Biomarkers, Risk, and Trials: De-escalation vs Intensification in HNSCC

The treatment landscape for head and neck squamous cell carcinoma (HNSCC) is continually evolving, driven by the goal of maximizing oncologic outcomes while minimizing treatment-related morbidity.The identification of human papillomavirus (HPV) as a key prognostic factor, particularly in oropharyngeal cancer, has fueled a robust area of research focused on de-escalation strategies for patients with favorable features. Conversely, patients with high-risk clinical, pathological, or molecular markers may warrant intensification of therapy to overcome poor prognostic profiles.

In an interview with Targeted Oncology®, Hisham Mehanna, PhD, professor at the University of Birmingham in the Cancer and Genomic Sciences department and director of the Institute of Head and Neck Studies and Education, provides critical insights into the current state of risk stratification and treatment modification in HNSCC. He addresses the crucial challenge of patient selection, emphasizing the necessity of precise biomarker analysis—moving beyond positivity alone to include definitive HPV testing.

Furthermore, Mehanna discusses the complex quantification of recurrence risk, the nascent role of immunotherapy de-escalation, and the imperative to adhere to evidence-based guidelines, preferably within the rigorous framework of clinical trials, before deviating into hyper-intensified or novel treatment plans.

Targeted Oncology: In terms of patient selection, what are the key clinical, pathological, and molecular biomarkers used to definitively identify patients who are suitable candidates for de-escalation without compromising survival or recurrence risk?

Hisham Mehanna, PhD: Well, currently it's HPV status. And in the past, we used to use p16 as an indication of HPV-associated disease. But recent work that we published in 2023 showed that a percentage of patients who are p16 positive are actually PC HPV-negative. So, you really need to be able to select them on p16 positivity and HPV positivity both positivity on both. So that's the first step. Then you can consider whether they are smokers as well or not, because that has an implication for the prognosis as well. And different studies if you do use different criteria for selecting that patient group, basically. But in general, it's HPV positivity. And then some studies have looked at also excluding smokers, or heavy smokers at least.

How do you precisely quantify the risk of recurrence to guide the decision, and at what threshold of low risk do the risks associated with the treatment itself outweigh the benefit of continued or intensified therapy?

So in a way, it's the same as the eligibility criteria that we just discussed. You know that if the patient's HPV-positive, then that puts them in a good prognosis risk. And then if you then select further within that, for example, patients who are non-smokers, or patients who are not T4 or N3, then that's an even better prognosis group, and they are the best prognosis group, basically. The other thing is, it's never stopping treatment altogether in de-escalation. It's just about different types of less intensive treatment.

When considering immunotherapy, what data support de-escalating immunotherapy duration in responders vs intensifying immunotherapy with combination regimens in patients with intermediate or poor prognostic features?

We don't have any data in head and neck yet about de-escalating immunotherapy. We have regimens that are pretty much standard. There haven't been any studies looking at reducing the intensity or the duration of immunotherapy. Now, that has come up even more as a question more recently, when the KEYNOTE-689 [NCT03765918]¹ study had been approved… The reason is, they continue the immunotherapy for a year after the surgery. And people are saying, well, does everybody really need that or not? Because they do that with everybody. That's become an even more important question now, and I think it's a very good question, but we haven't done it yet, partly because, immunotherapy approvals, apart from recurrent metastatic, are very, very new in head and neck cancers.

What would you say are some of the most significant challenges in achieving multidisciplinary consensus when deviating from standard guidelines to pursue hyper-intensified treatment plans?

Well, of course, it's the individual themselves, their fitness, the size of the tumor, the prognosis of the tumor[, if] there [is] any evidence to support a deviation from guidelines, and, of course, the patient themselves [and] what they want. In general, I'm not a fan of deviation and trying other things outside clinical trials. If you're going to deviate from guidelines, then it should really be within the context of a clinical trial. Otherwise, why are you doing that?

Is there anything else that you wanted to touch on about this topic?

In general, the de-escalation in head and neck cancer hasn't really worked. There are still some ongoing studies of interest [that are] trying to select out the really good actors … to de-escalate, and that might work. Secondly, my plea to clinicians is to not really change management without good evidence ... [For instance,] a lot of people started giving patients cetuximab (Erbitux) and radiotherapy instead of cisplatin radiotherapy if they were HPV-positive, but that turned out, when we did the [phase 3 De-ESCALaTE HPV] trial [ISRCTN33522080], to be detrimental. So, we have to be careful about deviating from guidelines without really good evidence and really good reasons.

REFERENCE

1.Study of pembrolizumab given prior to surgery and in combination with radiotherapy given post-surgery for advanced head and neck squamous cell carcinoma (MK-3475-689). ClinicalTrials.gov. Updated August 20, 2025. Accessed December 4, 2025. https://www.clinicaltrials.gov/study/NCT03765918