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Could you give us some background on oropharyngeal squamous cell cancer? How frequently is this type of head and neck cancer diagnosed, and what is the prognosis for these patients?

 Oropharyngeal squamous cell cancer is a primary malignancy of the back of the throat, specifically the tonsils, base of the tongue, upper back of the throat, and soft palate. Historically, the disease was primarily caused by behaviors such as smoking and alcohol use. The prognosis over time has been very poor, and the key to understanding oropharyngeal squamous cell cancer is to understand that the epidemiology has changed dramatically.

It became recognized in the 1990s and 2000s that, more and more, oropharyngeal cancer was being driven by the human papillomavirus (HPV), and in 2017 that is the etiology of the vast majority of oropharyngeal tumors. In the last 10 years, the increase in oropharyngeal cancer has been somewhat dramatic, and it’s all due to the rising prevalence of HPV driving the disease. We estimate now that there are approximately 10,000 to 15,000 cases per year in the United States, and almost all of that increase is due to HPV, with the majority of cases in men. It’s increasing in women a bit, but much more so in men.

When someone comes into the clinic asking what their outcome is going to be, we have to get into what is causing the tumor. For patients with HPV-positive disease, which comprises about 70% to 80% of new diagnoses, the prognoses are actually quite good if not excellent. A high-level study that helped to redefine the staging of HPV-positive cancer has shown that for all-comers, as long as their disease isn’t gigantic, there is about an 80% survival rate at 5 years for almost any stage, which is quite good. You have to contrast that with patients whose disease is driven by smoking (HPV-negative disease). If you look at all comers who have a new diagnosis of HPV-negative cancer, the survival rate is less than 50% at 5 years and can be as low as 30% in patients who have the most advanced disease-big primary tumors and very large positive nodes. So, the prognosis discussion relates to the driving etiology of the disease, and ranges from very good to quite scary. It’s so different, in fact, that the new staging system differentiates the two types, HPV-positive and HPV-negative disease.

What is the typical treatment for patients with oropharyngeal cancer? What are the highlights of the updated American Society for Radiation Oncology (ASTRO) clinical guideline that you coauthored, as far as the standard of care with radiation therapy?

 The first decision that the treatment team and the patient have to make is whether the patient is going to have surgery or radiation therapy. It’s a very controversial question and there are strengths and weaknesses to both primary surgery and primary radiation. We did not, as a guideline panel, want to weigh in on this controversy, in large part because there are no data, mostly just opinions.

Patients who are treated with surgery are then treated with adjuvant radiation therapy or chemoradiation. For those treated with primary definitive radiation, there are many different “flavors” of that radiation therapy, whether with chemotherapy or in terms of the different ways it is delivered. In the guideline, we addressed all of these different possibilities to help guide the radiation and chemoradiation piece of the decision-making process.

The guideline is divided into four sections. In the first, we looked at patients being treated with radiation therapy, and one of the take-home messages is that the standard of therapy for locally advanced disease is chemoradiation with a bolus of cisplatin chemotherapy. That was chosen because it has been established over many years, in many prospective trials, and has been the most consistently tested chemotherapy regimen for oropharyngeal cancer. For patients who cannot tolerate that, we also made recommendations for concurrent systemic regimens, particularly cetuximab or carboplatin/fluorouracil, both of which have been shown to improve survival in randomized trials. Weekly cisplatin is also a viable regimen and is commonly used. We included this option but make the point that if it is used, it needs to be discussed with the patient that the supporting data are significantly weaker for weekly cisplatin than for the regimens that we strongly recommended. Another take-home message from this part of the guideline is that patients with lower-volume disease don’t need chemotherapy, and the recommendation is not to use routine chemoradiation in these patients (stage III).

