Oncology's research boom

Merck & Co.’s sweeping cancer drug alliance with Daiichi Sankyo in late October highlighted the pharmaceutical industry’s newfound enthusiasm for so-called antibody-drug conjugates, a class of medicines that’s yielded major products like Seagen’s Adcetris, Roche’s Kadcyla and AstraZeneca’s Enhertu. 

Earlier this year, Pfizer agreed to pay $43 billion to acquire Seagen, the field’s pioneer. A few years prior, Gilead paid $21 billion to buy Immunomedics and its antibody-drug conjugate Trodelvy. 

Merck, which reportedly had also sought to buy Seagen, isn’t paying that much upfront, agreeing to send Daiichi Sankyo $5.5 billion over the next two years. But the deal’s total value is as high as $22 billion, if all sales milestones are met, making it one of the most lucrative pharma licensing arrangements in recent history. 

It will add to some $16 billion worth of antibody-drug conjugate licensing deals signed in 2022, according to analytics company Global Data. And it comes as the European Society of Medical Oncology’s annual meeting got underway in Spain, featuring clinical trial data for the drugs in lung, cervical, prostate and breast cancers.

Antibody-drug conjugates, or ADCs, pair the tumor-cell killing capabilities of chemotherapy with the targeting technology of synthetic antibodies. When the combined drug binds with a cancer cell, a chemical linker unleashes the toxin into the cell, sparing surrounding healthy tissue from exposure.

Merck has already been active in the field, paying Seagen $1.7 billion in cash, licensing fees and equity in 2020 for rights to an experimental ADC as well as to the marketed drug Tukysa. A few months later it signed a $3 billion deal to acquire VelosBio. And last year, it paid Kelun-Biotech $175 million upfront for rights to a number of early-stage ADCs.

In partnering with Daiichi Sankyo, Merck may have been spurred on by one of the more audacious big pharma bets on ADCs. In 2019, AstraZeneca paid Daiichi Sankyo more than $1 billion upfront and promised an additional $5.6 billion in contingent payments for rights to the drug that became Enhertu, a deal it funded with a $3.5 billion share offering. That bet is on the verge of returning blockbuster annual revenue for AstraZeneca, which reported $104 million in product sales and $475 million in alliance revenue through the first six months of 2023.

Gilead’s deal for Immunomedics was also bold as it sought to build an oncology business, although it had the cash from its HIV and hepatitis C drugs to tap. Like Enhertu, Trodelvy could also record blockbuster numbers soon, having accounted for $482 million in sales through June 30.

Other companies have been joining in. Bristol Myers Squibb, Merck’s rival in immunotherapy, paid Eisai $650 million in 2021 for rights to an ADC the Japanese drugmaker was developing for tumors positive for folate receptor-alpha, which include endometrial, ovarian, lung and breast cancers.

BioNTech, which made a name as a developer of mRNA vaccines and drugs, earlier this year signed a $170 million up front deal with Duality for rights to two ADCs.

Eli Lilly has also become active in the last two years, buying a German biotech called Emergence for its ADC pipeline, signing a deal with ImmunoGen, and acquiring French ADC developer called Mablink Bioscience.

AbbVie is expanding its investment in targeted cancer medicines, announcing Nov. 30 a $10.1 billion deal to acquire ImmunoGen, a pioneer in the field of so-called antibody-drug conjugates, and its newly approved ovarian cancer treatment Elahere.

The transaction was 2023’s fourth-largest biotechnology buyout and came as AbbVie’s oncology business is sputtering. Revenues for the company’s flagship drug Imbruvica have shrunk by more than one-fifth year over year through the first nine months of 2023, as competing therapies with fewer side effects have taken market share.

Elahere gives AbbVie an on-market drug that could help boost sales as the company awaits clinical trial results and the potential approval of experimental cancer drugs in its pipeline.

Robert Michael, AbbVie’s chief operating officer, highlighted Elahere’s rapid market adoption on a Nov. 30 call with investors. Sales, he noted, are already annualizing above $400 million, which he said would put it “on track to be one of the most successful new product launches in oncology.”

Elahere would also be the only drug in AbbVie’s portfolio approved to treat a solid tumor, rather than the blood cancers that Imbruvica and AbbVie’s other marketed medicines target.

“It has been a strategic priority for AbbVie to establish a strong foundation in solid tumors,” said AbbVie CEO Rick Gonzalez on the call.

