Immunotherapy in Novel Settings

Transcript:Mark A. Socinski, MD: I want to ask Howard in a second for his thoughts about the combination of anti-CTLA-4, anti-PD-1, and the PD-L1 approach. But we’ve certainly seen the nivolumab/ipilimumab combination, and the durvalumab/tremelimumab combination. Some of that data look very promising. Many thoughts are around maybe this in the PD-L1-negative population, maybe that’s an area where combination therapy would enhance the effect of immunotherapy. Certainly, that’s being addressed. I’ll come back to you to talk about the combination trials, MYSTIC, NEPTUNE, and that sort of thing, but tell us a little bit about your thoughts about the combination therapies.

Howard L. Kaufman, MD: No question that that’s a way to go. So, certainly there’s animal data to suggest that if you add these checkpoint inhibitors together, you see additive response. And, in fact, Jim Allison has some very nice data that show that if you block CTLA-4, PD-1, and PD-L1, you continue to get an added effect. I think that the future is actually not thinking about two-drug combinations but really getting into three- and maybe even four-drug combinations. And certainly in melanoma, I think the approval of the ipilimumab and nivolumab really points the way where we can go. I think there will be unique toxicity concerns because we’re also going to probably add to the incidence of toxicity with these additions. And so that may be a rate-limiting step. That may be manageable in some cancers, it may be more problematic in others.

Mark A. Socinski, MD: I think in MYSTIC, the three-arm trial, it’s looking at durvalumab alone versus the durvalumab/tremelimumab combination versus standard of care. And then in NEPTUNE, the combination versus standard of care. It will get some component contributions in these trials. That data probably are a year or so away from knowing that. Your thoughts on those trials?

John V. Heymach, MD, PhD: Right. So, here we’re learning from our colleagues in melanoma, we’re just following right behind them. It’s been profitable to do so in terms of the benefit the patients are getting. Howard pointed out that preclinical data from Jim Allison and others saying this combination looks like it may be really much more effective. They may work a little differently. Often T-cells have trouble getting into the tumor and this is where CTLA-4 may be better for mobilizing these T-cells earlier in their development. And then adding PD-1 may help their ability to recognize the tumor. But, in lung cancer—like in melanoma—the combination looks more effective. So, MEDI4736, or durvalumab, in combination with tremelimumab is clearly an active regimen. Nivolumab plus ipilimumab—and there are data from Matt Hellman and Naiyer Rizvi that’s been presented about this—is clearly an active regimen, more active than monotherapy. And the exciting parts are it looks like it may be active in the PD-L1-negatives as well as the positives. It’s very exciting.

But there is a price you pay, and the price is clearly much more toxicity. And for lung cancer patients, this may turn out to be more of a challenge than in melanoma patients in terms of comorbidities, possibility of lung toxicity. So far it’s manageable, but when we start thinking about the radiation trials it’s going to be more challenging. The trial you mentioned, the MYSTIC study, compares nivolumab and tremelimumab—the CTLA-4 and the PD-L1 blockade versus just durvalumab alone, so the PD-L1 blockade versus chemotherapy. And the second trial just compares the doublet (durvalumab and tremelimumab) versus chemotherapy, and I think the combination of those two will help us understand if we should we move up immunotherapy from second-line to first-line treatment. To me, there’s almost no question that sooner or later immunotherapy is going to move into the first-line setting, and these are two very promising combinations to do it; as the other studies show. The job of the lung cancer field is to figure out how to use immunotherapy in all these different settings, stage III disease, early stage disease, and so forth.

Mark A. Socinski, MD: I think we’ll probably see in the next 6 months the readout of CheckMate-026, which is a first-line trial in PD-L1—positive patients. I can’t remember the name of the KEYNOTE trial that’s in first-line. But I think you’re right, there are going to be a subset of patients that are going to do better than they would with carboplatin/Taxol in that setting.

So, John, in lung cancer, chemotherapy has been the mainstay of treatment, and we know immunotherapy doesn’t benefit all the patients. There are two things that are being studied right now, the immunotherapy combinations as well as the addition of an immunotherapy agent, whether it be a PD-1 or PD-L1 inhibitor, to chemotherapy. In fact, there are some studies looking at combining the PD-1, CTLA-4 with chemotherapy; so these combination things. What are your thoughts about that? How are you going to make decisions if the combination studies are positive and the add-on chemotherapy trials are positive? How do you choose?

