"Tumor type doesn't matter, receptor presence matters"

EXPERT PROFILE

Ilya Timofeev – Director of ANO "Cancer Research Bureau" (BUCARE), oncologist, member of the scientific committee of the European School of Oncology College (ESCO).

Graduated with honors from I.M. Sechenov Moscow Medical Academy, completed oncology graduate studies at N.N. Blokhin Russian Cancer Research Center.

In 2007 created the Kidney Cancer Research Bureau. In 2011 became co-organizer of the Russian Society of Clinical Oncology (RUSSCO), worked as its executive director until 2019. In 2020-2021: Director of Hadassah Moscow Institute of Oncology.

Over 18 years under Timofeev's leadership, 32 clinical and 27 fundamental studies were conducted, 64 scientific articles published in PubMed (Hirsch index—24). Research geography: Russia, Belarus, Kazakhstan, Azerbaijan, Uzbekistan, USA, China, Italy, United Kingdom.

Was part of the IDEA working group and twice on the American Society of Clinical Oncology (ASCO) international committee, on the scientific council of the Kidney Cancer Association USA. Member of the editorial board of international journal Kidney Cancer. Patent author in Russia, EU, and USA.

Awards: ASCO Merit Award (twice), First Prize for Best Oral Presentation (EMUC), 100 Best Russian Innovations, AACR-AstraZeneca Scholar-in-Training Award, ESMO Best Poster Award, and others.

What is FGFR

About the Experience of Developing Anticancer Agents

— Ilya, you already have successful experience developing an anticancer agent. Tell us about it; this is important for understanding where the current project originated.

— My scientific interest area is fibroblast growth factor receptors, FGFR. These receptors are on cancer cells, on blood vessel cells feeding tumors, and on microenvironment cells, which surrounds tumors and helps them evade immune response.

There are four types of such receptors, each present on different tumors. For example, FGFR1 is common in renal cell carcinoma and rare in gastric cancer. But FGFR2, conversely, is characteristic of gastric cancer. FGFR3, for bladder cancer. Each receptor type is a distinct topic: where it occurs, what it's responsible for, how it can be blocked.

Our first development, the agent alofanib, an allosteric extracellular FGFR2 inhibitor. We created an allosteric inhibitor, first in its class. This is a chemical agent that binds not to the receptor's active site but to its extracellular domain—and simply conformationally alters the receptor, changing its structure. After this, the receptor can no longer bind with the activating ligand from blood.

We successfully completed all preclinical work and phase I study for gastric cancer. There were international publications, conference presentations. Subsequently, substantial research extending beyond "just science" was needed. Therefore, we transferred development to R-Pharm company, and now they're completing the study for ovarian cancer.

— So the FGFR1 project that now entered clinical trials was developing in parallel?

— Yes, the FGFR1-antibody project was launched even earlier, but with biologic products everything always takes longer. Chemical synthesis is relatively rapid. However, developing a cell line that will produce antibodies in correct conformation, without aggregation, with required structure, that's substantially more complex. Therefore, the FGFR1-antibody project simply lagged in timeline. I want to emphasize that the agents aren't competitors to each other. As I stated earlier, each tumor depends on its receptor type. Consequently, each type requires its own selective inhibitor.

What are Monoclonal Antibodies

— Let's clarify terminology. There's considerable discussion now about cancer vaccines, and this confuses people. Is your agent a vaccine?

— No, our agent is a monoclonal antibody. This is a completely different class.

Vaccines in oncology are attempts to train the immune system to recognize and destroy tumor cells. mRNA vaccines are actively being studied, approximately 120 clinical trials worldwide are ongoing, including in Russia.

Our antibody is an immunoglobulin protein that very specifically binds with the FGFR1 receptor and blocks it. No immune system training, no personalization in the sense of creating an agent for a specific patient. This is a universal therapeutic: one vial is appropriate for everyone who has the required target on their tumor.

The Role of Immunohistochemistry

— How can you determine if the agent is appropriate for a specific patient? What diagnostics are needed?

— Since this is an antibody, we need to visualize receptor presence on cell surfaces, not intracellularly, but precisely on surfaces. The diagnostic modality is immunohistochemistry. The same is performed, for example, for breast cancer when prescribing agents against the HER2 receptor.

A tumor tissue specimen is obtained, stained with specialized reagents, and a pathologist determines whether FGFR1 receptor is present on cell surfaces.

Since our agent is first in its class, no standardized diagnostic method existed. We invested time in development: studied different staining reagents, assessed their specificity, and selected the optimal one. We now utilize the American Cell Signaling Technology platform.

Importantly, this isn't exotic diagnostics. An immunohistochemistry laboratory exists in the pathology department of any oncology center. Unlike molecular diagnostics, which is required for other FGFR inhibitors and isn't universally available.

— How does your agent differ from already existing FGFR inhibitors?

— These are fundamentally different entities, though the nomenclature is similar.

Existing FGFR inhibitors are chemical agents prescribed only for specific mutations. For example, for cholangiocarcinoma, only if there's an FGFR2 mutation. Prescription requires molecular diagnostics to identify these mutations.

