Dr. Tahamtan Ahmadi discusses treatment gaps in recurrent or metastatic head and neck cancer, the signals that matter in clinical trials and the complexities of advancing new therapies.
Head and neck cancer remains a significant global health issue, with an estimated 947,000 new cases and more than 482,000 deaths worldwide in 2022. These cancers can develop in areas such as the mouth, throat and voice box, where tumor growth and treatment can affect essential functions including speaking, swallowing and breathing.
Treatment has advanced with the introduction of immune checkpoint inhibitors, which can be used alone or in combination with chemotherapy for certain patients with recurrent or metastatic head and neck cancer. However, treatment options become more limited when disease progresses after immunotherapy.
Even with these advances, clinical guidelines highlight the complexity of treating recurrent or metastatic head and neck cancer, particularly given differences in tumor biology, disease location and previous treatment.
These challenges underscore the need for new therapies that provide meaningful and durable responses while remaining tolerable for patients who may already be physically weakened by their disease and previous treatments.
Executive VP and Chief Medical Officer,
Head of Experimental Medicines
Genmab
In an exclusive Xtalks Clinical Edge interview, Dr. Tahamtan Ahmadi, Executive Vice President and Chief Medical Officer, Head of Experimental Medicines at Genmab, discussed the treatment landscape for recurrent or metastatic head and neck cancer, the evidence that makes an early clinical signal compelling and the practical difficulties of moving a development program into larger trials.
He also explained why safety, patient selection and operational continuity are central to successful drug development.
The Treatment Gap After Immunotherapy
For recurrent or metastatic disease, first-line treatment may involve a checkpoint inhibitor combined with chemotherapy. Pembrolizumab alone is also an option for certain patients whose tumors express PD-L1.
Dr. Ahmadi noted that PD-L1 combined positive score (CPS), disease burden and the proximity of tumors to critical structures can influence treatment selection. Regional approvals and reimbursement practices can also affect the options available.
Once patients progress, however, the outlook becomes more challenging. Later-line treatment options are fragmented, with clinicians considering agents such as cetuximab, docetaxel or methotrexate, which have shown limited and inconsistent activity. He estimated that only about one-third of patients whose disease progresses are able to receive second-line therapy, underscoring the clinical fragility of this population.
These observations highlight the need for more effective treatments that do not add substantially to the burden faced by patients already struggling with eating, weight loss or symptoms related to tumor location.
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Why Tumor Response Alone Is Not Enough
Early-stage trials may show encouraging response rates, but Dr. Ahmadi emphasized that advancing a therapy requires looking at whether a drug demonstrates single-agent activity., This provides evidence that it can produce responses without relying on a combination partner. Equally important are how long responses take to emerge and how long they persist.
Safety and tolerability are inseparable from that evaluation. A therapy may shrink tumors in an early study yet prove difficult to sustain if adverse events repeatedly force patients to stop treatment.
Dr. Ahmadi explained, “One of the most important things that we pay attention to is the discontinuation rate due to AEs [adverse events].”
Adverse event-related discontinuation offers two useful signals. It helps indicate whether patients can remain on treatment long enough to benefit, and it provides insight into whether the drug might eventually be combined with other therapies. A manageable safety profile can therefore influence both the durability of benefit and future development options.
He cautioned that the relationship between treatment duration and response duration is not universal. Some immune-based approaches, for example, can produce durable effects after a limited intervention.
“The locality, the subtype, the biology, all of these things matter.”
– Dr. Tahamtan Ahmadi
The Hidden Risks of Moving Into Phase III
As a program expands from a few dozen participants to a much larger randomized trial, researchers may encounter risks that were difficult to detect in the original study.
A toxicity occurring in only a small proportion of patients may never appear in a trial enrolling 20 or 30 people. With larger enrolment, previously unseen safety signals can become apparent and may require changes to trial conduct or treatment management.
Patient selection adds another challenge. Participants in small, non-randomized studies may have better performance status or less aggressive disease than the broader population eventually enrolled in Phase III. When a treatment is tested against standard of care in a more heterogeneous group, its apparent efficacy may diminish.
