step,” said Pedro Valencia, vice president of AbbVie’s solid tumor pipeline and strategy. “One of the overarching strategies is a focus around ADCs, thinking about what we call the ADC toolkit with a series of novel antibodies, novel targets, novel payloads that can be first and also best in class.”

AbbVie is targeting tumors, like colorectal and small-cell lung cancers, that many other medicines haven’t treated well in the past. Some of its prospects also deliver a so-called TOP1 inhibitor to tumors, as Enhertu does.

“The reasoning is we have the ability to replace chemotherapy that has been used for decades, and … we’re trying to do that in colorectal, ovarian, non-small cell lung and small cell lung cancers,” Valencia said.

Although AbbVie is behind many other pharmaceutical companies in treating these types of tumors, Valencia said that gives it a chance to build franchises from scratch, as it did with Humira in immunology and Venclexta in blood cancers. “We like to be the newcomers,” Valencia said.

Like AstraZeneca, AbbVie envisions combinations of ADCs and other drug types as expanding the number of people who can benefit from treatment.

“If you combine ADCs and immunotherapies, for example, I see that as the next big wave to unlock patients who haven’t been unlocked before,” Valencia said.

Japan-based Taiho Pharmaceuticals on March 17 said it will acquire Switzerland’s Araris Biotech and its antibody-drug conjugate technology for $400 million upfront.

The two companies have worked together since 2023, when they agreed to use Araris’ technology to explore and develop new drug candidates aimed at targets chosen by Taiho. The deal announced in March could hand Araris up to $740 million more if certain milestones are met.

Antibody-drug conjugates, or ADCs, pair tumor-killing toxins with a targeting molecule via a “linker.” Improvements in this linking technology have helped buoy the field, yielding new treatments and sparking greater investment. Many large pharmaceutical companies, among them AstraZeneca, Pfizer and Merck & Co, have inked multibillion-dollar deals to pad their pipelines with ADC prospects. AstraZeneca, together with its partner Daiichi Sankyo, have arguably had the most success recently with their ADC drugs Enhertu and Datroway.

Spun off from the Paul Scherrer Institute six years ago, Araris was funded by 4BIO Capital in 2020 and again in 2022. The biotech touts its “AraLinQ” technology, which it claims can provide more stable and more potent ADCs. It is developing three candidates for blood and solid tumors, and expects to advance these prospects into clinical testing this year and next.

“Araris’ unique ADC technology represents a quantum leap for the ADC field, potentially offering precise payload delivery of multiple mechanisms of action simultaneously to the tumor, with less toxicity,” Dragan Grabulovski, CEO and co-founder of Araris, said in a statement.

Taiho, a subsidiary of Japan’s Otsuka, sells several cancer drugs in the U.S: Lytgobi for bile duct cancer, Lonsurf for colorectal cancer and the myelodysplastic syndromes treatment Inqovi. It also markets other anticancer medicines in Japan.

Pfizer in February named a longtime Novartis executive the leader of an oncology division it is leaning on to win back the support of investors in the years ahead.

The pharmaceutical giant said Jeffrey Legos, who has been leading Novartis’ hematology and oncology drug development since 2015, will become its new chief oncology officer. In that role, Legos will report to Chris Boshoff, who was formerly Pfizer’s cancer drug chief but stepped in as head of R&D last year when Mikael Dolston retired.

Legos will replace interim chief oncology officer and one-time Seagen R&D leader Roger Dansey, who joined Pfizer after it acquired Seagen in 2023 and will retire after Legos takes over. 

Legos has more than two decades of experience developing cancer drugs in various roles at GSK and, since 2015, Novartis. Through those positions, he’s played a part in over 40 regulatory approvals of drugs and companion diagnostics, Pfizer said. At Novartis, those approvals included the radiopharmaceutical Pluvicto and the breast cancer drug Kisqali, both of which are among the company’s fastest-growing medicines. 

At Pfizer, Legos looks to ignite investor interest in a cancer drug portfolio the company is counting on to boost sales in the coming years. Fast-fading sales of its COVID-19 vaccine Comirnaty and treatment Paxlovid, as well as missteps in some recent acquisitions, have led to cost cuts, a flagging stock price and a challenge from an activist investor. Multiple top-selling drugs, including Xtandi and Eliquis, will lose patent protection this decade, too.

While investors have focused their attention on Pfizer’s obesity drug research, the company has insisted that its cancer drugs — many of which were acquired in a $43 billion buyout of Seagen in 2023 — can help pick up the slack. 

That portfolio accounted for about a quarter of Pfizer’s roughly $64 billion in revenue last year and had four medicines — led by the breast cancer drug Ibrance — that eclipsed $1 billion in sales. Pfizer has claimed its pipeline could produce eight more so-called blockbusters by 2030, both by growing sales of marketed medicines and succeeding with others in testing. 