ImmunoGen’s focus on so-called “antibody-drug conjugates,” which combine targeting antibodies with cancer-killing chemotherapy, matches AbbVie’s own research strategy. The company has emphasized development of the medicines, known as ADCs for short, and lists five in its pipeline.

Founded in 1981, ImmunoGen was an early innovator in the ADC field, developing the targeting biological molecules, the tumor killing chemical payload and the molecules that link them.

Its technology helped make possible the Roche drug Kadcyla and the Sanofi drug Sarclisa. Still, its own drug development efforts didn’t bear fruit until the Food and Drug Administration last year gave conditional approval to Elahere.

The drug is now used for people with ovarian cancer whose disease has progressed despite one to three rounds of chemotherapy and whose tumors have high levels of a protein called folate receptor alpha. AbbVie estimates a majority of ovarian cancer patients have this biomarker.

A confirmatory trial of the drug recently succeeded, showing treatment reduced the risk of progression or death compared with chemotherapy in patients whose disease has worsened following at least one round of chemotherapy.

ImmunoGen is also approaching an important data readout for a second experimental drug called pivekimab sunirine in a rare bone marrow and blood cancer. That medicine is also in earlier testing for leukemia.

The biotech’s antibody-drug conjugates will join in late-stage testing of AbbVie’s most advanced ADC, telisotuzumab vedotin, which is in lung cancer trials.

The $10.1 billion deal continues pharma’s lavish spending on ADC developers. Pfizer earlier this year agreed to pay $43 billion to acquire Seagen, another pioneer in the field, while Merck & Co. signed a big collaboration deal with Daiichi Sankyo worth $5.5 billion over the first two years.

In 2020, Gilead spent $21 billion to buy Immunomedics, which had developed and launched an ADC called Trodelvy in breast cancer.

Sponsored content

By EVERSANA

The Oncology Market: A Rapidly Evolving Landscape

As a therapeutic class, oncology is one of the fastest-growing growing areas of pharmaceutical and biopharmaceutical innovation. There is enthusiasm in many types of cancer studies, thanks to ongoing innovation and breakthroughs in advanced therapy options to help address diversity gaps (such as biomarker-directed therapies, cell-and-gene therapies [CGT], and chimeric antigen receptor (CAR) T-cell immunotherapies), improved screening techniques, and expanded clinical trial enrollment). Such advances are contributing to steady improvement in terms of both overall survival (OS) and progression-free survival (PFS) metrics within many forms of cancer. With advancements reshaping the treatment landscape, there's a unique set of challenges that come with adopting new technologies.

Some primary challenges facing manufacturers are accelerated approvals and the subsequent fulfillment of confirmatory trials. These unmet needs in the disease area, coupled with the pace of the biotechnology industry, create unprecedented pressure for high-science brands to accelerate their speed to market to make a positive clinical impact on patients and the industry. As a result, more teams want to participate in the accelerated approval process.

As of April 2023, 23 oncology drugs with accelerated approvals had withdrawn the specific cancer indication, 74% of which (17 drugs) withdrew in the last 3 years. These withdrawals showcase a key pain point for companies to validate clinical benefit for accelerated approvals beyond the surrogate endpoints, by conducting confirmatory trials.

Staying abreast of rapid changes in data and navigating regulatory intricacies further add layers of complexity to the commercialization process. This includes the need for specialized expertise in areas like advanced market access to effectively navigate the comprehensive landscape.

Charting the Challenges: Modern-day Obstacles in Oncology Product Launches

Despite the promise of innovation, recent oncology launches have faced significant challenges, particularly for small to mid-size manufacturers. Limited resources and expertise often hinder their ability to navigate the complexities of bringing a new therapy to market. The risk associated with uncertain clinical endpoints and FDA approval, coupled with the need to quickly scale operations upon approval, poses significant financial hurdles.

Furthermore, engaging providers throughout the care continuum is necessary to ensure commercial success. Effectively communicating the value of these therapies to both HCPs and patients, and understanding the science behind them, including treatment regimens, side effects, and other factors, is essential but can be challenging.

Without the necessary internal resources and financing, today’s pharma/biopharma innovators are not able to carry out all the concurrent planning and strategic development, nor are they able to assume the risk on their own to ensure the successful commercialization of their lifesaving product.

