Transcript Details This is a transcript of a continuing medical education (CME) activity accessible on the ReachMD network. Additional media formats for the activity and full activity details (including sponsor and supporter, disclosures, and instructions for claiming credit) are available by visiting: https://reachmd.com/programs/cme/case-review-case-treatment-naive-patient-head-and-neckcancer/7879/ Released: 01/26/2016 Valid until: 01/26/2017 Time needed to complete: 15 Minutes ReachMD www.reachmd.com info@reachmd.com (866) 423-7849 A Case Review: Treatment-Naïve Patient with Head and Neck Cancer ANNOUNCER OPEN: Welcome to Project Oncology on ReachMD. This segment, entitled A Case Review: A Treatment-Naïve Patient with Head and Neck Cancer is provided by Prova Education. Joining us today at the University of Chicago Medicine is Dr. Tanguy Seiwert. Dr. Seiwert is Assistant Professor also at the University of Chicago, as well as the Associate Program Director for its Head and Neck Cancer Program. Joining Dr. Seiwert is Dr. Everett Vokes. Dr. Vokes is Physician-in-Chief, University of Chicago Medicine and Biological Sciences as well as the Department Chair. Prior to beginning the activity, please be sure to review the faculty and commercial support disclosure statements as well as the Learning Objectives. Or if you re listening to this as a podcast, go to this activity on ReachMD.com forward slash Project Oncology. 2018 ReachMD Page 1 of 7
And this now is a head and neck cancer case, Tanguy, that I want to ask you about. This is a 55-yearold woman. She smoked a little bit. She s a 1-pack smoker for 10 years and is clinically staged. She presents to her doctor with a sore throat, a very typical presentation, fairly short duration, and noticed a little bit of swelling on the neck. On examination, is found to have a left-sided tonsil cancer that has lymph nodes that are palpable, there are two very close together in the upper neck, that s level 2, and so she s staged as T1 N2b. She has fine needle aspirate and is diagnosed with a squamous cell cancer and it s HPV positive. So, otherwise healthy woman, no distant metastases, what would you do with her? Yes, this is a rather typical case presentation for a patient with an HPV-positive oropharynx tumor, so that would include the base of the tongue and the tonsil. It is remarkable that we ve seen a really dramatic increase in the incidence of these HPV-associated tumors, oropharyngeal tumors, and we really, some people call this the epidemic of HPV-associated head and neck tumors, and this is a very typical presentation in a patient who is a non or a light smoker, and presents with advanced nodal disease but a small primary, and that s somewhat different than what we are used to see with tobacco or substance-related head and neck tumors. The other thing that I think is really remarkable about these tumors is even though they present with advanced stage, so this would be a Stage IVA tumor; however, the prognosis tends to be much more favorable. It s much more in line with an early stage HPV-negative tumor. And so, what I would tell this patient is that while this is a local-reaching advanced tumor, it is highly, highly curable and very amenable to curative therapy. So, in her case after appropriate staging, as you mentioned, she doesn t have any distant disease, she just has the local regional disease, I would recommend her to get combined-modality treatment. Because she has the lymph nodes, this could be a combination of radiation and chemotherapy. Typically cisplatin would be the choice. By the FDA, or by approval, one could also consider a combination of radiation and cetuximab; however, that s based on a single trial, a single Phase III trial, and I think most experienced centers at this point say the body of evidence is much larger for use of chemotherapy for use of cisplatin and I think most people in a setting that s curative would probably choose a combination of cisplatin and radiation. Her chances of cure with that treatment are excellent; I would say 80 to maybe 90%; very good outcomes. I think the debate in the field right now that s ongoing is that we know that these patients are highly curable and do very, very well; however, we apply a treatment that was developed for HPV-negative tumors onto a different disease entity, or different biologic tumor that has a much more favorable prognosis. So, at this point, within the field, a lot of people are considering 2018 ReachMD Page 2 of 7
maybe we should give less treatment. Maybe we should decrease the dose of radiation, decrease the dose of chemotherapy. Maybe we should alter the treatment that, in these younger patients, that have many decades of life ahead of them, we can potentially decrease long-term toxicities. You know, that being said, it s a double-sided sword. We re talking about a curative-intent therapy and this is not something you would do without a clinical trial, but I think it s very much worthwhile to consider a clinical trial of what we call deescalation and there s a number of efforts that are ongoing. Some people will use induction chemotherapy, a concept that s otherwise controversial, as a predictor of those patients that do well, and then give less treatment for those patients. Some people will substitute cetuximab for cisplatin, some people will use less radiation, but I think it has to be done on a clinical trial. But she would be a really, really good candidate, given that this is a good-prognosis disease and she is a nonsmoker which is a risk factor. That s one thing I didn t mention. It