Transcript:Ezra Cohen, MD: Capitalizing on the fact that a substantial number of head and neck cancers are caused by HPV, we begin to realize that because this is a virus—because it’s a foreign body, if you will—that it will present peptides or molecules to the immune system that should be completely different from the self. Those are viral genes that, if presented to the immune system, should trigger an immune response to destroy a cell that’s been infected with that viral gene. So, with that in mind, people began to think, well, could we develop therapeutic vaccine strategies—not a preventative vaccine—that could combat HPV-positive cancers, including cancers of the head and neck?

One such strategy is the Advaxis HPV vaccine that uses a very interesting technology. What Advaxis has done is taken a bacteria that is very immunogenic, called Listeria, and they’ve modified it to not allow that bacteria to infect and proliferate. So, it’s not the regular strain of that bacteria that you’d find in the environment. It’s a modified bacteria, and they’ve coupled it with an HPV gene, specifically the HPV-E6, in order to produce an immune response to HPV. And that vaccine is presented to the immune system with the hopes that the Listeria will act as an adjuvant, that it will stimulate an immune response, and it will stimulate an immune response specific to HPV, because that’s the gene that’s being presented to the immune system.

We’ve also realized, from many years of vaccine work, that a vaccine alone, in advanced cancer, is unlikely to work. So, the clinical trial using this Advaxis vaccine has done one additional thing, and that’s added a drug that stimulates the immune system. We talked about checkpoint inhibitors and the ability to inhibit a specific checkpoint of PD-1, PD-L1, and that’s exactly what’s being combined with the Advaxis vaccine. In fact, it’s specifically pembrolizumab. The idea that we can stimulate the immune system to respond to HPV, and then augment that response with a checkpoint inhibitor, is the rationale behind the trial, and that’s exactly what’s being attempted right now.

Another way to stimulate the immune system is through oncolytic viruses. We’ve tried oncolytic viruses as primary therapies for some time and, in fact, in head and neck cancer, as well. Unfortunately, those phase III trials so far had been negative. But the good thing about the technology is that it has continuously improved. And what we’ve come to realize, as well, along with the technological improvements in the virus themselves, is that they can stimulate an immune response. And that, perhaps with emerging immunotherapies that appear to be effective, we can enhance that immune response and result in, actually, elimination of the tumor or dramatic reduction of the tumor.

For instance, in melanoma, we have the talimogene laherparepvec (TVEC) virus that appeared to do exactly that. And so for head and neck cancer, this has been something that is now being revisited in combination with immune modulators and immunotherapies, especially checkpoint inhibitors.

LUX-Head and Neck 1 was a study in second-line recurrent metastatic head and neck cancer, patients who were platinum-refractory—who were randomized to either afatinib or methotrexate. The randomization was 2:1 in favor of afatinib, with a primary endpoint of progression-free survival. In fact, the study met its primary endpoint, progression-free survival hazard ratio of .8, which was statistically significantly different. In combination with the study, we looked at biomarkers with some a priori hypotheses around specific biomarkers. One of those was p16, indicating an HPV-positive or HPV-negative cancer. And what we saw was, apparently, HPV-negative cancers had a more dramatic benefit to afatinib versus methotrexate. In fact, almost exclusively, the responses we saw were in p16-negative or HPV-negative cancers. Moreover, we looked at EGFR amplification, and, again, tumors that were EGFR-amplified appeared to benefit from afatinib versus methotrexate.

And then we looked at two biomarkers that could be indicative of an intact or a constitutively activated PI3-kinase pathway. Let’s talk about those in a little bit of detail. First, PTEN. PTEN is a tumor-suppressor gene that essentially turns off PI3-kinase signaling, and we’ve known for a long time that a substantial number of head and neck cancers—anywhere from a third to a half—actually eliminate or downregulate PTEN. And when PTEN is downregulated, the PI3-kinase pathway activates. Along with that, another biomarker, HER3, can associate with other members of its family—specifically EGFR and HER2—and preferentially activate the PI3-kinase pathway. Again, when we look at head and neck cancers, a substantial number of head and neck cancers will upregulate HER3 signaling. It’s a little bit tricky because, actually, upregulated HER3 signaling is indicated by lower expression of HER3. And, if you think about the biology, the pathway is activated by the ligand called neuregulin, and when neuregulin expression is very high, HER3 levels, in a compensatory way, go down. So, paradoxically, low HER3 actually indicates an activated PI3-kinase pathway.

