NEW YORK – In the biomarker-targeted treatment space, experts are anticipating more research in 2025 that will further refine patient selection and are expecting continued advancement of next-generation precision therapies, including antibody-drug conjugates (ADCs), cancer vaccines, and protein degraders.
As biomarker-targeted therapies continue to move toward earlier lines of treatment with a larger addressable market, strategies for patient selection also need to evolve to identify those who may benefit from these treatments. Oncologists are further grappling with a surge in trials and approvals for rare novel biomarkers, which adds even more biomarkers for oncologists to consider when choosing treatment.
Last year, the US Food and Drug Administration for the first time approved treatments that target three novel tumor biomarkers: claudin (CLDN) 18.2 expression, IDH1/2 mutations, and NRG1 gene fusions. The agency also expanded indications for biomarker-targeted therapies as first-line treatment in non-small cell lung cancer, including for Johnson & Johnson's dual EGFR inhibitor combination of Rybrevant (amivantamab) and Lazcluze (lazertinib), AstraZeneca's EGFR inhibitor Tagrisso (osimertinib), and Genentech's kinase inhibitor Alecensa (alectinib).
With pharma companies expected to bring more tissue-agnostic indications to market in the coming year, oncologists also need to shift away from the traditional approach of considering treatments based on the tumor's location.
The FDA approved several tissue-agnostic indications in 2024, including for AstraZeneca and Daiichi Sankyo's Enhertu (trastuzumab deruxtecan) in HER2-positive tumors, Bristol Myers Squibb's Augtyro (repotrectinib) for NTRK-positive tumors, and Eli Lilly's Retevmo (selpercatinib) in metastatic solid tumors with RET gene fusions.
Refining patient selection
With more biomarker-targeted therapies in the first-line and tumor-agnostic settings, selecting patients for treatment is becoming ever more important. But even with the help of biomarkers, picking the right treatment is challenging for doctors in indications that have multiple precision medicine options, often ones in the same class.
Particularly in the immunotherapy space, Julie Gralow, chief medical officer of the American Society of Clinical Oncology, flagged the need for head-to-head studies alongside research evaluating patient selection.
Last month, for example, the FDA approved another new immunotherapy, BeiGene's Tevimbra (tislelizumab) with chemo as a first-line treatment for patients with unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma tumors that are HER2-negative and have a PD-L1 tumor area positivity (TAP) score of at least 1 percent. In the Phase III trial that led to Tevimbra's approval, the drug was evaluated against investigator's choice of chemotherapy. However, a head-to-head comparison trial would assess the drug against other checkpoint inhibitors approved for the treatment of gastric cancer, such as Bristol Myers Squibb's immunotherapy Opdivo (nivolumab) or Merck's Keytruda (pembrolizumab).
"We have these broad categories where you get some improvement in progression-free or overall survival but it's unclear how many patients are benefiting because some may either do fine without the treatment or they're going to recur even with it," Gralow said. "That's where we need to go with the immune checkpoint inhibitors, and we need more information on how they compare and on better predictors of benefit."
Another example of the challenges in interpreting biomarkers, Gralow pointed out, is the rapid evolution in the field's understanding of Enhertu's activity across breast cancers with different levels of HER2 expression. In the first quarter of 2025, the FDA is expected to decide whether to approve Enhertu for HER2-ultralow breast cancer, defined by an immunohistochemistry (IHC) HER2 expression score of greater than 0 and less than 1 or an IHC 0 result with membrane staining.
The debate over how to best identify and treat HER2-low and -ultralow breast cancer patients intensified in 2024 and will likely continue into 2025 if Enhertu comes to market in the ultralow population. And before that debate is settled, AstraZeneca and Daiichi Sankyo are trying to advance Enhertu in patients who are HER2-negative by IHC.
The research so far has raised more questions about the use of ADCs and how much biomarker expression is needed for the ADC to bind to cancer cells, Gralow said.
"You're using, in this case HER2, as a receptor to get a chemo into the cell, so you don't need as much expression as you do when you're actually targeting [the biomarker]," she explained. "That's a really important finding and we're going to have to learn how to exploit that more with other molecules. The question is: Should we go back and look at some of these other biomarkers, and when we make antibody-drug conjugates just use [the biomarker] as a conduit for getting the chemo to the cancer cell?"
Also in 2024, research using minimal residual disease (MRD) to monitor patients for relapse in drug trials took off, and pharmaceutical companies will continue to use the biomarker in their drug development efforts in 2025. Howard McLeod, director of the Center for Precision Medicine and Functional Genomics at Utah Tech University, said some research is expected this year that may shed light on the management of patients who are MRD-positive in certain solid tumors.