On a first quarter earnings call, CEO Albert Bourla pointed to a pair of breast cancer drugs in late-stage testing, among them a type of protein-degrading therapy it’s co-developing with biotechnology company Arvinas. One antibody-drug conjugate it inherited from Seagen is in a Phase 3 trial in lung cancer, while a second ADC aimed at a popular immunotherapy target, PD-L1, will join it this year, he said. 

Bourla also claimed Pfizer’s multiple myeloma drug Elrexfio is poised to become a “mega blockbuster.” The drug generated more than $130 million in sales in its first year despite only being available for a “very niche indication,” Bourla said. The company has four ongoing Phase 3 studies that could help broaden use. But it’s already battling for market share with a similar therapy from Johnson & Johnson, and could potentially face additional competition from Regeneron. 

“This product will become a very big oncology product for Pfizer,” Bourla said. 

Sales growth of Padcev, another Seagen drug, is also a key part of Pfizer’s plan. Study results expected this year in a type of bladder cancer could “nearly triple” the number of patients eligible for treatment, he added. 

Padcev earned about $1.6 billion in sales for Pfizer last year. 

An antibody-drug conjugate developed by Daiichi Sankyo and Merck & Co. met the main goal of a Phase 3 lung cancer trial, delaying tumor progression in people whose disease has a specific mutation by longer than chemotherapy, the companies said in September.

The companies didn’t release detailed data from the trial, which tested patritumab deruxtecan against a two-drug chemo combination in people whose non-small cell lung cancer has a mutation in a gene called EGFR. The trial enrolled people whose disease had progressed following treatment with EGFR-targeting drugs.

Daiichi previously used positive data from a Phase 2 trial to support an application to the Food and Drug Administration for accelerated approval and attract billions of dollars in Merck partnering cash. However, the FDA later rejected Daiichi’s application over inspection findings at a manufacturing plant.

Daiichi and Merck’s drug, like the others in its class, use an antibody to home in on a protein expressed on tumor cells and then release a toxic chemical directly to diseased cells. The first ADCs were in blood cancers, but more and more drugmakers are developing them for solid tumors like those of the breast and bladder.

Their development has been helped along by Daiichi, which discovered the breast cancer ADC Enhertu — one of the most successful drugs in the class. Enhertu, which AstraZeneca helps market, had sales of $3.7 billion last year.

The Japan-based drugmaker has six ADCs that use the deruxtecan chemotherapy. Those include Enhertu, another agent partnered with AstraZeneca, an additional two drugs partnered with Merck and one Daiichi is developing alone.

The Merck deal saw the New Jersey-based drugmaker pledge up to $22 billion, including $3 billion on the deal’s signing in October 2023. Merck is seeking to boost its pipeline as it faces a potential loss of revenue later in the decade when key patents for its immunotherapy Keytruda begin to expire.

The type of lung cancer patritumab deruxtecan is being tested in is usually treated first with EGFR-blocking small molecule drugs like AstraZeneca’s Tagrisso. The cancer typically becomes resistant to those agents over time and, once that happens, people have a poor outlook and few effective drug options.

Gilead no longer sells its combination drug Trodelvy to treat bladder cancer after announcing last October it had agreed with the Food and Drug Administration to withdraw it following negative trial results.

The FDA granted Trodelvy accelerated approval for bladder cancer in 2021, based on results that found it shrank tumors in people whose disease had progressed following treatment with chemotherapy and immunotherapies like Merck & Co.’s Keytruda. But a confirmatory study, titled TROPiCS-04, failed to show the medicine helped people live longer.

Trodelvy’s withdrawal is one of several conditional approvals that have been rescinded in recent years, most notably among the “PD-1” class of drugs that includes Keytruda and Bristol Myers Squibb’s Opdivo. The Trodelvy decision, however, came months after negative trial results, a sign the FDA has become more vigilant about resolving so-called “dangling” accelerated approvals.

Trodelvy has been a key part of Gilead’s foray into cancer treatment. An antibody-drug conjugate, it’s designed to home in on a prevalent protein on tumor cells and then release a toxic chemical into those cells while sparing surrounding healthy tissue.

Gilead’s top seller in oncology is the cell therapy Yescarta. But that drug is primarily used to treat blood cancers like lymphoma, while Trodelvy is aimed at a variety of solid tumors. The setback in bladder cancer is a small disappointment, representing less than 10% of sales compared with 90% in breast cancer, TD Securities analyst Tyler Van Buren wrote in a note to clients.

Van Buren forecasts Trodelvy sales of around $1 billion by 2030 in breast cancer, its remaining approved setting.

Expansion into lung cancer has also hit a roadblock, when a study generated disappointing results in a patient group in which a similarly acting drug from AstraZeneca and Daiichi Sankyo has been more successful.