Our antibody blocks the receptor on cell surfaces, and intracellular mutations don't affect its effectiveness. We verified this in preclinical studies. For antibodies, mutations are irrelevant, only receptor presence and its isoform are relevant.

Additionally, chemical inhibitors are nonspecific, they can affect multiple receptor types simultaneously. Each type is associated with its own toxicity profile, and the more receptors blocked, the higher the toxicity. Our antibody is specific: it blocks only FGFR1 and nothing else.

Tumor-Agnostic Approach

— The study includes patients with different cancer types—renal, lung, breast, prostate, head and neck tumors. Why such broad coverage?

— We're following a tumor-agnostic approach. Our study is called TAGNOT, Tumor Agnostic Therapy. Here tumor type is irrelevant, receptor presence is paramount. By blocking this receptor, we hypothesize we can arrest tumor growth regardless of anatomical location. However, this requires verification in clinical trials.

The study has five cohorts, by tumor types expressing FGFR1. Each cohort will have 11 patients. We'll assess how receptor presence affects treatment effectiveness regardless of tumor location.

This approach is no longer unique. Russia has approved tumor-agnostic agents: for example, trastuzumab deruxtecan, if there's HER2 expression, it can be utilized for different tumors. Or NTRK inhibitors, if there's an NTRK mutation, tumor type is irrelevant.

— You're simultaneously conducting colorectal cancer research?

— Yes, this remains preclinical research. Colorectal cancer also has FGFR1 expression, but there angiogenesis, formation of new vessels perfusing tumors, is also critically important. One treatment standard is bevacizumab, which blocks vascular endothelial growth factor.

We conducted comparative research and demonstrated our antibody also affects vasculature. Moreover, FGFR1 stimulates angiogenesis even more potently than bevacizumab's target. Results of this work were presented at the AACR-NCI-EORTC conference in Boston, and an expanded study version will be presented at ASCO GI 2026 in San Francisco.

About the Drug Trials

— Let's discuss toxicity. This always concerns patients, how will they tolerate treatment?

— Contemporary oncology treatment modalities are unfortunately toxic. Obviously, chemotherapy. However, targeted agents also have their toxicity profiles: diarrhea, hypertension, neuropathy.

Our antibody's advantage is its specificity. It blocks only one receptor type. Pan-FGFR inhibitors target multiple types simultaneously, and each is associated with its own adverse effects. For example, hyperphosphatemia or ocular toxicity, up to retinal detachment.

In preclinical studies across different animal species, we didn't observe such toxicity. Obviously, animal models differ from humans. We cannot directly extrapolate results. However, preliminary data are encouraging.

In our clinical trial, we definitely monitor phosphate levels and conduct ophthalmologic examinations. We anticipate toxicity will be lower than with nonselective agents.

— The study involves patients who have already exhausted standard treatment options. What can the novel agent provide them, is this palliative care or a realistic opportunity to attenuate disease?

— We believe in the latter, otherwise we wouldn't conduct research. The agent is targeted, personalized in the sense that it's prescribed when a specific target is present. We anticipate it can arrest progression and extend survival.

Our study endpoints include disease control, survival, and quality of life. Generally, there's a paradigm shift in oncology now, and it initiates precisely with later therapy lines. Previously for such patients, only stabilization was discussed. Now many novel agents produce favorable responses even in patients who've progressed through all therapy lines. For example, CAR-T therapy for solid tumors or novel HIF-2α inhibitors for renal cell carcinoma.

Subsequently, these agents gradually advance to earlier lines. The objective is making the most effective first-line therapy so subsequent lines aren't necessary.

Can International Patients Receive the Drug

— Can international patients participate in the study?

— Yes, it's feasible. I know Russian studies with participants from Belarus, Kazakhstan. One study had a participant from the United Kingdom.

Logistics, visas, travel, is a separate consideration. However, from a medical standpoint, everything's straightforward. In clinical trials, the sponsor covers expenses; patients don't require insurance. They come to one of our centers (for example, Hadassah clinic in Skolkovo), undergo screening, and if they meet eligibility criteria, are enrolled in the study.

— Where is the agent for clinical trials produced?

— This is a fully Russian agent, from concept to production. We have a contract with Petrovax company for research work. The clinical trial batch was manufactured there. Petrovax is an established manufacturer with GMP certification, not only Russian but European. This certification permits conducting research in other countries as well. We're extremely grateful to colleagues for their responsiveness and manufacturing assistance.

— How is development financed?

— Currently the study is financed by our Cancer Research Bureau. We're pursuing grants. There are Moscow grants, federal programs.

The challenge is that substantial grants, for example, recent ones from the Ministry of Industry and Trade, up to 70 million rubles, are issued only to organizations with their own manufacturing facilities. That is, it's designed more for Russian big pharma, which already has research funding. And for small developers, either microgrants or eligibility criteria we don't meet.

However, we're accomplishing what we can. Over the past decade, only four original monoclonal antibodies have emerged in Russia. Three of them are PD-1 and CTLA-4 inhibitors; foreign analogues already exist. And our agent is first in its class; there are no analogues anywhere in the world.