And that’s exactly what we looked at in LUX-Head and Neck 1. We looked at PTEN expression and HER3 expression, and what we saw was essentially what we hypothesized. Patients who had high PTEN or who had low HER3 were the ones that seemed to benefit from afatinib versus methotrexate. In other words, patients who had biomarkers that indicated that the PI3-kinase pathway was not constitutively activated with an intact normal pathway were patients who could benefit from afatinib.

And although this is still a hypothesis that needs to be tested, what we’ve come to realize—with some fairly strong data—is that we can actually begin to select patients for EGFR inhibitors, at least for afatinib. And those patients appear to be ones that are HPV-negative, EGFR-amplified, or high gene copy—number, and who have an intact PI3-kinase pathway that isn’t constitutively activated by mutations or alterations. Hopefully, we can actually do this and test it prospectively in a way that finally validates these observations.

Another emerging therapy for a squamous cell carcinoma of the head and neck is a drug called palbociclib. It’s a multikinase inhibitor, but its primary targets are CDK4/6. Interestingly, we know that there is dysregulation of cyclins, cyclin-dependent kinins in head and neck. We know from The Cancer Genome Atlas (TCGA) that, for instance, cyclin D1 is amplified in about a third of patients with HPV-negative head and neck cancer. We also know that because of the way HPV infects a cell and expresses its genes, that HPV-positive cancers almost always have very high expression of p16. P16, of course, counteracts CDK4/6; it’s a CDK inhibitor. So, with all that in mind, with what we know about the biology, we begin to think about drugs like palbociclib as potential therapies for patients with HPV-negative squamous cell carcinoma of the head and neck. A group of patients are set up to activate this cell cycle machinery because of genomic level alterations—and who have low level p16 expression, again, because of mutations or epigenetic dysregulation of p16.

And, in fact, we saw some very interesting data at the 2016 multidisciplinary symposium on head and neck cancer in Scottsdale, Arizona, that looked at the combination of palbociclib and cetuximab. This was a phase I study, so it’s difficult to draw definitive conclusions other than the fact that the two drugs can be combined quite readily without excessive toxicity or dose-limiting toxicities. And both drugs were used at the recommended phase II dose with the expected toxicity that we already know for single agents. But what we saw was, in a group of patients that were heavily pretreated—and some patients even pretreated with cetuximab itself—a response rate of about 30%, with even a complete responder in the cohort. This suggests that the combination of palbociclib and cetuximab may be profoundly active in patients with HPV-negative disease, a group of patients who we know, unfortunately, don’t do very well.

With those data in mind, a phase III trial has been initiated combining palbociclib with cetuximab versus cetuximab alone in patients with platinum-refractory second-line recurrent metastatic head and neck cancer. That trial actually does allow for prior therapy with PD-1 or PD-L1 agents, and it’s exclusive to HPV-negative patients.

Jared Weiss, MD: It’s been so long since we’ve had really major advances in head and neck cancer. It’s a really, really exciting time to be here. We have cetuximab for immunoradiotherapy. We have cetuximab together with chemotherapy for palliative care. We now have the checkpoint inhibitors, with their favorable toxicity profile and possibility of durable control, and a plethora of new immuno-oncologic agents that will hopefully further revolutionize our field.

Ezra Cohen, MD: I can safely say that there’s a lot of excitement for head and neck cancer right now and for the future. That excitement stems from several areas of research and discovery that we made really in the last few years. First of all, around molecular profiling, we’ve begun to understand these cancers a lot better. We’ve begun to understand the molecular differences between HPV-positive and HPV-negative disease and some of the targets that may be actionable in both HPV-positive and HPV-negative. We’ve begun to discover novel therapies for these patients, mostly around EGFR targeting, but other targets that can be relevant in patients with head and neck cancer, both HPV-positive and HPV-negative, as well. And, most recently, we began to realize that immune therapy can be quite active in head and neck squamous cell carcinoma.

Right now, we have some preliminary data around a drug called pembrolizumab, a PD-1 blocker that appears to produce about a 20% to even 25% single-agent response rate much better than we’ve seen with any other single agent in this disease. Of course, there’s a lot of excitement about integrating that with not only standard of care, but other immunotherapies to further augment that response and further augment durable responses especially. So, head and neck cancer is a field now that I think is going to change markedly in the next few years. Fasten your seatbelts because there’s a lot or excitement, and we’re going to see a lot of differences that are all, I think, positive for patients in the very near term.

Transcript Edited for Clarity