SCRI’s Vivek Subbiah, MD, Highlights Trials on Tumor-Agnostic Cancer Therapies During ESMO

The story of cancer care today is one of increasingly powerful therapies, used with increased precision on increasingly smaller groups of patients.

For this approach to succeed, patients must be found efficiently—and that means the old way of studying one tumor type at a time won’t work. Biomarkers make up today’s roadmaps, explains Vivek Subbiah, MD, who serves as chief of early-phase drug eevelopment at Sarah Cannon Research Institute in Nashville, Tennessee.

And when a biomarker shows a therapy works in one tumor, he said, it’s likely to work elsewhere.

Vivek Subbiah, MD | Image: SCRI

“Cancer is a genomically driven disease, and tumor-agnostic therapies and tumor-agnostic treatment is a different way we think about drug development and cancers,” Subbiah said during an interview with The American Journal of Managed Care®, during a break in his schedule at the European Society for Medical Oncology (ESMO), which ran October 17-21 in Berlin, Germany.

Besides being a coauthor on posters presenting 2 very different tumor-agnostic therapy trials, Subbiah cochaired the discussion, “Accelerating Tumor Agnostic Therapies,” with Niamh Coleman, MD, PhD, a fellow in the Department of Investigational Therapeutics at MD Anderson Cancer Center. He also published an article on the topic in Cancer Discovery on the opening day of ESMO.1

In a field long accustomed to thinking about treatments for cancer based on where they are located—whether its breast cancer, lung cancer, or prostate cancer—tumor-agnostic therapy “transcends the anatomical location,” Subbiah said. Because cancer is a genomically driven disease, “this makes more sense.”

“The more we learn about the biology of cancer, the biomarker driven, tumor-agnostic precision medicine is going to be the wave of the future” he said.

This concept is not new. The FDA’s first tumor-agnostic approval came in May 2017, for pembrolizumab (Keytruda; Merck) in patients with unresectable or metastatic, microsatellite-instability–high (MSI-H) or mismatch-repair–deficient (dMMR) solid tumors, regardless of tumor site or histology.2 Today, there are 10 such approvals,3 but Subbiah believes that number is about to explode—perhaps dozens more therapies can be approved over the next 25 years.

Two New Trials Enrolling

The posters at ESMO represented very different approaches. The first resembles the 2017 pembrolizumab approval: the DiscovHER PAN-206 trial (NCT06695845) with zanidatamab (Ziihera; Jazz Pharmaceuticals) involves a bispecific antibody that is already approved by both the FDA and the European Medicines Agency for patients who have received at least 1 systemic therapy for advanced, unresectable, or metastatic HER2-positive biliary tract cancer.4,5

The second, the first-in-human GUARDIAN-101 trial (NCT06778863), involves a new therapy with a completely novel mechanism of action.6 CLSP-1025, under development by Clasp Therapeutics, is the first clinical stage T-cell engager targeting an oncogenic driver mutation, in this case R175H, the most common mutation in p53. R175H is presented by a common human leukocyte antigen (HLA) serotype, HLA-A*02:01. This serotype is often studied for its role in immune responses to infections, including SARS-CoV-2.

The R175H mutation is seen across a range of solid tumors, and patients in the trial must have both this mutation and the HLA-A*02:01 antigen to take part in the trial. But that will still mean sizable numbers will be eligible across many common cancer, Subbiah said.

DiscovHER PAN-206: New Uses for an Approved Drug

“Today, we have an antibody drug conjugate approved for all HER2-positive cancers that are IHC3+ immunohistochemistry,” he said, referring to trastuzumab deruxtecan (Enhertu; AstraZeneca).7 “But one of the main challenges of an antibody drug conjugate that we are seeing are toxicities, chronic toxicities, and also pneumonitis and interstitial lung disease. And so, we are looking for other options for patients who have lung disease, and better tolerated options.”

Zanidatamab, Subbiah said, is a dual HER2-targeted bispecific antibody that binds to 2 distinct sites on HER2, “promoting HER2 receptor crosslinking and driving multiple antitumor mechanisms of action.” With a single therapy, he explained, there is degradation of HER2 cell surface expression and limiting of HER2 signaling pathways, which “has an immune-mediating effect.”

With the existing approval, “It would be great if we test this in other solid tumors other than biliary tract cancer.”

Subbiah explained that the phase 2 DiscovHER PAN-206 trial will evaluate 3 distinct cohorts of patients with previously treated HER2+/IHC3+ tumors.

• Cohort 1 will enroll patients with a wide range of locally advanced, unresectable, or metastatic solid tumors, except biliary tract cancer, as the therapy is already approved in these patients. Prior treatment with a HER2-targeting therapy is not permitted in this cohort.
• Cohort 2 will enroll patients with breast cancer; HER2-targeted therapy is permitted and prior therapy with trastuzumab deruxtecan is required. Subbiah explained that these patients will be “post-Enhertu. That’s an unmet need.”
• Cohort 3 has the similar criteria to Cohort 2, except for patients with gastroesophageal adenocarcinoma.