The second section in the guideline looks at postoperative radiation. We didn’t address whether the patient should have surgery, but if he or she did have surgery, we made several recommendations on postoperative management, again relying on bolus cisplatin with radiation therapy as the strongest recommended treatment for patients with high-risk disease-mainly those with positive margins or extranodal extension on pathologic review. Weekly cisplatin may be used, but it is important to mention the lack of data there, and this should be pointed out to the patient in the discussion. For those who can’t tolerate a cisplatin-based regimen, the routine treatment that is recommended is radiation alone. Another important point is that for patients who don’t have high-risk disease, even if they have other intermediate-risk factors on a pathology specimen, the recommendation is not to use routine chemoradiation (which makes adjuvant therapy easier to tolerate), since there is no obvious benefit from the additional systemic therapy.

The third section we looked at is the use of induction chemotherapy. Induction chemotherapy is a controversial topic, and we have experts arguing for and against it. We spent a lot of time on this specific topic and did a careful review of the literature. We recommended that induction chemotherapy not be routinely used in the management of patients with oropharyngeal cancer, because the three trials that have tested this in a prospective randomized fashion were all negative.

The fourth section of the guideline focused on how to deliver the radiation treatment. For patients who have locally advanced disease who can’t receive chemotherapy, we recommended what we call “altered fraction radiation,” which can be delivered either in a more accelerated fashion for 6 weeks or delivered with twice-a-day hyperfractionation. We didn’t recommend one over the other but just assessed and described the literature supporting improved local control with both regimens in advanced disease. In summary, those are the big highlights of the guideline with respect to managing patients with oropharyngeal cancer.

You mentioned that there has been a recent uptick in patients diagnosed with HPV-positive oropharyngeal cancer, yet the new guideline mentions not basing treatment on HPV status of the patient’s tumor. Can you talk about that?

 This is an important point. As a panel and as a community, we clearly recognize that HPV-positive patients do substantially better than HPV-negative patients, especially when you look at the improving prognosis over the years. The new staging system now reflects this. But the key point is that these outcomes have been achieved with standard therapies that have been recommended in the guideline. When thinking about the purpose of the guideline-to use the evidence to recommend standard therapies-it was very clear from the start that there are insufficient data to support deviating from these standard treatments even in the most favorable cases of oropharyngeal cancer, specifically the HPV-positive nonsmokers. We are all very excited about, and are enthusiastically supportive of, entering clinical trials and testing different modalities of de-escalation and de-intensification, but those are trial-based therapies, and we wanted explicitly to make the point that standard therapies are recommended for all patients in standard practice.

Are there any ongoing clinical trials that have the potential to be practice-changing-that you and your colleagues are looking forward to reading about?

 That is a great question, and we as a panel strongly encourage all patients to enroll in these de-escalation trials. Given the favorable prognosis of HPV-positive patients and the toxicity associated with therapy, there are different paradigms to reduce the intensity of therapy, and they run the gamut. There is a Radiation Therapy Oncology Group trial that should be coming out in a few years that is evaluating a change in chemotherapy from cisplatin to cetuximab, and there are parallel trials in the United Kingdom and Australia looking at the same thing.

There are approaches to using induction chemotherapy, and then selecting responders to de-intensify the radiation. That approach has actually been published already, and certain aspects of that paradigm seem to be satisfying, safe, and potentially useful. There are other cooperative group trials in the United States: one is called NRG-HN002, which is lowering the dose, to try to reduce the overall intensity of the radiation treatment-and that concept may be carried out through other cooperative group trials.

Surgeons are getting into it too and have some exciting trials in which they are de-escalating the dose of the postoperative radiation in certain scenarios (there is a well-known trial, ECOG 3311, by the Eastern Cooperative Oncology Group that is attempting that), or just dropping the chemotherapy altogether in the patients with the lowest risk, the HPV-positive population.

The flip side to these are the dose-intensification trials, and I think it’s very important to remember that HPV-negative disease is almost like an orphan disease now, and there is some hope to use more novel systemic therapies like immunotherapy to increase the local control in this population as well.