"We already know you can detect someone's disease earlier, but some of these new studies will [show whether] you intervene at that point or wait until they're symptomatic," he said. "That's been one of the things that's held up that part of molecularly driven care. We know MRD can show some harbingers of disease, but do we act on it when there's no other evidence, or do we wait until there's a problem? I'm hoping that [these studies] will open up that area a bit and help us better understand its value."
For example, in the Phase II DECIPHER trial, which began in 2024, researchers are using Natera's Signatera circulating tumor DNA MRD test to guide which gastroesophageal cancer patients receive additional treatment with Enhertu. Similarly, Myriad Genetics and MD Anderson Cancer Center, in a collaboration announced this month, said they will assess the utility of Myriad's Precise MRD assay in gauging therapy response and monitoring for recurrence in patients with breast, gastrointestinal, genitourinary, and gynecological cancers.
Jordi Rodón Ahnert, associate professor in the department of investigational cancer therapeutics at MD Anderson, also highlighted MRD testing as an area to watch in 2025. He noted that trials using MRD to identify patients for treatment and the continued expansion of coverage for MRD testing suggests that the technology "is almost ready for [wider] use in precision medicine."
In the same vein, Gralow highlighted the need for more specific patient selection strategies within trials testing targeted therapies in early lines of treatment like in the first-line, adjuvant, or neoadjuvant setting. In breast cancer, for example, researchers are designing trials to optimize treatment based on a patient's clinical and genomic risk factors. Some of these types of studies are already happening in breast cancer, she said, where therapy is escalated or de-escalated based on response to prior treatment or genomic factors. One example of this type of trial is a study evaluating Reveal Genomics' TNBCDX assay to predict triple-negative breast cancer patients' response to standard neoadjuvant treatment and their risk of relapse. Those who are predicted not to respond to standard treatment or have a higher risk of relapse can get additional therapy.
"We have to be more careful … especially when we get to [early disease] populations where the majority are already cured without any further therapy and [make sure] we're not adding toxicity and risk in a population who's already cured," she cautioned. "We have to design trials differently."
However, biomarker-informed changes to therapy selections may take time to reach patients as oncologists are adapting to the rapidly changing treatment landscape. The challenge is particularly notable with the entrance of more tissue-agnostic drugs, which necessitates that an oncologist specializing in treating patients with lung cancer, for example, rethink the treatment approach for a patient so it is instead based on the presence of an NTRK fusion, rather than the tissue.
"It's hard for established oncologists who have been thinking about what to do for lung cancer to think about what to do for cancer that happens to be in the lung?" McLeod said. "The psychological barrier is sometimes greater than the scientific barrier. "
Novel drug classes to watch
In the coming year, experts expect continued interest in ADCs and increased development efforts in cancer vaccines and protein degraders.
Gralow suggested that ADC development will "explode" in 2025. "We've got several different antibodies and different payloads, different chemo payloads, and you can just mix them around to find the optimal combination," she said.
One new ADC that could hit the market this year is AstraZeneca and Daiichi Sankyo's TROP2-directed ADC datopotamab deruxtecan (Dato-DXd). The companies submitted an application to the FDA in November seeking approval for Dato-DXd for previously treated advanced EGFR-mutated non-small cell lung cancer.
She also expects the cancer vaccine space to mature, particularly after advances in mRNA vaccines spurred by the COVID-19 pandemic.
In October, Merck and Moderna launched a Phase III trial of the personalized neoantigen cancer vaccine V940 with Merck's checkpoint inhibitor Keytruda in NSCLC patients, making it one of the first late-stage trials for a cancer vaccine. The firms had previously launched a Phase III trial of V940 with Keytruda in melanoma.
"These new mRNA vaccines, that really the pandemic helped push forward, are the breakthrough we needed with cancer vaccines," she said.
In earlier-stage research, Rodón highlighted protein degraders as a modality with promise. These drugs bind to a protein that is contributing to the disease and regulate its activity and destroy target proteins. He said some of the most advanced protein degraders that have shown activity include drugs targeting SMARCA4, BRAF, and KRAS proteins.
However, he noted that they don’t look better than classic inhibitor small molecules in these settings. "They have a lot of potential, but they also have pharmacokinetics issues,” he said. “We need to find the best in class [among] these agents."
Rodón also highlighted next-generation drugs targeting novel biomarkers that have shown promise and are advancing through clinical studies, such as MAT2A inhibitors or PRMT5 inhibitors being developed by BMS, Tango Therapeutics, and others in MTAP-deleted tumors.
"With [advances in] structural biology research, you end up finding new pockets, and people are developing drugs for biomarkers that we didn't even know were druggable," Rodón said.