Pioneering Progress: Contemporary Strategies for Oncology Commercialization

In light of these challenges, manufacturers must explore innovative approaches to enhance their commercialization strategies. Outsourcing efforts can provide smaller companies with access to expertise and resources they may lack internally. By leveraging innovative solutions such as electronic benefit verification (eBV) and direct-to-patient initiatives, manufacturers can optimize patient engagement and access.

Connectivity across all levels of the commercialization process is paramount, with a focus on innovative solutions that streamline operations and maximize efficiency. Emphasizing dispensing and alternative sites of care can also optimize distribution channels and ensure broader patient access.

Navigating the complexities of the oncology market requires a multifaceted approach that addresses regulatory requirements, leverages innovative solutions and prioritizes patient engagement. By implementing tailored commercialization strategies that address these considerations, pharmaceutical manufacturers can enhance their ability to bring innovative oncology therapies to market and ultimately improve patient outcomes in this ever-evolving landscape.

The Next Phase of Evolution for Pharma: EVERSANA Oncology™ Commercialization

EVERSANA benefits pharmaceutical manufacturers by offering a dedicated team of experts who possess a deep understanding of the oncology market. A specialized focus on oncology offers unparalleled capabilities to guide clients through the complexities of commercializing oncology therapies. By leveraging this expertise, EVERSANA provides comprehensive support across three key pillars:

• A deep bench of industry experts
• An agile, fit-to-scale model that addresses the unique needs of each tumor type and therapy needs
• All commercial services under one roof

The power of EVERSANA Oncology Commercialization lies in its flexibility, allowing manufacturers to seamlessly adapt to changing market dynamics and make informed decisions that optimize spending. A unique ability to pull levers and flex resources enables clients to efficiently allocate assets, pulling in service areas when needed and pausing when circumstances dictate. With all capabilities and connectivity housed under one roof, EVERSANA streamlines operations and enhances collaboration, empowering pharmaceutical manufacturers to navigate the oncology landscape with confidence and meaningfully impact patients’ care.

When the Food and Drug Administration approved a new prostate cancer drug last year, 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 appears to finally be 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 struggled to meet 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 and Advanced Accelerator Applications. Right alongside Novartis is Bayer, which has also brought a radiopharmaceutical to market and is testing others.

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 report last year.

Some, like the publicly traded biotech Fusion Pharmaceuticals and startup RayzeBio, are going after the same targets as Pluvicto and Lutathera, but with different radioactive components or guiding molecules.

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 has raised $418 million since its start, making it one of the field’s most well-funded companies.

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, like Fusion, Plus Therapeutics and Point Biopharma, as well as initiatives started by diagnostics firms or suppliers of nuclear material.

How far along are these new companies?

Unlike other hotspots of startup activity, radiopharmaceutical developers are, in many cases, already deep into clinical development.

Several companies are testing drugs that, like Lutathera, target tumors expressing the protein SSTR. RayzeBio began a Phase 3 trial in May, while ITM is further along in its late-stage program. Molecular Targeting Technologies, Arecium Therapeutics and Orano Med also have SSTR-targeting medicines in human trials.

A group of developers are following in Pluvicto’s footsteps with drugs aimed at cells expressing PSMA. Curium Pharma has a Phase 3 study underway in prostate cancer. Point and partner Lantheus are expecting late-stage results later this year. Medicines from Fusion, Convergent and Advancell are in earlier stages.

ArtBio’s lead program is also for prostate cancer and has entered human trials. It uses a radioactive isotope called Pb212 that the startup claims has an “ideal clinical profile.” Advancell and Orano Med use Pb212 as well.

Other companies are earlier in their journeys. Aktis, for example, hasn’t disclosed a lead program. But it has revealed the radioactive material, Actinium-225, it intends to deliver with drugs. Abdera plans to ask regulators next year to begin its first trial.

Pfizer believes the answer to its sliding valuation lies in oncology. 

The company, which is coming off one of the worst years in its history, unveiled March 1 a new business unit dedicated to cancer research. The division, created in the wake of Pfizer’s $43 billion buyout of Seagen last year, houses a sprawling portfolio of experimental medicines both companies discovered and acquired through deals. It also includes the marketed drugs Pfizer and Seagen have long been selling for a variety of tumor types. 

Pfizer claims the pipeline it now has could produce more than eight blockbuster medicines by 2030, up from five today, and double the number of patients the company’s drugs currently treat. By then, biologic medicines should account for nearly two-thirds of its oncology revenue, up substantially from the 6% they comprise now, Pfizer said. 

