De-Escalation, Novel Therapy Trends Emerge in Head & Neck Cancer

The management of human papillomavirus (HPV)-positive oropharyngeal cancer is shifting as oncologists balance high cure rates with the need to minimize long-term toxicity. Although these tumors often respond well to standard chemoradiation, current research is focused on identifying which patients can safely undergo de-intensified treatment.

In an interview with Targeted Oncology, Ranee Mehra, MD, director of head and neck medical oncology, and professor of medicine at the Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland Medical System, Baltimore, discussed the nuances of treatment de-escalation, emerging therapies such antibody-drug conjugates (ADCs) and bispecific antibodies, and the critical role of multidisciplinary support in maintaining patient quality of life.

TARGETED ONCOLOGY: HPV-positive oropharyngeal cancer now represents a significant and growing proportion of head and neck cancers. How should community oncologists be thinking differently about managing HPV-positive vs HPV-negative disease?

Ranee Mehra, MD: We have been trying for years to develop what we call de-intensified treatments for HPV-positive disease. Oftentimes, HPV-positive oropharynx cancer has greater sensitivity to standard treatments like chemotherapy and radiation. The hope in the field has been that perhaps we can find ways to de-intensify treatment.

I think this is something that in academic centers we are still trying to find the best approach and the best patient population for. I would caution [oncologists] in the community against de-intensifying without fully understanding the [whole] picture.

We do know that cure rates are very high, but we also need to be selective in which patients may not need as much intensity of therapy. This is where community physicians can reach out for guidance. We work very closely with our community colleagues, sometimes to plan the initial plan of care, and then patients can go home and [be treated] locally. Maintaining communication with academic centers to understand the nuance of this is very important. Patients can certainly get treated locally, closer to home, but it is important to maintain communication with academic programs when making some of those decisions.

What is your current thinking on which patients are appropriate candidates, and what does the evidence actually support at this point?

A lot of this has largely been studied in the HPV-positive space, and de-escalation is not something we have really talked about for HPV-negative disease. Historically, the cure rates were not as high in that population.

In the HPV-positive space, some strategies that were studied included whether we could perhaps just do radiation without chemotherapy for a subset of HPV-positive oropharynx cancers. But the initial prospective trials found that people who got radiation alone did not do as well as those who got radiation with cisplatin.¹ So we were not able to develop this in larger studies because there was no justification to do that.

Still, for many HPV-positive patients who are getting chemoradiation, we offer cisplatin and radiation. Where there have been some advances is in radiation planning and use of proton therapy.

Proton therapy is just a different energy source for radiation compared with intensity-modulated radiation therapy. There are data that outcomes for patients with oropharyngeal cancers can be more favorable with proton therapy, and even though they are still getting the standard dose of radiation, because of the nature of the radiation planning, there may be less toxicity. We do not think of that as de-escalation, but it is a way to minimize toxicity.

Other strategies that have been looked at involve the way the treatment is planned. I really rely on my radiation colleagues, who have a lot of experience in head and neck cancer, to know what areas they can avoid and what areas they need to focus on. That is really critical.

Antibody-drug conjugates (ADCs) are generating considerable excitement across oncology. Are there any agents in this class that you feel are particularly promising for head and neck cancer?

For HPV-positive disease, there is a class of agents called ADCs targeting nectin-4, which has been of interest in HPV-positive disease.² Many of these are still in early-phase trials. It is still an emerging target, but something we are all really interested in seeing how it develops. Another area of interest for HPV-positive disease is ADCs that target ROR2.³

Locoregionally recurrent disease after prior radiation is notoriously difficult to manage. What options do you discuss with these patients, and what guidance would you offer community oncologists navigating re-irradiation or salvage surgery decisions?

This is often where patients benefit from a multidisciplinary care team. We see many patients in this situation in our multidisciplinary clinic.

The first question is whether there is a role for salvage surgery. You really do need an experienced head and neck surgeon to be able to evaluate that.

If that is not possible, the next question for locoregional recurrences is whether there is a role for re-irradiation. There are sometimes safety considerations, and we do not like to do that too soon after the prior course of radiation. That is not appropriate for everybody, and it really should be done in specialized centers.

If that is not possible, then that is where we look more to systemic therapies. Sometimes in our practice, we may even start with systemic therapy and then save re-irradiation for a future effort if there is a good response. So if another local treatment is not possible, then that is where we look to clinical trials for newer approaches, either for local delivery or for systemic therapies. This is now the setting where many of the current EGFR bispecifics are being tested.

There is growing interest in EGFR in head and neck cancer. How could these approaches potentially change outcomes for patients?

We have been talking about EGFR, the epidermal growth factor receptor, in head and neck cancer for over 20 years. We have known for a long time that this is a target of interest.