seems like smoking, even though this is an HPV-driven tumor, smoking still has negative prognostic implications for patients. So if you have more than 10, some people say 20-pack years of smoking, it essentially worsens the prognosis, even of these better-prognosis HPV-positive cancers. I always jokingly say, HPV doesn t protect you from the negative effects of smoking, but keep that in mind that really we have to look at the risk factors. So, I think we treat her with curative intent, likely with chemoradiotherapy, and I think she would likely have a very good prognosis with that. So, let me just clarify a little bit. So, she did smoke a little bit, or a little bit more, so she has about a 10- year pack history, so with that the prognosis should still be very good? I think the prognosis is still very good, but the smoking would have a negative impact. She doesn t have the same prognosis as a patient who has a nonsmoking history or a less than 10-pack year. So, 10-pack years by the RTOG is considered a risk factor for somewhat worse outcome, and so that s one risk factor, although it doesn t go anywhere close to an HPV-negative cancer. So, on her second visit, her husband comes with her and they ve now read about HPV and he asks you is this contagious and is he at risk, and what would you say? Those are oftentimes very interesting and animated discussions because, obviously, HPV is a sexually transmitted disease, best as we know the transmission may be oral sex and there s a lot of data we 2018 ReachMD Page 3 of 7
extrapolate from cervical and other HPV-associated cancers, and so I think it s important to talk about this. The one thing that I always say is that the infection probably happened a long time ago. This could be 10, 20 years, and frankly we don t know the time point, but it may pre-date many other things and the virus probably lay dormant, just like what we know for cervical cancer, and that over time additional mutations accumulate in a patient who is not able to eradicate HPV. And so, the risk for partners generally is not higher when they present with head and neck cancer. For women, so if the situation was reversed, I would say that regular Pap smears are indicated and just regular preventative measures, but the studies right now indicate that for a partner the risk is not higher. The other thing that I think is important to point out is that HPV is very, very common. So, if you look at women age 50 or, about 70 or 80% have been exposed at some point to HPV and most patients are able to clear the HPV infection; however, there are some subtypes of HPV that are high risk and sometimes they are not cleared, and those are the ones that likely, over time, will become pre-cancer and then cancer. And for HPV-associated head and neck cancers, unlike cervical cancer, we actually don t know the precursor and that s an area of active ongoing investigation. Can we potentially screen for this? And then, maybe the last point about this is that I always mention in discussions of that is, if they have children, think about the HPV vaccine which potentially may have an impact on all HPV-associated tumors. Obviously it s approved for cervical cancer prevention but the impact on other HPV-associated cancer types is probably just as big or bigger, and so I think that s important to use that opportunity to educate that the HPV vaccine is safe and very, very effective, especially for HPV 16, but also now we have multivalent vaccine that probably prevents even more HPV-associated tumors. Yes. So the prognosis is very good. Cure rates are 80, 90% for this kind of a patient, but not all patients are cured, and what happened for this patient is that at about 2 years of followup, on routine surveillance screening, new lung metastases are found, they are multiple, they are fairly small, but there are several of them and a biopsy is done. It is confirming that it s a squamous cell tumor, it is HPV positive, and so most likely coming from the original tumor. So, what now? So, as you very appropriately pointed out, 80, 90% are cured; however, there is clearly a fraction of patients with these HPV-positive tumors that recur and that actually have a worse disease, and so we don t actually fully understand which patients those are, but smoking may be a factor, and so she is one of those diseases, one of those patients where the tumor did come back. And one thing that is true, though, is that even though this patient has now recurrent disease, or metastatic disease, HPV still influences the prognosis and still this patient has a better prognosis than a patient who would have an 2018 ReachMD Page 4 of 7
HPV-negative disease. The treatment, I would say in this case, is fairly similar to an HPV-negative tumor. I would treat this patient with doublet chemotherapy, potentially add cetuximab. We consider that the EXTREME regimen. In the United States this is usually done when a patient has a good performance status. If a patient doesn t have as good a performance status, you may consider just doing the doublet chemotherapy; typically a platinum agent plus either a taxane or 5-FU. In the classic EXTREME regimen it would be 5-FU, and then you could do sequentially cetuximab. So, if she s in good performance status and has no other comorbidities and is still feeling well, I would probably give her carboplatin/5-fu/cetuximab and I would pick carboplatin in this case. You could choose either cisplatin or carboplatin, but because there s a better tolerability in a palliative setting, I would probably pick carboplatin. So, I would give her