The author has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

This interview was originally published online at 

In this interview we discuss new clinical guidelines from ASTRO on the use of radiotherapy in treating oropharyngeal cancer.

David Sher on the Updated ASTRO Guidelines for Oropharyngeal Cancer

The phase 3 KEYNOTE-689 trial showed a median EFS of 59.7 months with the pembrolizumab regimen in locally advanced head and neck squamous cell carcinoma.

Neoadjuvant Pembrolizumab/Radiotherapy Earns EU Approval in HNSCC Group

The BURAN trial revealed no overall survival benefit for buparlisib and paclitaxel in recurrent head and neck cancer, despite some response rate improvements.

Buparlisib/Chemo Does Not Improve OS in PD-1 Recurrent Head and Neck Cancer

Data from the BL-B01D1-301 study support iza-bren as a potential standard of care for pretreated recurrent or metastatic nasopharyngeal carcinoma.

Iza-Bren Increases Responses in Recurrent Nasopharyngeal Carcinoma

The investigator-evaluated ORR was 39.0% among those treated for recurrent/metastatic HNSCC, and the CR and PR rates were 9.8% and 29.3%, respectively.

Enfortumab Vedotin/Pembrolizumab Display Frontline Efficacy in PD-L1+ HNSCC

A median OS of 21.3 months was found in the phase 1/1b trial evaluating ficerafusp alfa plus pembrolizumab in those with metastatic and recurrent HNSCC.

Ficerafusp Alfa/Pembrolizumab Receives FDA BTD in Frontline HNSCC

The phase 3 NIVOSTOP trial evaluated an anti–PD-1 immunotherapy, nivolumab, in a patient population similar in the KEYNOTE-689 trial.

Nivolumab May Enhance Outcomes with SOC Therapy for Locally Advanced HNSCC

Douglas R. Adkins, MD, professor and medical oncologist in the John T. Milliken Department of Medicine of Washington University in St. Louis, MO, suggested that results from the 

 (NCT03576417)may impact standard of care (SOC) treatment in patients with locally advanced head and neck squamous cell carcinoma (HNSCC) in Europe, where the trial was conducted, and abroad.

 The trial evaluated the addition of adjuvant nivolumab (Opdivo) to cisplatin and radiotherapy in this patient group.

In a discussion with CancerNetwork®, Adkins discussed which presentations he was looking forward to seeing at the 

2025 American Society of Clinical Oncology (ASCO) Annual Meeting

 He highlighted these sessions in the context of a conversation on results from the 

 assessing the addition of neoadjuvant and adjuvant pembrolizumab (Keytruda) to SOC treatment in this patient population, which he presented at ASCO.

Adkins identified the presentation on the phase 3 NIVOPOSTOP trial as one of the sessions he was looking forward to, given that it, like KEYNOTE-689, was evaluating PD-1 inhibition in patients with locally advanced HNSCC. Furthermore, he explained that the topline report in a press release on the trial favored the use of immunotherapy given after surgery-based treatment, suggesting a potential impact on SOC treatment for this patient group.

In the context of locally advanced head and neck cancer, the trial called the NIVOPOSTOP trial [was] one of the plenary sessions at [ASCO 2025]. This is a trial conducted in Europe, and in contrast to the KEYNOTE-689 trial, in which pembrolizumab was given before and after surgery-based treatment for patients with locally advanced head and neck cancer, NIVOPOSTOP enrolled patients who [previously received] surgery and then received adjuvant radiation-based treatment, either with or without nivolumab.

Both pembrolizumab and nivolumab are a type of immunotherapy drug that inhibit the PD-1 receptor and have the opportunity to enhance the immune response [that reduce] the chance of recurrence. The topline report in the press release stated that outcomes were better in the NIVOPOSTOP trial with nivolumab given after surgery-based treatment.

I am looking forward to seeing these results, and I am excited to see how they may also impact the [SOC] treatment, particularly in Europe, where the trial was conducted.

