Precision Oncology Inches into Head and Neck Cancer Paradigm

Everett E. Vokes, MD

Treatment of head and neck cancer is moving away from invasive surgery and chemoradiotherapy and toward precision medicine, according to Everett E. Vokes, MD. But the field still has a long way to go, compared with other solid tumors.¹

Patients with squamous cell cancers of the head and neck cancers are typically treated with chemoradiotherapy, said Vokes, the John E. Ultmann Distinguished Service professor of Medicine, professor of Radiation and Cellular Oncology, chair of the Department of Medicine, and physician-in-chief, at University of Chicago Medicine and Biological Sciences, during a presentation at the Inaugural Miami Cancer Institute Precision Medicine Oncology Symposium.

The only targeted therapy available is for HRAS-driven tumors. Although the farnesyltransferase inhibitor, tipifarnib (Zarnestra), has achieved anti-tumor activity in the HRAS-positive population, the activity is modest for patients with HRAS-mutated salivary gland cancer.² Vokes explained that more therapies are needed for these patients, but other investigational strategies like de-escalation are promising.¹

For thyroid cancers, the precision medicine landscape is vaster, Vokes said. In addition to immunotherapy, lenvatinib (Lenvima), a tyrosine kinase inhibitor, is FDA approved for multiple indications.

Looking ahead, Vokes hopes research leans towards a multidisciplinary approach to get patients with all forms of head and neck cancer to remission.

In an interview with Targeted Oncology™, Vokes, discussed his recent presentation and explained how the molecular biology of head and neck cancers is an opportunity for new investigations and treatment development.

Targeted Oncology: Can you give a brief overview of the presentation you gave at the Inaugural Miami Cancer Institute Precision Oncology Symposium?

Vokes: I was asked to talk about precision oncology as it applies to squamous head neck cancer. Unlike lung cancer, where we have many targetable mutations, for which increasingly we have available drugs, that does not occur frequently in head neck cancer. If we look, squamous head neck cancer has 2 distinct pathways. One of the pathways is viral mediated and the other is carcinogen mediated, and that does allow us some degree of precision medicine.

Starting with nasopharyngeal cancer, which is virally mediated in endemic regions, particularly Southeastern Asia, the EBV titer can be assessed in multiple ways. For one, it's been used to screen large populations of patients, and it can identify those at risk for developing early-stage nasopharynx cancer. That information has been published and is true for an endemic region. It would not work in the United States where nasopharyngeal cancer is less common. The other item could work, and EBV titers have been used to determine who needs less therapy. For example, if patients have intermediate-stage disease, then they are considered to be at less risk. Various de-escalation therapies and strategies have been investigated to do that, such as giving this induction chemotherapy, giving a lower dose of radiation, or not giving concurrent chemoradiotherapy. We do not yet know which of those is the best approach, but we do know that EBV titers in addition to traditional staging can probably be used in the future to tailor individual therapies more precisely. For HPV tumors in the United States, the same information may apply.

Here again, we've known for many years that the prognosis for patients with HPV-positive tumors is good. That then invariably leads to the question of how to do de-escalation best. There's a variety of approaches to that. Some approaches are surgical. The 1 that I favor and that we've used at the University of Chicago is to use induction chemotherapy, measure the responses, and give reduced-dose chemoradiotherapy to those patients who do really well.

The other question is, can we predict recurrence? HPV-related cell-free DNA can be used. Cell-free DNA can for early detection of recurrence. For prognosis, this is still investigational, but there's a growing body of evidence saying that maybe in the future, cell-free DNA could be used during treatment to monitor response. It would be used in addition to the traditional scanning and PET scans that we do.

Regarding specific mutations, we lag in the field compared with lung cancer. HRAS is the 1 that stands out, and that can be targeted with tipifarnib. Response rates are not as high as you would see with an EGFR mutation in lung cancer, but patients can benefit, at least for some time. That's what we have at this point in terms of targeted therapies for head neck cancer.

I think we're moving toward precision oncology, but at this point we are still lagging behind some of the other areas. I do think that liquid biopsies are going to be actively investigated moving forward.

For thyroid cancers, what do we now about how to precisely target these tumors?

Thyroid cancers are in the head neck cancer, but they are a distinct entity. Thyroid cancers do have targetable mutations, and we target them successfully with drugs like lenvatinib, which can lead to prolonged responses. Importantly, that is only for metastatic and refractory tumors that no longer respond to iodine, and are second-, third-, or fourth-line. So, it is appropriate for these patients after prior curative approaches.

What advice do you have for oncologists on the clinical application of next-generation sequencing for head and neck cancers? What about other forms of testing?

In thyroid cancer, next-generation sequencing is clinically applicable. Even though a kinase inhibitor such as lenvatinib is the recommended first-line drug, if there's another mutation such as BRAF or something else, that may lead to a more informed treatment decision for subsequent therapies.

For squamous cell tumors, because of the potential presence of HRAS, it is working looking. We also test for PD-L1 expression because there may be a patients one can treat with a PD-1 inhibitor by itself. Most patients will get a PD-1 inhibitor combined with chemotherapy though.

What investigational strategies excite you most about the future of the head and neck cancer space?

I think the de-escalation trials are of great interest. Various strategies are being investigated, some have failed, such as using cetuximab [Erbitux] instead of cisplatin with concurrent radiation. It’s not less toxic because the radiation toxicity is dominate. Long-term outcomes may show that it’s a less toxic, but the outcome is inferior. That is a hypothesis that is not successful. Surgery, I think for very early stages, a transoral robotic approach may be useful, but for others, there has been much success for patients treated with de-escalation strategies.

What are some of the unmet needs in head and neck cancer that more research should focus on?

I think any time we talk about unmet needs and cancer, it's about can we cure a patient or not? We can get many patients with locally or regionally advanced disease into remission, but in carcinogen type A tumors, which are induced by tobacco and/or alcohol, the cure rates are not what they are in HPV-positive tumors. We do need to do better with carcinogen type A tumors.

I think new drugs, and maybe smarter ways of putting together chemoimmunotherapy with radiotherapy approaches, are going to be important. I also think that for some oral tumors, maybe we can move away from these invasive surgeries for larger tumors and test the use of combined modality approaches on the patients where chemoradiotherapy or immunotherapies lead to sufficiently satisfying outcomes, such as remission.

_REFERENCE:

_{1. Vokes EE. Precision oncology opportunities in head and neck cancer. Presented at Inaugural Miami Cancer Institute Precision Oncology Symposium; February 3-4, 2022; Coral Gables, FL}

_{2. Desilets A and Ho AL. Targeting HRAS in head and neck cancer: lessons from the past and future promise. Cancer J. 2022 Sep-Oct;28(5):363-368. doi:10.1097/PPO.0000000000000616.}