To achieve those goals, Pfizer will need steady sales growth and additional approvals for its currently marketed medicines. It will also need a pipeline of 16 experimental drugs across four broad areas of cancer research to come through in testing. 

The oncology push comes after a tumultuous year for Pfizer marked by fast-declining sales for its COVID-19 treatments and little growth elsewhere. Company shares lost a large chunk of their value, and Pfizer responded with a cost-cutting plan that aims to reduce expenditures by $4 billion. Pfizer is facing pressure elsewhere too, as looming patent expirations and competition to some of its top-selling medicines leave the company with “uncertain long-term .. prospects,” wrote Leerink Partners analyst David Risinger. 

Pfizer’s breast cancer medicine Ibrance, for example, has seen its market share decline amid a growing threat from Eli Lilly’s Verzenio and Novartis’ Kisqali. Oncology revenue has been stagnant too as sales in 2023 fell from $12.1 billion to $11.6 billion.

The company anticipates a boost from Seagen’s portfolio, which includes the marketed medicines Adcetris and Padcev and could boost its oncology revenues by another $10 billion by the end of the decade. Pfizer believes its marketing and manufacturing might can accelerate sales of both, surpassing what Seagen was able to do on its own. 

Study results due later this year and early next could show whether Pfizer is on that path. The company expects readouts from marketed and experimental drugs in its four main areas of oncology research – thoracic, breast, genitourinary and blood cancers. Pfizer is also launching Padcev in first-line bladder cancers, a setting analysts believe could transform the drug into a multi-billion dollar product. 

Additionally, the company is running Phase 3 trials for newer prostate and breast cancer drug prospects, including an experimental medicine called atirmociclib that could potentially supplant Ibrance if successful in a head-to-head trial. 

After attending Pfizer’s presentation, Louise Chen, an analyst for Cantor Fitzgerald, wrote that she believes the oncology business will be the company’s “largest growth driver through 2030,” something that “is not reflected in the stock's valuation yet.”

She added that Pfizer is “being conservative” in its revenue estimates because of Padcev’s likely growth in bladder cancer as well as “increasing usage” of antibody-drug conjugates, Seagen’s specialty.  

Advisers to the Food and Drug Administration have endorsed the use of two cellular medicines for multiple myeloma earlier in a patient’s disease, overlooking safety concerns raised by agency reviewers.

The advisory committee in mid-March voted unanimously, 11-0, that the benefits of Johnson & Johnson and Legend Biotech’s Carvykti outweighed the risks when administered to patients as early as after their first relapse. They cast a narrower, but similarly positive vote, 8-3, for Bristol Myers Squibb’s Abecma. 

The impact ot treatment “is significant and offers our patients a chance of significant time off therapy with associated quality of life improvement,” said Christopher Lieu, an associate medical professor at the University of Colorado, who voted in favor of Abecma and Carvykti. “But it's a closer margin than I think we would like, and patients will need to have in-depth discussions about the risks and benefits.” 

The votes increase the likelihood that use of both therapies, which are currently available to myeloma patients following at least three lines of treatment, will be expanded in the U.S. European regulators have already endorsed such a decision. The FDA doesn’t always follow the advice of its advisory committees, but usually does. 

The panel threw their support behind Carvykti and Abecma based on studies showing they helped people with the blood cancer live longer without their disease progressing when compared to standard drug regimens.

In doing so, panelists waved off concerns flagged by FDA reviewers in briefing documents posted earlier this week. In those documents, the agency cited an increased risk of early death in patients who received Carvykti or Abecma. Specifically, FDA statisticians found a higher risk of death in patients who’d received Carvykti in the first 11 months of the study supporting its application. For Abecma, that elevated risk lasted 15 months. 

While acknowledging the FDA’s findings, some experts countered that patients would likely choose treatment anyway given the length of the remissions observed in testing of Carvykti and Abecma.

“The question is whether or not the patients are willing to undertake the risk,” Lieu said following the positive Carvykti vote. “The answer will likely be ‘yes’ for patients who may want just a chance at a longer time off treatment.”

The FDA, for its part, noted that the therapies haven’t yet clearly shown they can extend lives. “It may be when the data are more mature, but it's not there yet,” said Robert Sokolic, the head of the agency branch that reviews hematology drugs.