Bourhis J, Auperin A, Borel C, et al. NIVOPOSTOP (GORTEC 2018-01): A phase III randomized trial of adjuvant nivolumab added to radio-chemotherapy in patients with resected head and neck squamous cell carcinoma at high risk of. 

. 2025;43(suppl 17):LBA2. doi:10.1200/JCO.2025.43.17_suppl.LBA2

Adkins D, Haddad RI, Tao Y, et al. Neoadjuvant and adjuvant pembrolizumab plus standard of care (SOC) in resectable locally advanced head and neck squamous cell carcinoma (LA HNSCC): exploratory efficacy analyses of the phase 3 KEYNOTE-689 study. 

. 2025;43(suppl 16):6012. doi:10.1200/JCO.2025.43.16_suppl.6012

GORTEC announces new trial success for head and neck cancer treatment. News release. GORTEC. January 7, 2025. Accessed June 5, 2025. https://tinyurl.com/5n8wuez7

Conference

Opportunities to further reduce relapses include pembrolizumab-based combination therapy and evaluating the agent’s contribution before and after surgery.

KEYNOTE-689 Results Provide “Foundation” for Alternative HNSCC Strategies

Douglas R. Adkins, MD, professor and medical oncologist in the John T. Milliken Department of Medicine of Washington University in St. Louis, MO, spoke with CancerNetwork® about next steps for researching pembrolizumab (Keytruda)-based treatment in patients with head and neck squamous cell carcinoma (HNSCC). The discussion was contextualized by findings from the 

assessing the addition of neoadjuvant and adjuvant pembrolizumab to standard-of-care (SOC) surgery and radiation or chemoradiotherapy in this patient population he presented at the 

Adkins suggested that data from the trial provide a new foundation to develop strategies that can elicit higher cure rates among patients with locally advanced head and neck cancer, given the potential of relapse even with the addition of neoadjuvant and adjuvant pembrolizumab to surgery followed by radiation or chemoradiation. He explained that potential strategies may include adding other therapeutic agents to pembrolizumab to enhance its efficacy.

Another opportunity, he claims, might include an investigation into the relative contribution of pembrolizumab to responses both before and after surgery in this patient population. He concluded by emphasizing the potential to develop new research pathways that expand upon the results uncovered in the investigation of KEYNOTE-689.

[The KEYNOTE-689 data] provide a new foundation to work on developing alternative or additional strategies that can further improve the chance of curing patients with locally advanced head and neck cancer. Relapse is still an event that does occur in patients who are treated with pembrolizumab, along with surgery-based treatment. There are opportunities to further reduce the chance of relapse and improve the [cure rates].

These opportunities could include [adding] drugs to pembrolizumab before and after surgery-based treatment––drugs that might enhance the efficacy of pembrolizumab. There are other opportunities to investigate the relative contribution of pembrolizumab given before surgery vs given after surgery. There are rich opportunities to develop new research pathways that build upon the results of the perioperative pembrolizumab approach that was investigated in KEYNOTE-689.

 2025;43(suppl 16):6012. doi:10.1200/JCO.2025.43.16_suppl.6012

For patients with locally advanced head and neck cancers, the current standard of care for curative therapy has a cure rate of less than 50%.

Addition of Pembrolizumab to SOC May Enhance HNSCC Cure Rates 

In a conversation with CancerNetwork®, Douglas R. Adkins, MD, discussed what the standards of care (SOCs) were for patients with resectable locally advanced head and neck squamous cell carcinoma (HNSCC). The discussion served as context for findings from the 

 assessing the addition of neoadjuvant and adjuvant pembrolizumab (Keytruda) to SOC in this patient population he presented at the 

2025 American Society of Clinical Oncology Annual Meeting

Adkins is a professor and medical oncologist in the John T. Milliken Department of Medicine of Washington University in St Louis, Missouri.