Investigators need to understand who benefited in the initial study, which toxicities could emerge with broader exposure and whether the trial population reflects the patients who may ultimately receive the treatment.
Moving Treatments Into Earlier Lines of Care
A treatment that shows promise in heavily pretreated patients may eventually be considered for earlier use. According to Dr. Ahmadi, this transition depends partly on whether the new agent can be added to existing therapy or must replace it.
When a drug has independent activity and a tolerable safety profile, combining it with standard of care may be feasible. A replacement strategy which includes a new regimen must demonstrate that it can perform at least as well as, or better than, an established option.
Clinical development strategies therefore need to account for the changing balance of potential benefit, added toxicity and the performance of the comparator regimen.
Why Head and Neck Cancer Trial Results Need Context
Even a large Phase III trial cannot be fully understood through its headline result alone. Dr. Ahmadi emphasized that head and neck cancer is a heterogeneous collection of diseases rather than a single biological entity.
Tumors associated with human papillomavirus (HPV) can differ from those linked to tobacco and alcohol exposure. The anatomical site also matters: an oropharyngeal tumor may present different clinical considerations from a laryngeal or oral cavity tumor. Proximity to major blood vessels or structures involved in speech and swallowing can further influence progression and the urgency of treatment.
Patient characteristics add another layer. A younger person with HPV-associated disease may have a different comorbidity profile from someone with a long history of tobacco and alcohol exposure. Understanding these distinctions can help researchers assess whether a treatment effect holds across clinically meaningful subgroups.
For clinicians assessing trial data, the questions go beyond average response or survival outcomes. Which patients were enrolled? What was driving their disease? Where were their tumors located? And do those characteristics resemble the patients being treated in practice?
Head and neck cancer encompasses a diverse group of diseases that differ in biology, location and patient characteristics. HPV-associated tumours, for example, can differ from those linked to tobacco and alcohol exposure, while tumour location can introduce distinct clinical challenges.
“The locality, the subtype, the biology, all of these things matter,” said Dr. Ahmadi.
These differences, along with patients’ underlying health and treatment histories, are important considerations when interpreting clinical trial results and determining how findings may translate into clinical practice.
Keeping Clinical Trials on Track After an Acquisition
Dr. Ahmadi also talked about maintaining an ongoing clinical trial’s integrity when a program changes ownership.
While acquisitions can bring promising assets into organizations with greater development resources, the transition involves substantial operational work. Sponsor responsibilities, legal entities, regulatory notifications, safety oversight, quality management systems and clinical databases may all need review or transfer.
“Sometimes it’s just harder to prove that something works because the standard of care already has changed.”
– Dr. Tahamtan Ahmadi
These details matter most when a study is already enrolling participants or approaching a regulatory filing. Changing a database vendor or integrating a new quality system during an active trial can introduce complexity, even when the scientific strategy remains unchanged.
Continuity requires detailed planning and a clear understanding of how the original sponsor established its systems and obligations. The goal is to preserve data quality and regulatory accountability without losing development time.
As Standards Improve, New Research Questions Become Harder
As immunotherapies become more established, novel immune-directed treatments may first be studied in patients whose disease has already progressed after checkpoint inhibition.
Dr. Ahmadi noted that this may not be the most informative population for evaluating a new approach that relies on similar immune mechanisms.
“That’s not necessarily the best place to interrogate another immune therapy that essentially, in one way or the other, is manipulating the same immune system and the same immune effector cells to generate a response,” he explained.
“Sometimes it’s just harder to prove that something works because the standard of care already has changed,” said Dr. Ahmadi.
What Meaningful Progress Will Require
In oncology development, a promising response is most useful when considered alongside durability, tolerability and the characteristics of the patients who experienced it.
Dr. Ahmadi raised a question: “Are patients able, when they benefit from the drug, to stay on the drug?”
For recurrent or metastatic head and neck cancer, the need for better post-immunotherapy options remains substantial. Progress will depend on identifying treatments that patients can tolerate, designing trials that reflect the complexity of the disease and maintaining rigorous clinical and operational standards as programs advance.
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