Expert Discusses Key Immunotherapy Trials and Next Steps in Head and Neck Cancer

Joshua Bauml, MD

Immunotherapy in head and neck cancer continues to evolve and advance patient care. Challenges remain in the field, however, such as how to better target patients with HPV-associated disease, says Joshua Bauml, MD.

OncLive: What is the current role of immunotherapy in head and neck cancer?

In an interview with OncLive, Joshua Bauml, MD, assistant professor of Hematology/Oncology and co-deputy director for the Lung/Head and Neck Medical Oncology Clinical Research Program, Abramson Cancer Center, University of Pennsylvania, discussed the current role of immunotherapy in this disease, potential next steps, and unmet needs in HPV-associated head and neck cancer.Bauml: Immunotherapy has a key role to play to in the management of head and neck cancer. Patients who have metastatic head and neck cancer currently have very limited options, so the arrival of PD-1 inhibitors has been a huge boon for patients. Specifically, head and neck cancers have overregulation of PD-L1 and PD-L2, which are known to be biomarkers of response to PD-1 inhibition. In addition to that, much of head and neck cancer is virally mediated. Virally mediated tumors tend to have a relatively high mutational burden, which also tends to lead to response to immunotherapy. So, it is complete logical to utilize immunotherapy in the management of head and neck cancer.

This has led to a couple of studies that are worth mentioning. KEYNOTE-012 was the first one—this was a multicohort phase I study looking at pembrolizumab (Keytruda) in the management of recurrent or metastatic head and neck cancer. This was a standard phase I study, so it included anyone with prior treatments, no certain restriction. But what they saw was there was a pretty impressive response rate, much better than what you would expect from standard-of-care agents.

The subsequent study with pembrolizumab was KEYNOTE-055. This study specifically focused on patients who had disease that was refractory to both platinum and cetuximab (Erbitux). This is a particularly [high-need] group because those patients really have no option, the only historical comparator that has been used amongst those patients is methotrexate, which has a response rate of about 5% or lower, with significant toxicity. The PD-1 inhibitors have a lot of benefits there, because it actually has very little toxicity, and significant activity. So, the response rates in KEYNOTE-012 and KEYNOTE-055—which was a specific subgroup of highly ill and highly pretreated patients—were pretty much identical. That was really reassuring that this is a different treatment paradigm.

What are the next steps for immunotherapy in this disease?

At the same time we presented KEYNOTE-055, CheckMate-141 was also presented. This was a randomized phase III study that compared nivolumab (Opdivo) to 3 different chemotherapeutic options for patents who platinum-refractory head and neck cancer. The investigators had the choice of giving methotrexate, docetaxel, or cetuximab. That study, in a randomized phase III setting, showed an overall survival benefit for nivolumab versus investigators choice chemotherapy. Based upon KEYNOTE-012, and separately based upon CheckMate-141, both nivolumab and pembrolizumab are both FDA approved for the treatment of head and neck cancer after progression on a platinum. I think 1 of the key next steps of immunotherapy is moving it earlier in the course of treatment. As I mentioned, we are currently giving it for metastatic patients who have progressed on platinum, but immunotherapy has significant advantages in the earlier setting as well. Patients who have radiation, for instance, secrete a large amount of their tumor antigens as a result of radiation, and this may act as a sort of automated vaccine to enhance the response to immunotherapy. This is really exciting.

This year at ASCO there were 2 studies presented looking at immunotherapy earlier. One evaluated pembrolizumab along with radiation in locally advanced head and neck cancer. That study was really small, and what we can say is, it seems relatively safe.

Are there any other particularly impactful developments in the treatment of head and neck cancer?

What was a more exciting study though, was a trial looking at pembrolizumab in the neoadjuvant space for patients who had resectable tumors. They gave 1 dose of pembrolizumab and they [observed] response rates that were very impressive—major pathologic responses after a single dose of immunotherapy. That is really very exciting. The idea that these patients with intact tumors may actually have a more amplified response than we were even seeing in the metastatic setting when they are heavily pretreated and their immune systems are relatively down from chemotherapy. So that, I think, is a real next step for immunotherapy. Looking at other treatments for head and neck cancer, 1 of the things we have to figure out how to do is to better target patients with HPV-associated head and neck cancers. As you know, HPV-associated head and neck cancers tend to occur amongst patients who are younger and have fewer comorbidities—it’s less associated with smoking and alcohol exposure.

One of the most exciting abstracts that was at ASCO this year, I thought, was Dr Gillison’s work which looked at oral HPV prevalence amongst patients in the NHANES data. What they did, was they looked at patients who had self-stated that they had gotten a single vaccine against HPV. And amongst men, they could decrease the rate of oral HPV infections by almost 100%. That’s really really exciting, right? I am not saying it is preventing cancer, it is preventing HPV infections, but we all believe that the HPV infections are causing the cancer; we don’t have any precursor lesions like we do in cervical cancer.

So, what this data really said to me was that we really have to increase vaccination rates. Not just for women, but for men, as well. Really, this is something that needs to be targeted in youth, as HPV is ubiquitous once someone reaches 18 or 19 years old—by the cutoff in their 20s, they've already been exposed. This is a huge need—the fact that we could turn the tide of this epidemic rise of head and neck cancer with a vaccination, that is amazing. And this is even understanding the efficacy because in NHANES it was only patients that received a single vaccination.

Amongst the patients who already have these tumors, there are 2 approaches—1 is to try to de-escalate care. Patients who have HPV-associated head and neck cancers have much better outcomes, so maybe we don’t need to blast them with high doses of radiation and chemotherapy. And there are some emerging studies that are exciting.

Are there any other pressing challenges or unmet needs in head and neck cancer?

The other thing which we can look at is targeted vaccines, not the preventative vaccines that are available, but there are some emerging therapeutic vaccines that target aspects of HPV that are expressed on these tumor cells. I think that is a really cool step for HPV-associated head and neck cancer. I think 1 of the things that is going to come up—because HPV-associated head and neck cancer is so much more common now and because we are doing so well for these patients—is the concept of survivorship in head and neck cancer is really not explored at all. Unfortunately, historically, patients with head and neck cancer did not survive. But now, we have this enlarging cohort of patients who are young, healthy, and have HPV-associated head and neck cancer for which they receive a highly toxic therapy, and we need to figure out how to support these patients moving forward. I think that is a huge unmet need.