Insights From: Ezra Cohen, MD, Moores Cancer Center; UC San Diego Health; Jared Weiss, MD, UNC Lineberger Comprehensive Cancer Center
Ezra Cohen, MD: There are, of course, other immunotherapies being looked at in squamous cell carcinoma of the head and neck. Now that we have the proof of principal that nivolumab and pembrolizumab clearly work, as you can imagine, there’s a lot of excitement to look at other immune agents. The first group of immune agents are the anti–PD-L1 antibodies that, in other cancers, have shown similar activity to anti–PD-1 and have garnered approval in lung cancer, bladder cancer, and some other cancers. Of course, as you might guess, they’re being evaluated in head and neck cancer.
For instance, durvalumab is being evaluated as a single agent and in combination with anti–CTLA-4 antibodies. Avelumab, again, is an anti–PD-L1 antibody, but is somewhat unique because it is an IgG [immunoglobulin G] -based antibody. In theory, it should also activate ADCC [antibody-dependent cell-mediated cytotoxicity], another arm of the immune system. It’s being evaluated in head and neck cancer. We will soon see data, as a single agent, in recurrent and metastatic patients. And, there is an ongoing phase III study looking at avelumab, in the context of chemotherapy radiation, compared to chemotherapy radiation alone. This is a 600-plus patient trial that’s being conducted internationally that is moving immunotherapy, now, into the locally advanced curative setting.
And, lastly, atezolizumab. Although it hasn’t been rigorously evaluated in squamous cell carcinoma of the head and neck, studies are beginning to look at other settings—the neoadjuvant setting, other settings in the locally-advanced disease space, and some settings in the adjuvant space. We will see several PD-1, PD-L1 antibodies in squamous cell carcinoma of the head and neck. It would not surprise me if a few of those, if not all of those, are eventually approved in different patient populations.
Jared Weiss, MD: There are many outstanding studies evaluating the role of immunotherapy in the first-line setting. As one example, the KESTREL trial randomized patients to single-agent immunotherapy with durvalumab; the combination of the PD-L1 inhibitor, durvalumab, with the CTLA-4 inhibitor, tremelimumab; or standard of care chemotherapy with the extreme regimen of platinum 5-FU and cetuximab. That effort has completed accrual in the United States, and is finishing accrual in the rest of the world now.
There are similar studies ongoing with other agents, including nivolumab, that will help answer these similar questions. Based on the data that we have in the second-line setting, it’s very promising for immunotherapy to replace chemotherapy in the frontline setting. But, we’re going to have to wait and see what the data actually show. There are dual rationale for combining PD-1 or PD-L1 inhibitors with CTLA-4. One is that these are both T-cell checkpoint inhibitors involved at different stages of T-cell activation. The other is that they’re both clinically available with extensive safety data, and that there have been favorable clinical results in melanoma.
Ezra Cohen, MD: The natural progression of immunotherapy is to go and build on what we’re seeing with the anti-PD-1 antibodies and to try to combine different immunotherapies. The first combinations that entered the clinic in a systematic way were with anti–CTLA-4—nivolumab and ipilimumab, and durvalumab and tremelimumab. The one with the most mature data is ipilimumab and nivolumab.
Although we don’t have data in squamous cell carcinoma of the head and neck, we do have very promising data in non–small cell lung cancer, renal cell carcinoma, and, earlier than that, in melanoma, suggesting that the combination can increase response rates substantially, with the caveat that it does also appear to increase the adverse event profile—going from about 10% grade 3/4 with anti–PD-1 alone, to as high as 50%. As we’ve learned to use these drugs together, that grade 3 adverse event rate has dropped to about the upper 20% to 30% range. Still, this is clearly higher than with anti–PD-1 alone.
Another interesting combination is lirilumab and anti–PD-1, in this case nivolumab. We saw some very exciting data at last year’s SITC meeting with that combination in squamous cell carcinoma of the head and neck. Specifically, we saw a response rate that appeared to be higher than with nivolumab alone. In fact, it appeared to be about double what nivolumab did in the CheckMate-141 trial—around 25%. Interestingly, most of the responses were in patients with PD-L1-positive disease, suggesting that we may be able to enhance the response rate in patients who have a preexisting propensity to respond.
Lirilumab is an anti-KIR antibody, so it affects another part of the immune system, namely NK cells. But, that may also have an effect on T-regulatory cells. So, this idea of combining different mechanisms of the immune system to enhance a response appears to be playing out in some very real ways.
When we think about squamous cell carcinoma of the head and neck, we have to begin to consider not only patients with recurrent metastatic disease, but how we are going to treat the majority of patients that we see—and those are the ones that present with locally advanced disease. Those are patients who we will attempt to cure, in many cases. This is a curative setting. There is a widely held hypothesis that immunotherapy would be able to impact those patients to the same degree or, perhaps, even to a greater degree than patients with recurrent or metastatic disease.
In that context, we now have phase III studies looking at immunotherapy in the context of chemotherapy radiation. One of those trials, the KEYNOTE-412 trial, compares standard chemotherapy radiation, cisplatin radiation, to pembrolizumab added to standard chemotherapy radiation. We now have phase II data, presented at the American Society of Clinical Oncology Annual Meeting, demonstrating that the addition of pembrolizumab to cisplatin radiation is safe. It does not appear to impact the availability to deliver curative intent therapy. And, of course, the phase III trial is now attempting to improve survival in high-risk patients being treated with curative intent with locally advanced head and neck cancer.
Jared Weiss, MD: Head and neck cancer, in general, is a little different than some of the other cancers that we discuss on OncLive in the sense that the average patient is locally advanced and treated for cure. That’s very important in any discussion of head and neck cancer.
The current paradigm for the treatment of these patients is typically the combination of cisplatin with high-dose radiotherapy, or cetuximab with high-dose radiotherapy. There are many attempts to integrate the immunotherapy agents into attempts at cure. We can start, chronologically, in terms of a patient’s path. Chronologically, the first place that these are being studied is in combination with chemotherapy—neoadjuvant therapy or, as we call it in head and neck cancer, induction therapy. We are looking at using PD-1 inhibitors, either alone or in combination with chemotherapy, prior to whatever is used to try to cure those patients. And multiple studies are ongoing, or planned.
The next phase is to combine these agents with radiation. There are 2 ways to do this. You can combine them with radiation alone. An example of that might be my LCCC 1509 study that combines pembrolizumab with radiation. Alternatively, you could try to graft these agents on to existing paradigms. We will see safety data on the combination of platinum-based therapy and radiation, a standard therapy right now, plus the addition of a PD-1 agent. There are similar studies being done with cetuximab radiation and the PD-1 agents. And we’ll have to see what all of these data show, both for safety and for efficacy. All that we know, so far, is that the combination of platinum-radiation and PD-1 is at least safe.
The final way to study these agents is adjuvant therapy. There is a study planned. I believe it started already. The study looks at using pembrolizumab in the adjuvant setting. Which of these will be the right way to go? We have a long time until we’re going to be able to answer that, but I think they all merit study. They’re all appropriate, promising studies that I would put a loved one on if they were unfortunate enough to be in this situation. We’ll just have to wait to see which looks best.