a doublet plus cetuximab. Great. Yes, I agree with that. Do you think that in HPV-positive tumors the response to chemotherapy is different at all than it would be in a classic head and neck cancer, a smoking/alcohol-induced tumor, or is it the same drugs that work at about the same rate? So, it s a difficult question. I think we don t have complete data. It does appear that HPV tumors continue to be more sensitive to treatment and continue to have a better prognosis, as I alluded to. So, I think there s a higher chance of benefit, especially survival benefit, from treatment with chemotherapy; however, ultimately all these cancers will become resistant and eventually also she will fail. So, I think I would expect that she s more sensitive to the treatment but, in the end, even the HPV, the betterprognosis HPV-positive patients, will require a salvage treatment after that. So, you ve worked with immune-modulating drugs in head and neck cancer in particular. I know you ve reported activity for those. What s the current knowledge? Where would that come in? Is it HPVpositive, HPV-negative tumors? Can you comment a little on that? Yes. So, immunotherapy we have early data, not mature data, but it s actually a fairly large body of evidence now in head and neck cancer. We have about 200 patients treated with a PD-1 antibody, another 60 patients treated with a PD-L1 antibody with head and neck tumors, and those include both the HPV-positive and the HPV-negative patients. In addition, we also now have a small trial in nasopharynx tumors. Those were largely EBV-positive tumors. And it is actually, in my mind, a very 2018 ReachMD Page 5 of 7
positive signal or very encouraging signal, to see activity in head and neck tumors that s very much on par with what we have seen in lung cancer. We see response rates between 20 and 25%. There were data presented at ASCO 2015 reporting a 25% response rate in head and neck tumors in a 190-patient cohort. I would like to actually add to that that in addition to those 25, 1-in-4-patient response rate, there s also about a 25% response rate of stable disease and I believe that s actually meaningful. So unlike what we ve seen with chemotherapy or even targeted therapies, it seems like some patients benefit for long periods of time, and that s not only present for patients who respond, but also for some patients who have prolonged disease stabilization and stable disease. So, if you put that into context, cetuximab has a response rate of 10 to 13% as a single agent. These agents are twice as active based on response. In addition, there was an early and, again, I think you have to caution those data, look at survival. This was reported at the European Cancer Congress, and the median survival in a patient population that was heavily pre-treated, so a second, third-line treatment, using pembrolizumab, showed a median overall survival on the order of 10 months, even more, and that s on the order of what we see with EXTREME. So I think we have an encouraging response rate. We have long-term benefit in some patients, a fraction of patients, and then we have survival data that looks quite encouraging, very much in line with what we see in first-line treatment, and actually even in line with what we see, for example with nivolumab, in squamous lung cancer where we had a very striking hazard ratio of 0.6. So, I m very encouraged by these early data. At the same time, I think we have to wait for more definitive data. I think it s very appropriate to consider a clinical trial for second-line head and neck cancer patients given these very encouraging data. There s a Phase III study with nivolumab. There are two Phase III studies with pembrolizumab and, I believe, within the next year or two, we ll actually have more data, but I m very encouraged by this activity signal. The last thing I didn t comment about, is there a differential between HPV-positive and HPV-negative tumors? So, obviously, the HPV-negative tumors are very similar biologically to squamous lung cancers, so large number of mutations, smoking-associated phenotype. So that s clearly an active disease and very much mirrors lung cancer for lung squamous cell tumors. For the HPV-positive tumors we have viral antigens, and we actually don t know why they respond, but it seems like the activity level is about the same as what we see for HPV-negative tumors. So, right now, I would not differentiate using an immune therapy or enrolling them on a trial with an immunotherapy based on the HPV status. Great. And I take it that, in turn we talked a lot about these mutation-driven tumors in lung cancer, that in head and neck cancer we haven t made that impact yet. 2018 ReachMD Page 6 of 7
Yes. In fact, we know that the rate of mutations are high in head and neck tumors. They re actually very much comparable with lung tumors, and actually even in the HPV-positive tumors, there are high rates of mutations. So, in a preliminary analysis it was hard to correlate mutations with inflammation which may be an additional biomarker of benefit, but I think we need more definitive data. So I think we are a bit behind with respect to biomarker testing for head and neck cancer, but I do believe that probably the same principles will apply eventually. Great. So, thanks very much. Thank you, Everett. ANNOUNCER CLOSE: You have been listening to Project Oncology on ReachMD. To earn your CME credit, please take the post-test and activity evaluation. Or if you re listening to this as a podcast, go to ReachMD.com forward slash Project Oncology. 2018 ReachMD Page 7 of 7