Agency staff also claimed that the early deaths in testing weaken the overall results and purported long-term benefits of treatment. The known side effects of CAR-T therapy, as well as the conditioning regimens used to prepare patients for treatment, may have elevated patients’ death rates in testing, making the benefits of therapy less clear.  

“All these risks should be considered integral to the benefit-risk assessment of CAR-T cell therapy,” Helkha Peredo-Pinto, an FDA clinical reviewer, told committee members.

However, Jordan Schecter, J&J’s vice president of R&D, argued that the picture would look different outside the confines of a clinical trial. Some of the early deaths in testing could have been averted if physicians had been able to give patients the best possible “bridging” therapy while they awaited CAR-T treatment. The complex therapies take weeks to manufacture, during which time patients’ disease can progress.  

The increased risk of early deaths in the trials “need to be explained,” said Brian Durie, the chairman of the International Myeloma Foundation. But “the key point for me is that it was occurring in this preparatory period,” and was “not associated with the CAR-T therapy itself.”

Jorge Nieva, an associate medical professor at University of Southern California, added that other cancer therapies, such as stem cell transplants, have a “front-loaded” risk of death but better long-term outcomes than alternative treatments.

But Nieva, along with other panel members, agreed that the issues surrounding the use of bridging therapy in testing shouldn’t be as much of a problem in clinical practice. Physicians won’t be burdened by clinical trial rules that delay CAR-T treatment and restrict bridging therapies, he said.

“A reason for some of the problems here is, in a way, an artifact of the clinical trial process,” he said. “In the real world, where collection and manufacturing could occur early in the course of disease, that may be less of an issue for patients.”

The development of therapeutic vaccines for cancer has met repeated disappointment over the years, as treatments aimed at cancers of the brain, lung and kidney have failed in clinical testing.

But now, developers like Moderna, BioNTech and Gritstone Bio are pushing forward with personalized, messenger RNA vaccines that have revitalized hopes these treatments could boost human immunity to keep cancer at bay.

The American Society for Clinical Oncology’s annual meeting, held in Chicago in early June, was the latest forum for Moderna and partner Merck & Co. to disclose data for a cancer shot they’re developing, called mRNA-4157. The companies had announced the trial met its goal in December, and presented more detailed results in April.

In the background, Roche and partner BioNTech published early clinical trial data for a pancreatic cancer vaccine last month, and the companies are working toward concluding an early-stage melanoma study sometime this year. Gritstone, meanwhile, expects to have early data in colorectal cancer in early 2024.

The development of messenger RNA-based COVID-19 vaccines has helped accelerate some of these advances, showing how developers can quickly tailor and produce treatments using the genetic material.

“We saw something really amazing since the winter of 2020,” Gavin Dunn, director of the Center for Brain Tumor Immunology and Immunotherapy at Massachusetts General Hospital.

“We’ve seen the high immunogenicity of nucleic acid-based vaccines,” he said. Using mRNA’s speed and applying it to cancer vaccine research, “a lot of the time frames may start to be compressed.”

There are a number of reasons why past cancer vaccines have disappointed. Some haven’t targeted enough of the mutated proteins present in tumor cells to spur an immune response, or they’ve stimulated the wrong kind of immune cells or haven’t been able to overcome cancer’s natural immunosuppression. (One approved treatment, an individualized immunotherapy derived from patients’ blood called Provenge, is considered by some to be a cancer vaccine.)

Cancer vaccines now in development target multiple mutated cancer proteins, called neoantigens, and are tailored to the specific ones present in each individual patient.

“The question is whether we didn’t have good enough vaccine technology or whether we didn’t target the correct antigen,” Olivier Michielin, a medical professor at the University of Geneva, said of past cancer vaccine disappointments in a discussion of Moderna’s data at ASCO.

Moderna is testing its shot, mRNA-4157, together with Merck’s immunotherapy Keytruda in people with melanoma who have had their primary tumors removed. The goal of such “adjuvant” treatment is to prevent cancer from returning.

In December, the company reported the two drugs reduced the relative risk of death or recurrence by 44% over Keytruda alone. The new data came from an analysis of the risk of cancer spreading to distant organs or tissues, or “distant metastasis free survival.”

One-third of patients who receive Keytruda in this setting experience such spread, driving researchers’ work to come up with better options. “We know that patients with distant metastases experience more morbidity and mortality,” said Adnan Khattak, a clinical professor at Edith Cowan University in Australia, who presented the Moderna data at ASCO.

