Expert Anticipates Bright Future for Immunotherapy in HNSCC

Ezra Cohen, MD

The treatment paradigm of head and neck squamous cell carcinoma (HNSCC) has evolved rapidly with the introduction of immunotherapy. Currently, the anti—PD-1 agents pembrolizumab (Keytruda) and nivolumab (Opdivo) are approved for patients who have progressed on platinum-based chemotherapy.

Ezra Cohen, MD, said that while recent data have brought excitement to the field of head and neck cancer, challenges remain in selecting patients, resistance, and treating those who do not respond to current immunotherapies. Overall, he said, the future is bright for head and neck cancer.

OncLive: What updates can you share regarding immunotherapy in head and neck cancer?

In an interview with OncLive, Cohen, professor of medicine, Division of Hematology/Oncology, University of California, San Diego, associate director for Translational Science, Moores Cancer Center, discussed the future role of immunotherapy in the treatment of patients with HNSCC.Cohen: For HNSCC, we have certainly seen some incredible advances in the last few years for immunotherapy. What is startling is that things are happening so fast. We now how 2 immunotherapy agents in head and neck cancer—nivolumab and pembrolizumab—which are approved for patients with platinum-refractory disease.

The future is going to be incredibly exciting. We have seen combinations that appear to double the response rate, such as agents that modulate the tumor microenvironment through myeloid-derived suppressor cells like a STAT3, oligonucleotide, or an IDO inhibitor. We are seeing a more than doubling of response rate with anti—PD-1 alone. We have seen the combination with innate immune activators, like toll-like receptor 9 agonists, that appear to double the response rate compared with anti–PD-1 alone.

Recently, a publication using an HPV vaccine in HPV-positive head and neck cancers appeared to enhance the response rate. Combinations are now being explored in larger randomized trials to make sure that they will hold up. Thus far, both the response rates and the duration of those responses appear to be incredibly promising.

What results are you looking forward to from the 2018 ESMO Congress?*

In the near term, we are going to see the first-line data for the phase III trials. Now, nivolumab and pembrolizumab are approved in platinum-refractory patients, and we are very excited to see what happens to patients who have yet to be exposed to platinum-based therapy, either alone or in combination with chemotherapy. We already have a hint that those studies may be positive.I have said, half-jokingly, that it is the year for head and neck cancer. I have never been as excited to attend a conference as I will be for the 2018 ESMO Congress. We know that we are going to see the KEYNOTE-048 data, which are the first-line data for pembrolizumab alone or in combination with chemotherapy versus the standard of care of platinum, 5-fluorouracil, and cetuximab (Erbitux). We already have a hint from a news release that this study, at least in part, is going to be positive.

The other major trial that is going to be presented is the De-ESCALaTE trial, which enrolled patients with HPV-positive disease in the locally advanced setting and treated them with curative intent—with either cisplatin and radiation or cetuximab and radiation. We are very excited for those data, because it is going to dramatically influence the standard of care for HPV-positive patients, no matter the result.

How prevalent are HRAS mutations in HNSCC?

What are the remaining questions regarding immunotherapy in head and neck cancer?

Then we have some phase II studies that will make us believe that the future is going to be very bright for head and neck cancer. For instance, [studies are] looking at patients whose tumors harbor HRAS mutations using a drug called tipifarnib that we think will show a very good response rate. Other trials are looking at different biomarkers, and the use of other targeted therapies in combination with immunotherapy. Again, this is a harbinger of some wonderful things to come in the future. What we are beginning to realize in some patients with HNSCC is that those tumors can harbor an HRAS mutation. Now, this is different than KRAS or NRAS, which we see in other cancers. HRAS can be seen in about 10% of HNSCCs. These are exclusively HPV-negative cancers. What is interesting is that some early data have suggested that tipifarnib is especially active in HRAS-mutated cancers. HNSCC is no exception. We will see some more data at the 2018 ESMO Congress, and it is likely that the response rate to single-agent tipifarnib is going to be very high in HRAS-mutated patients.Some of the issues and challenges that we still have with immunotherapy in HNSCC are first, predicting which patients are going to respond to anti—PD-1 therapy, which gets more complicated once we start to bring in the combinations. We do have a sense that if the tumor cells or stroma express PD-L1, that the chances of response and benefit are higher. But, it is still not a perfect test by any means. Moreover, we need to begin to understand why these cancers become resistant.

We have to remember that as excited as we are about immunotherapy in cancer, we are still only talking about 15% of patients who respond initially. What about the other 85%? Why are they not responding? We still have two-thirds of our patients treated with anti—PD-1 therapy who will not make it to 1 year. How can we help them?

Are there any developments in targeted therapies?

We will begin to understand that in some of them; there are elements in the tumor microenvironment that do not allow that cancer to respond to anti—PD-1 therapy, and we need to figure out ways to address that. For some of them, we understand that the immune system is not recognizing the tumor cells anymore, and we need to have ways to overcome that. We have the tools to do it; now we have to advance our understanding to figure out how to implement those tools.In terms of targeted therapies for HNSCC, there is a lot of work being done. But again, there is a lot of work that [still] needs to be done. There are less common alterations, such as FGFR, and new agents are coming on board targeting that. Although we are all excited about immunotherapy, let us not forget that cancer is a genomic disease driven by specific alterations. If we target those alterations, we can often get high response rates that are durable.

*Note: This interview took place prior to the 2018 ESMO Congress. Please follow these links for our coverage of the KEYNOTE-048 and De-ESCALaTE HPV trials.