With the initial agents that were approved in this setting, the responses were more modest, so it has taken time to really develop newer agents. The ones now in development are what we call bispecific. They target EGFR in combination with something else, and they are also being used in conjunction with immunotherapy.

Our ability to now combine EGFR with other targets is where we are seeing a lot more activity, and there has been a lot more excitement in the field. Some of the trials that have been reported so far have really shown much higher responses than what we have historically seen with first-generation agents like cetuximab (Erbitux), and the responses are lasting longer. This is giving renewed hope to patients and to the physicians treating them.

Biomarker development in head and neck cancer has lagged behind other tumor types. What progress is being made in identifying predictive markers that could help community oncologists better match patients to specific therapies?

I agree with you. It has been lacking. We really need research and well-annotated clinical databases to help us understand which biomarkers can be predictive.

There is heterogeneity in this disease as well, which also makes it harder. P16 is a clinically validated biomarker and a surrogate biomarker for HPV-positive disease in the oropharynx.⁴

The one that we now use in both the locally advanced curative setting and the recurrent metastatic setting is the PD-L1 CPS score. Even as we hope to develop new biomarkers, we are still at a point where sometimes it takes time at initial diagnosis to get the PD-L1 score, and there are some challenges related to that.

You cannot check that on a fine needle aspirate. You need a larger piece of tissue because you are looking at PD-L1 on the tumor cells but also on the surrounding immune cells. You need at least a core biopsy. Many times when patients are initially diagnosed in the community, they just get a fine needle aspirate, and we are not able to do the testing on that. Sometimes tissue is sent to an outside lab without PD-L1 being requested. When we see the patient, we either have to do a new biopsy or try to get the outside tissue, and that is another delay in care.

It is important for everyone in the community to realize that we really do use PD-L1, especially in someone who is going to have surgery. For stage 3 oral cancer, we have discussions about neoadjuvant and perioperative immunotherapy, and we really need to know the PD-L1 score to know if that is the appropriate treatment approach.

We do not want to delay care in that setting. We are trying to cure someone, and sometimes they are very symptomatic and the tumors are changing very quickly, so every week is critically important. The sooner we get that information, the earlier we are able to plan the best treatment for the patient. Hopefully one day we will have better biomarkers, but even now, the PD-L1 CPS is giving us valuable information.

The TORPEdO trial (ISRCTN 16424014)⁵ data highlighted the differences between 2 radiation modalities. How do you structure multidisciplinary support around them?

Nutrition is so critical for our patients, both during and after treatment, and it can be very challenging because the modalities we use can affect dryness and taste. Certain foods are harder, and during treatment when things do not taste good, you just do not have the motivation to eat. So we extensively counsel our patients.

We have dietitians who follow our patients through the course of treatment. They are great cheerleaders, and they have a lot of strategies to try to help maintain nutrition, especially if we need to move more to liquid diets.

Most high-volume centers really try to move away from just putting feeding tubes in patients unless they absolutely need it. There are data that show that people who are able to eat [during] treatment also have better functional outcomes afterward. So we do try to encourage people to eat, but it is not easy, and we recognize that.

We also work closely with our speech and language pathologists. This is another resource that I encourage patients to use, especially after treatment, to help rehabilitate after everything. It is a process, and sometimes patients do not understand how long the recovery can take and how much work and rehabilitation is needed to get back to a good functional level. It can be very frustrating, especially when I tell people it can take months to recover. That sounds daunting initially, and it can be very frustrating.

We just have to keep in mind that many of these treatments that we are doing are to cure people, and patients have to recognize that as they are going through the entire process.

REFERENCES

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2. Sanders C, Lau JF, Dietrich D, Strieth S, Brossart P, Kristiansen G. Nectin-4 is widely expressed in head and neck squamous cell carcinoma. Oncotarget. 2022;13:1166-1173. Published 2022 Oct 20. doi:10.18632/oncotarget.28299

3. Chang HW, Frey G, Wang J, et al. Preclinical development of ozuriftamab vedotin (BA3021), a novel ROR2-specific conditionally active biologic antibody-drug conjugate. MAbs. 2025;17(1):2490078. doi:10.1080/19420862.2025.2490078

4. Shelton J, Purgina BM, Cipriani NA, Dupont WD, Plummer D, Lewis JS Jr. p16 immunohistochemistry in oropharyngeal squamous cell carcinoma: a comparison of antibody clones using patient outcomes and high-risk human papillomavirus RNA status. Mod Pathol. 2017;30(9):1194-1203. doi:10.1038/modpathol.2017.31

5. Thomson DJ, Cruickshank C, Baines H, et al. TORPEdO: A phase III trial of intensity-modulated proton beam therapy versus intensity-modulated radiotherapy for multi-toxicity reduction in oropharyngeal cancer. Clin Transl Radiat Oncol. 2022;38:147-154. Published 2022 Nov 21. doi:10.1016/j.ctro.2022.11.010