In the combination trial, mRNA-4157 and Keytruda reduced the risk of distant spread or death by 65% compared to Keytruda alone.

BioNTech’s candidate autogene cevumeran, which had the promising data in pancreatic cancer in May, soon could have results from a Phase 2 trial in melanoma in combination with Keytruda, too. The company said the trial has completed enrollment and needs a sufficient number of events in order to measure the shot’s effectiveness.

However, the trial is in previously untreated patients, which could raise the threshold for determining success, SVB analyst Daina Graybosch wrote in a Dec. 8 note to clients. Quoting BioNTech executives, Graybosch wrote, “the bar for success is lower in adjuvant settings, as there are fewer tumor cells” for immune cells to attack.

Gritstone, meanwhile, reported in May that it had enrolled 71 of an initially planned 80 participants in a Phase 2 trial of its personalized neoantigen mRNA vaccine program in colorectal cancer. It is now expanding its planned enrollment to 100. The trial, which involves patients who typically don’t respond to Keytruda, is expected to generate preliminary results in early 2024, executives said.

Aiding the development of these personalized vaccines has been artificial intelligence-aided genetic profiling that helps identify the antigens present in patients and how to better target them. That, in turn, has helped speed clinical testing and, if the vaccines are ever approved, could help meet patient demand, said Christina Corridon, a principal at the consulting firm ZS.

“There’s a limited capacity of human pathologists to be doing all of this work,” she said. “One of the limitations to scaling [personalized vaccines] is human pathologists versus computational pathology.”

Gritstone also has an “off-the-shelf” cancer vaccine technology that targets shared neoantigens, an area where the private Swiss company Nouscom has been working.

The recent progress appears to be shifting the views of researchers and physicians, as they try to build on the cancer immunotherapy advances of the past decade.

“We have clearly a new groundbreaking technology that will open a new era in cancer vaccines,” Michielin said in comments on the Moderna data.

Wedged into the surface of a tumor cell, the protein called HER2 acts as a homing beacon for some of the most potent cancer medicines developed. Its discovery decades ago, and abnormal abundance in some breast cancers, led to the development of targeted drugs like Herceptin that have greatly improved patient care.

Results from an exploratory clinical trial unveiled in early June suggest targeting HER2 could also be a useful strategy against other cancers that are not as widely associated with the protein.

The findings, which were presented at the American Society of Clinical Oncology’s annual meeting in Chicago, show that a newer HER2-targeting drug called Enhertu shrank tumors of the uterus, cervix, ovaries, bladder and, to a lesser extent, bile duct. In this way, they’re another data point in a yearslong shift toward describing cancers by their genetics, rather than only by their location in the body.

Developed by AstraZeneca and Daiichi Sankyo, Enhertu is different from drugs like Herceptin, which interfere with how HER2 incites tumor growth. Instead, Enhertu combines a targeting molecule aimed at HER2 with a cell-killing toxin in a biochemical assemblage known as an antibody-drug conjugate.

“The reason why this [result] is exciting is that the tumor doesn't have to be addicted to HER2 to respond to this therapy,” said Angela DeMichele, a medical oncologist at Penn Medicine. “The HER2 in this case is acting as a docking station for delivery of the chemotherapy.”

“It’s almost like a proof of concept that we can get benefit from these drugs, these antibody-drug conjugates, even when what the antibody is binding to is not what is driving the tumor,” added DeMichele, who was not involved in the study.

Enhertu is already approved in the U.S. to treat HER2-positive and HER2-low breast cancer, as well as HER2-positive gastric and lung cancers. It has proven a powerful option for those types of tumors, and in the process recast how doctors think of HER2 status for breast cancer.

Monday’s results point in new directions. AstraZeneca and Daiichi’s study is what’s known as a “basket” trial, enrolling patients with a range of cancers meeting certain criteria and testing a targeted therapy against them. In this case, participants had locally advanced or metastatic solid tumors that were positive for HER2 and had received at least one prior systemic treatment.

Among trial volunteers whose tumors had the highest HER2 expression, researchers reported that more than 50% of those with endometrial, cervical, ovarian, urothelial or biliary tract cancer responded to Enhertu. Response rates, which reflect reduction in tumor size, were lower when participants with less HER2 expression were included, ranging from 22% overall in biliary tract cancer to nearly 58% in endometrial cancer.

