Transcript:Ezra Cohen, MD: Tanguy, you’re intimately familiar with KEYNOTE-012, of course, being the first author on the manuscript. Tell us very briefly what the primary data points were.

Tanguy Y. Seiwert, MD: KEYNOTE-012 was an expansion cohort in head and neck cancer. KEYNOTE-012 also had other cohorts and other diseases, but the head and neck cohort is obviously what we’ll focus on. So, there were 192 patients that were treated with 2 doses of pembrolizumab. In the end, the largest group was dosed at 200 mg flat every 3 weeks, and that’s actually the dose that was approved. There’s always some debate. But in the end, it’s all about saturating the receptor, and 200 mg flat is likely the dose that we’ll see across the board everywhere. And even for the other agents, flat dosing is actually becoming the standard.

Getting back to KEYNOTE-012: we saw a response rate of about 16% to 18%, depending on which cohort you look at. But more importantly, some of those patients had prolonged benefits. In addition to patients who had responses, and durable responses, patients were actually living far beyond what we expect usually for metastatic disease. We now have a number of patients who have actually completed 2 years of treatment, and the median life expectancy is probably 6 months on a population like this. So, it’s remarkable benefit. In addition to those patients with responses, we also see it with prolonged stable disease. That’s likely why these agents have an effect on overall survival. So, that’s the first point. They are active. They are active in both HPV-positive and in HPV-negative patients, and those patients do remarkably well.

The other thing that was apparent right away was that these are quite tolerable agents. Most patients have very few or no side effects—skin itching, rash, hypothyroidism. And, generally, these are agents that are very well tolerated. So, if you have a patient who just comes off chemotherapy and they have hair loss, weight loss, and are not feeling well, when they go on an immunotherapy such as pembrolizumab or PD-1 inhibition, they oftentimes feel better right away because they’re no longer on chemotherapy. In addition, these drugs actually seem to really have an impact on overall survival. We saw that on CheckMate-141, and that’s likely why these agents are such a big advance—because they’re overall survival drugs.

So, in general, it’s a very favorable toxicity profile. The one thing I would like to point out, though, is that there are severe side effects, but they are rare. The one that I would like to mention is pneumonitis. It only occurs in about 1% to 2% of patients; however, you have to screen for that because it’s a life-threatening complication. Most patients do very well, but we have to be vigilant for these rare yet potentially severe side effects. And they can be treated with high-dose steroids, like 2 mg of Solu-Medrol a day, but you have to treat quickly and right away if somebody says, “I am short of breath” or “I have a little bit of a cough.” I like to scan them right to look for that and screen for side effects.

Ezra Cohen, MD: Absolutely. We’re talking about low single-digit percentage points of these toxicities occurring, especially the pneumonitis. But we have to be aware of it and be vigilant about treating it. The other toxicity that I pay attention to, especially in head and neck cancer patients, is hypothyroidism, which does happen a little bit more, interestingly enough, in the head and neck cancer population than in other diseases where these agents had been tried. But again, it’s the idea of looking for it so that you can manage it and intervene.

So, I totally agree with you, Tanguy. I think we’re excited by the fact that there are responses, and in some of those patients, those responses are incredibly durable. The pembrolizumab data, of course, were uncontrolled, as both you and Viktor discussed. We do have control data for a PD-1 blocker in squamous cell carcinoma of the head and neck, and that’s, of course, from CheckMate-141. Kevin, I know you were very involved in that trial. Tell us a little bit about what Checkpoint-141 was, what it means to us, and what it’s going to be for the field.

Kevin Harrington, MD, PhD: I think it’s a very important trial, but, of course, I was involved in it, so I would say that, wouldn’t I? So, CheckMate-141 was a randomized phase III study in 361 patients with relapsed or metastatic squamous cell carcinoma of the head and neck. Patients were eligible for entry if they had progressed on, or within 6 months of, prior platinum therapies. The group of patients who progressed shortly after chemoradiation were also eligible for this study. Patients were randomized in a 2:1 fashion between intravenous nivolumab, given every 2 weeks at a dose of 3 mg/kg, and investigated-choice chemotherapy—methotrexate, docetaxel, or cetuximab—given on a weekly basis intravenously according to standard schedules. The primary endpoint of the study was overall survival, but other secondary endpoints were analyzed.

In terms of the overall survival, it met its primary endpoint. Indeed, the data monitoring committee closed the study early because it had crossed the statistically significant boundary predefined in the statistical analysis plan. The survival benefit at overall survival at the median was 7.5 months versus 5.1 months. And at the landmark analysis at 1 year, 36% of patients receiving nivolumab remained alive compared with about 17% on investigated-choice chemotherapy.

In addition—and I think this is a strength of the study—there was a very detailed analysis of patient-reported outcomes in that study using 3 well-validated questionnaires, including the EORTC QLQ-C30, the H&N35, which is a head and neck cancer—specific questionnaire, and a more generic questionnaire, the EQ-5D. And what all 3 of those questionnaires showed systematically across almost all of the domains was that nivolumab was able to maintain patients’ reported outcomes in terms of their quality of life, their functioning, and their symptom scores. And the patients treated with investigated-choice chemotherapy had serious detriment in those scores, as measured at 9 and 15 weeks, indicating deterioration in both function and in terms of symptoms. So, not only do we have clear evidence that these drugs can work in terms of improving survival and delivering meaningful responses, but they do so with fewer episodes of treatment-related toxicity and also disease-associated morbidity. I think that really represents a significant body of evidence in this field.

Transcript Edited for Clarity