The treatment landscape of head and neck cancer has changed significantly over the past year. With the approval of Keytruda (pembrolizumab) in August 2016 and Opdivo (nivolumab) in November 2016, immunotherapy has become a key player in patient care.
Following in the tracks of KEYNOTE-012, which led to the approval of pembrolizumab, and CheckMate-141, which led to the approval of Opdivo, several trials are examining whether anti–PD-1/PD-L1 agents can succeed in the frontline, as well as whether combination regimens can build on the single-agent success.
KEYNOTE-048 (NCT02358031), a phase III randomized study, is evaluating the safety and efficacy of Keytruda as a first-line treatment alone or in combination with chemotherapy in patients with recurrent or metastatic head and neck squamous cell carcinoma.
Another trial that is currently ongoing is KESTREL (NCT02551159), which is looking at the anti–PD-L1 agent durvalumab, in the first-line setting, as well. This is a phase III randomized, open-label, multicenter, global study of durvalumab alone or in combination with the CTLA-4 inhibitor tremelimumab versus standard of care for patients with recurrent or metastatic head and neck squamous cell cancer who have not received prior treatment.
“There is so much ongoing. The field has really shifted from an area where there was not much going on to now where there is almost too much going on,” said Tanguy Seiwert, M.D.
In an interview with CURE, Seiwert, assistant professor of medicine, The University of Chicago Medicine, discussed advances and next steps with immunotherapy, as well as the overall challenges and goals for treating patients with head and neck cancer.
What is the current role of immunotherapy in head and neck cancer?
Seiwert: The role of immunotherapy has changed dramatically. In 2016, there was the approval of two anti–PD-1 agents and a lot of interesting and exciting data. For the last 20 or 30 years, there has been very little progress for recurrent metastatic head and neck cancer. The only approval was Erbitux (cetuximab), which actually is not very active. But then, data with immunotherapy came out and it became clear that these drugs have really striking activity — especially when you look at overall survival. We saw data with pembrolizumab, and we saw data with Opdivo, then there was durvalumab, all of which seem to have a striking effect on survival, in particular. At one year, about 40 percent of patients are alive, which is much better than what we typically see. So, it feels like, for the first time, there is really progress because of these novel agents.
Are any of these agents distinguishing themselves?
They are all quite excellent and well tolerated. Whether there are any differences between the agents, that is hard to tell. It seems like they are more similar though, and obviously, we do not have comparisons to look at. It seems like they have certain key features that are shared. There is some debate over slight differences — the dosing can be slightly different and one targets a receptor, one targets a ligand, but by and large, they are more similar than not.
What ongoing research are you excited about?
We have approval of two agents in the second-line setting, but we will likely in 2017 or early 2018 see data in the first-line setting. There are two trials that will mature, KEYNOTE-048 with Keytruda and the KESTREL study with durvalumab.
There are also efforts ongoing in the curative setting. We actually do cure a lot of people with head and neck cancer, but the question is can we introduce or integrate immunotherapy into the curative setting? These studies are starting now.
We actually already saw some combination data from the PD-1 inhibitor Opdivo with lirilumab, an anti-KIR antibody, and that looked quite good. There seems to be excitement about combinations. There will be data about combinations with CTLA-4 inhibitors: durvalumab in combination with tremelimumab, as well as Opdivo with Yervoy (ipilimumab). There is also combination data emerging with other agents, such as talimogene laherparepvec (T-VEC; Imlygic), which is an oncolytic virus, and the IDO1 inhibitor epacadostat.
There is lots and lots of new stuff coming out — it is a really exciting time for the field, as well as encouraging for patients.
What is the most pressing challenge in the treatment of head and neck cancer?
We need better treatments that are more effective and have more lasting benefits. The problem is that for recurrent metastatic disease, our treatments are not very good. And really trying to extend patients’ lives — even potentially living for a long period of time — would be really important and so far, we haven’t done very well. Maybe PD-1 is a step in the right direction, but it clearly isn’t anywhere close to where we want it to be.
What is the status of HPV-related head and neck cancers?
It is an epidemic. HPV-positive tumors are becoming more a more common and the makeup of head and neck cancer is shifting toward more and more of these HPV-positive tumors. They are actually a very distinct entity and they tend to do better, but they need different treatments. HPV-positive cancers are quite curable upfront and we often overtreat these patients. We can de-escalate these patients, with equally, or in fact better, outcomes because there will be fewer toxicities.
I think that we will start understanding some of the treatments that are specific for HPV-positive cancers better, including maybe some immunotherapies or HPV-specific treatment vaccines. We have the preventative vaccine, but maybe we should also be vaccinating people against the HPV that they already have. I think we will have a much more biologically based understanding of HPV-positive head and neck cancer in the future, but right now we are just treating head and neck cancer the same way.
Where do you see this treatment landscape progressing in the next five to 10 years?
I think immunotherapy will change the field dramatically. I think it will integrate with many of the treatment modalities that we already have and will go into the curative setting. I think we will also see some head and neck cancers that we can control long term. I do believe the future is going to combinations with chemotherapy, combinations with radiations and with immunotherapy, maybe even some targeted therapies. I believe that immunotherapy will change the field.
Right now, for head and neck cancer, we do not use any other meaningful biomarkers other than HPV status. I do believe that over the next five years or so we will use more biomarkers. That could be PD-L1 as an immunotherapy-related biomarker. But I also believe it will be broader. I think we have an opportunity to actually understand better whether it is gene signatures or single-cell analysis, these very powerful profiling technologies will not just be used in other cancer types but will start having a role in head and neck cancer.