“We think this is really exciting data,” said Funda Meric-Bernstam, chair of the University of Texas MD Anderson Cancer Center’s investigational cancer therapeutics department and the study’s lead investigator.

Meric-Bernstam noted how, across all study participants, responses to Enhertu lasted a median of nearly one year. However, in those with the highest HER2 expression the median duration of response doubled to 22 months — a finding she described as “compelling.”

Across all 267 people in the trial, the rate of response was 37%, in part reflecting how few patients with pancreatic cancer had their tumors shrink after Enhertu treatment.

“The pancreatic [data are] a disappointment, but it has to do with the fact that there’s just not a lot of HER2 on the surface,” said DeMichele, who hypothesized that less drug might have reached the tumor.

The data are interim findings, and don’t describe measures like how long patients went without their disease progressing, or how long they lived following treatment.

Like all cancer drugs, Enhertu comes with side effects, including a type of lung inflammation called pneumonitis that can be dangerous. Of the 18 participants who were diagnosed with it, 17 had asymptomatic or treatable symptoms, but one died. The risk is treatable, said DeMichele. “but it’s going to be a limit.”

Enhertu was also associated with nausea, fatigue and low levels of blood cells.

Mohit Manrao, a senior vice president with AstraZeneca’s U.S. oncology business unit, said the data “open up avenues” for bringing Enhertu to patients with different HER2-expressing cancers.

“This data will support our ongoing conversations with regulatory authorities,” Manrao said. “This was a Phase 2b study, so depending on [those] conversations the next steps would be informed from there.”

One takeaway from the study’s findings, if borne out in further research, could be encouraging wider testing of HER2 expression in cancers beyond breast and gastric.

“The fact that we're seeing such clinically meaningful activity, one could argue that, across tumor types that are epithelial, we should consider HER2 testing,” said Meric-Bernstam.

“We all need to become biomarker experts now,” said DeMichele, “because we need to understand the biomarker profile of our patients’ tumors and how they change over time.”

A cancer drug combination developed by Johnson & Johnson succeeded in an important late-stage trial testing the new regimen against a widely used medicine from AstraZeneca.

According to J&J, treatment with its approved drug Rybrevant and an experimental therapy called lazertinib kept a common type of metastatic lung tumor at bay for longer than AstraZeneca’s Tagrisso alone. The results were from an interim analysis of the study, which is continuing to study patient survival.

J&J’s trial, called Mariposa, has been followed closely by analysts as it could offer J&J a chance to compete with AstraZeneca in a large cancer drug market. 

According to J&J, its drug combination is the first chemotherapy-free option to show a “clinically meaningful” benefit over Tagrisso in a pivotal study. The positive results follow the success of another Phase 3 study, dubbed Mariposa-2, which showed a progression-free survival benefit over chemo for lung cancer patients who received Rybrevant plus chemo with or without lazertinib.

The two studies focused on people whose non-small cell lung cancer was driven to growth by mutations in a gene called EGFR that helps control cell division. The mutations are found in anywhere from 10% to 15% of European and North American patients with non-small cell lung cancer, and an even higher proportion among people in Asia.

Tagrisso has become a go-to treatment for these lung tumors. Last year, AstraZeneca earned about $5.4 billion from sales of the drug, which is also approved in the U.S. as an “adjuvant” therapy after surgery for people with EGFR-mutated non-small cell lung cancer.

Earlier this year, analysts were predicting that a four- to six-month progression-free survival benefit over Tagrisso would be enough to support the use of Rybrevant and lazertinib. But an AstraZeneca study recently showed that combining Tagrisso with chemotherapy extended median progression-free survival by nearly nine months over Tagrisso alone, potentially raising the bar for J&J.

More than 1,000 patients with EGFR-mutated non-small cell lung cancer who had not previously been treated participated in J&J’s study. The main objective was to show a progression-free survival benefit over Tagrisso, but investigators are also tracking response and survival rates. J&J said the data showed a survival “trend” favoring its combination compared to Tagrisso, but the difference was not yet statistically significant.

Rybrevant, which was approved in the U.S. in 2021, is a bispecific antibody, meaning it binds to two targets at once — in this case EGFR and another cancer drug target called MET. Lazertinib is a small molecule drug that’s aimed at certain types of EGFR.