He began by contextualizing the state of head and neck cancer in the US, explaining that of the approximately 60,000 new cases every year, most patients have locally advanced disease. He remarked that the SOC for this patient group was surgery followed by radiation or chemoradiation, iterating that the cure rate for this SOC option was less than 50%.

Furthermore, he expressed that the addition of pembrolizumab to this regimen, both before and after surgery, was thought to help enhance cure rates for this patient group. He concluded by affirming that the trial supported the hypothesis, given a significantly improved major pathological response (mPR) rate, as well as event-free survival (EFS) and distant metastasis-free survival.

Results from the trial revealed that pembrolizumab extended EFS by more than 20 months, with the investigational arm (n = 363) experiencing a median EFS of 51.8 months (95% CI, 37.5-not reached [NR]) vs 30.4 months (95% CI, 21.8-50.1) with SOC alone (n = 351; HR, 0.73; 95% CI, 0.58-0.92; 

= .0041). Furthermore, among patients in the respective arms, the mPRs were 9.4% and 0%, with an estimated difference of 9.3% (95% CI, 6.7%-12.8%; 

For context, in the US, each year, about 60,000 new cases of head and neck cancer [occur]. Of these cases, most patients have locally advanced disease and are therefore candidates for [the current SOC for] curative therapy, typically with surgery followed by radiation with or without chemotherapy…. The chance of curing patients with the current SOC is just under 50%; there lies the problem.

[Many] patients unfortunately develop recurrence of their cancer after [SOC]. The introduction of pembrolizumab before and after surgery [with] radiation offers the opportunity to improve the chance of [curing them]. Indeed, that is what the KEYNOTE-689 trial showed.

Durvalumab Inferior to Cetuximab in Contraindicated Cisplatin HNSCC

Christina Henson, MD, Residency Program Director for Radiation Oncology at Oklahoma University, discussed results from the phase 3 NRG-HN004 trial (NCT03258554) that found durvalumab (Imfinzi) was not comparable to cetuximab (Erbitux) in terms of efficacy for patients with locally advanced or metastatic head and neck squamous cell carcinoma.

At the median follow-up of 6.4 months, a progression-free survival event was observed in 22% of patients in the durvalumab arm and 21% in the cetuximab arm (HR, 1.05; 95% CI, 0.53-2.09). Because of these outcomes, the NRG Oncology Data Monitoring Committee recommended that permanent accrual close for this trial. Additionally, 69 PFS events need to occur during the phase 2 end point analysis.

In a later part of the interview, Henson noted, “It checked 1 [treatment option] off the list of possible things that we keep in mind that might be a good fit for this patient population.”

The standard treatment for head and neck cancers, for most of them, and for most stages, is a combination of radiation and a chemotherapy agent called cisplatin. The issue with that is that cisplatin has a lot of toxicities that we’d like to try to avoid, or that make some patients ineligible to receive it, because they have preexisting conditions that make them not a good candidate. They might already have hearing loss, kidney damage, have neuropathy, or just patients over a certain age, who have other medical comorbidities [and may not be] candidates for cisplatin. There’s this constant search to find something for those patients. The current best thing that we have is a drug called cetuximab, that has been the most studied in this patient population, but it too, has adverse effects. This study was looking to compare an immunotherapy agent called durvalumab to cetuximab, in hopes that it would be equivalent or better.

The trial was intended to go a lot longer than it did, and the goal was to recruit a lot more patients than it ended up recruiting. The reason that it did not is because it closed early, because the planned analysis of the data at that point showed that the experimental arm was not performing as well as the control arm, the cetuximab arm. What we saw after following the patients for 2 years after they received treatment, was that the cure rates were about 13% lower in the experimental arm, which is a pretty big difference.

Mell LK, Torres-Saavedra PA, Wong SJ, et al. Radiotherapy with cetuximab or durvalumab for locoregionally advanced head and neck cancer in patients with a contraindication to cisplatin (NRG-HN004): an open-label, multicentre, parallel-group, randomised, phase 2/3 trial. 