Targeting an Elusive p53 Mutation With Diabody Technology

Subbiah said the GUARDIAN-101 trial will seek to break new ground by targeting a very common but seemingly undruggable p53 mutation, in this case p53 R175H.8

Making p53 targetable and actionable would be a huge milestone in cancer treatment, on part with the groundbreaking ability to finally target KRAS. “It was considered as one of the undruggable genes. Now we drug KRAS.”

Clasp Therapeutics develops T-cell engagers that can selectively bind HLA-presented peptides only to oncogenic drive mutations, sparing other cells to reduce toxicity.7 Its diabody technology follows a principle similar to a bispecific antibody in that there are 2 binding sites. But in this case, Subbiah said, the technology is engineered “for absolute tumor specificity and immune synapse mimicry.”

On one side, he said, the therapy perfectly binds with p53 R175H and the peptide HLA complex on the tumor cells, and on the other, it binds with CD3 on the T cells, “resulting in a potent, selective T-cell–mediated tumor killing.”6 Preclinical studies have been “exceptional.”

Opening the Flood Gates

Tumor-agnostic therapies were among ESMO’s themes, highlighted during the opening press conference by Toni K. Choueiri, MD, director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute and one of the meeting’s scientific chairs.

Better biomarkers and the arrival of artificial intelligence make tumor-agnostic therapies a reality, reducing the time and cost of trials and speeding solutions to patients. “We want to stop really treating, let's say, lung cancer, per se, per organ. And when I go back to the biology, I personally believe we are ready. It's there,” Choueiri said.

Subbiah said the tumor-agnostic approach is essential to getting treatments to patients in an equitable way. “I personally believe that every drug that is a precision medicine,” he said. “A drug that is a biomarker-targeted drug should be developed across multiple tumor types. Why? Because if we don't develop drugs based in a biomarker fashion, in all cancers, patients with rare cancers may not have access to drugs.

“Take, for instance, ALK fusions,” he continued. “We have 6 drugs approved in non–small cell lung cancer that are ALK-fusion positive. But think about that patient with ovarian cancer or a patient with prostate cancer who has an ALK fusion—they don't have a drug approved in the real world; unless a drug is FDA approved, you may not have access to the drugs.”

Such a system leads to what Subbiah calls, “molecular inequity,” and tumor agnostic approaches can work to eliminate that.

Since the pembrolizumab approval in 2017, he sees the tumor-by-tumor approach waning, and the silos are coming down. “Absolutely, that opened up the flood gates,” he said, rattling off the list of tumor-agnostic approvals FDA has since granted.

“Hopefully we'll have more drugs approved in this space so that more patients with rare cancers and biomarker driven cancers can be eligible for these therapies.”

References

1. Subbiah V. Rethinking cancer drug development through tumor-agnostic precision medicine. Cancer Discov. Published online October 17, 2025. doi:10.1158/2159-8290.CD-25-145
2. Lemery S, Keegan P, Pazdur R. First FDA approval agnostic of cancer site — when a biomarker defines the indication. N Engl J Med. 2017;377(15):1409-1412. doi:10.1056/NEJMp1709968.
3. Shah NM, Meric-Bernstam F. The present and future precision oncology and tumor-agnostic therapeutic approaches. Oncologist. 2025;30(6):oyaf152. doi:10.1093/oncolo/oyaf152
4. Makker V, Oh D-Y, Meric-Bernstam F, et al. DiscovHER PAN-206: phase 2 tumour-agnostic study of zanidatamab in patients with previously treated human epidermal growth factor receptor 2 (HER2)-overexpressing solid tumours. Presented at: 50th Congress of the European Society for Medical Oncology; October 17-21, 2025; Berlin, Germany. Abstract 1028eTiP.
5. FDA grants accelerated approval to zanidatamab-hrii for previously treated unresectable or metastatic HER2-positive biliary tract cancer. News release. FDA. November 20, 2024. Accessed October 20, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-zanidatamab-hrii-previously-treated-unresectable-or-metastatic-her2
6. Harshman LC, Gutierrez M, Shepherd J, et al. GUARDIAN-101. A first in human, tumor-agnostic phase 1 study evaluating safety and preliminary antitumor activity of CLSP-1025, a first in class, HLA-directed T-cell engager (TCE) for advanced solid tumors harboringthe p53 R175H mutation. Presented at: 50th Congress of the European Society for Medical Oncology; October 17-21, 2025; Berline, Germany. Abstract 998TiP.
7. FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HER2-positive solid tumors. News release. FDA. April 5, 2024. Accessed October 27, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-fam-trastuzumab-deruxtecan-nxki-unresectable-or-metastatic-her2
8. Clasp Therapeutics. Accessed October 27, 2025. https://www.clasptx.com/home#news