. 2024;25(12):1576-1588. doi:10.1016/S1470-2045(24)00507-2

Christina Henson, MD, spoke about the impact negative trial results can have on advancing the head and neck cancer field forward. 

Expert Discusses Safety of Toripalimab in Advanced Nasopharyngeal Carcinoma

Burtness 2

The safety profile of toripalimab-tpzi (Loqtorzi) in patients with metastatic or locally advanced nasopharyngeal carcinoma (NPC) appear to be comparable with prior reports of other PD-1 inhibitors, said Barbara Burtness, MD.

FDA approval of toripalimab in advanced/metastatic nasopharyngeal carcinoma,

Burtness, a professor of medicine at Yale School of Medicine and chief translational research officer and associate cancer center director for translational research at the Yale Cancer Center, discussed the toxicity associated with the agent as observed in the phase 3 JUPITER-02 trial (NCT03581786).

 11.6% of patients who received toripalimab and 4.9% of those who were treated with placebo discontinued treatment due to any adverse effects (AEs).

 Additionally, immune-related AEs affected 54.1% and 21.7% of patients in each respective arm, and grade 3 or higher immune-related AEs occurred in 9.6% vs 1.4%. Investigators reported that rates of grade 3 or higher AEs and fatal AEs were comparable between the toripalimab and placebo arms.

Burtness also stated that the vascular toxicity associated with other agents like pembrolizumab (Keytruda) did not occur with toripalimab among those with metastatic or locally advanced NPC in the JUPITER-02 trial.

[Toripalimab] appears to be very similar to other PD-1 inhibitors. If you look at the incidence of grade 3/4 adverse effects in the JUPITER-02 trial, it’s actually driven by the gemcitabine and cisplatin, which are more toxic. But if you look at adverse effects that lead to discontinuation of toripalimab vs placebo added on top of the chemotherapy, that was [11.6%] for toripalimab and 4.9% for placebo.

Toripalimab does not really seem to have the vascular toxicity that, for example, pembrolizumab [Keytruda] does, which was the other drug that was being explored in nasopharyngeal carcinoma.

Coherus and Junshi Biosciences announce FDA approval of LOQTORZI™ (toripalimab-tpzi) in all lines of treatment for recurrent or metastatic nasopharyngeal carcinoma (NPC). News release. Coherus Biosciences. October 27, 2023. Accessed January 17, 2024. http://tinyurl.com/4e8635a9

Mai HQ, Chen QY, Chen D, et al. Toripalimab plus chemotherapy for recurrent or metastatic nasopharyngeal carcinoma: the JUPITER-02 randomized clinical trial. 

2023;330(20):1961-1970. doi:10.1001/jama.2023.20181

Treatment with toripalimab does not yield the same vascular toxicity seen with pembrolizumab in patients with advanced or metastatic nasopharyngeal carcinoma, according to Barbara Burtness, MD.

Toripalimab Yields ‘Striking’ PFS Improvement in Nasopharyngeal Carcinoma

Burtness 1

“Solid” progression-free survival (PFS) and overall survival (OS) data with toripalimab-tpzi (Loqtorzi) support the role of PD-1 inhibition in the frontline treatment of those with recurrent or metastatic nasopharyngeal carcinoma (NPC), according to Barbara Burtness, MD.

, Burtness, a professor of medicine at Yale School of Medicine and chief translational research officer and associate cancer center director for translational research at the Yale Cancer Center, spoke about how efficacy findings from the phase 3 JUPITER-02 study (NCT03581786) support the 

FDA approval of toripalimab in metastatic/recurrent NPC

What has changed the standard of care is the JUPITER-02 trial,

 where [289] patients were randomly assigned between the standard of care at that time, which was gemcitabine/cisplatin, or the same thing with the addition of toripalimab. When we first saw the data published in 

Overall survival also appears to improve with toripalimab compared with chemotherapy among patients with metastatic or advanced nasopharyngeal carcinoma.

Head & Neck Cancer

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