John V. Heymach, MD, PhD: Well, there’s a lot we have to learn about this so we really don’t have the answer yet. But if you think about it theoretically to start with, it’s unclear how chemotherapy and immunotherapy would combine because, of course, chemotherapy can be immunosuppressive on one hand. So, if you give chemotherapy with immunotherapy at the same time, they may be fighting against each other. You may lose the benefits of immunotherapy. On the other hand, there is some chemotherapy that selectively kills certain types of immune cells. For example, there’s some data suggesting that gemcitabine might kill myeloid-derived suppressor cells, and that might be beneficial.

There’s a question of which chemotherapy would you combine? Are some better than others? And then, do you give them all at the same time or do you give the chemotherapy first and the immunotherapy afterwards? So, there’s a lot of different ways you can think about combining them, and we don’t know the best way yet. The good news is we’ll have the answers to this because there’s a lot of trials going on. There’s trials, for example, with nivolumab after chemotherapy as maintenance therapy in different combinations or nivolumab with chemotherapy. There are similar studies with atezolizumab with maintenance therapy afterwards with or without bevacizumab. There’s combinations with durvalumab and chemotherapy combinations as well. So, there’s a good number of well-developed, well-designed studies that will address this completely.

Now, a separate interesting question is let’s say chemotherapy plus immunotherapy is better than chemotherapy alone, and I believe it will be. And let’s say immunotherapy plus immunotherapy drugs work very well. So, we already have clear hints that nivolumab plus ipilimumab or durvalumab plus tremelimumab will be better than the individual agents by themselves. Which would you pick first? The way I would frame this to my lung cancer patients, I usually try to take the approach of taking the most effective and best-tolerated thing first. Use your best shot first, because as our therapies are getting better and better, there may be even better things coming along. And I always hate the possibility that may occur, that you take your less good drug first and patients never make it to second-line therapy. And from our big studies of maintenance therapy, we know that even though we all are trying to be conscientious doctors, one-third of patients or more may never make it to second-line therapy because of an infection, or a blood clot, or whatever therapy. So, you’d hate to use the best-tolerated therapy on the table and never give it to them. I think the data will tell us how to combine chemotherapy and immunotherapy, but if immunotherapy combinations turn out to be comparable, or more effective, and better tolerated, I personally would start with them.

Mark A. Socinski, MD: Let me ask you this. One of the areas that I think is quite exciting with regard to these agents is the role that they may play in the chemoradiotherapy or radiotherapy field. One of the trials in lung cancer that I’m most interested in is the PACIFIC trial, which gives durvalumab, a PD-L1 inhibitor, following concurrent chemoradiotherapy. This is where we really haven’t moved the bar in well over a decade in terms of our standard of care. Your thoughts on that?

John V. Heymach, MD, PhD: I think this actually is one of the settings where we may really see a dramatic increase in cures, and real cures is what we’re going after. For people who don’t treat lung cancer regularly, these are usually our stage III patients. It means they’ve got lymph nodes in the center of their chest that are involved but it hasn’t spread outside the chest. And chemoradiation is very effective in inducing an initial response, but at 5 years only 10% of those patients are typically still alive with our typical chemotherapy and radiation. So, part of the reason I think immunotherapy is so promising here is you’ve got their tumor bulk down to a minimum, but inevitably it is coming back. You can imagine, it might be appealing to put immunotherapy afterwards—first of all because when you get that tumor bulk down, the immune system may be better able to control it. And secondly, radiation may stimulate the immune response, either by killing cancer cells and releasing antigens, possibly by inducing cytokines that may be supportive.

But, if you give radiation and immunotherapy at the same time, you may also be killing T-cells, so radiation itself is a double-edged sword. It can suppress the immune system. So, in the PACIFIC study, they’re giving chemoradiation—that would be the standard for stage III patients—and then randomizing patients to either durvalumab or placebo. Should we give maintenance after chemoradiotherapy? I think it’s a wonderful question. It’s a well-designed study, and I’m optimistic about it. We and others are also studying if we should give the immunotherapy during radiation. That’s an interesting thing that’s going on as well, whether you get more enhancement or not. You may suppress the immune system and the jury is out. So, now it’s time for us to work through the details. How do we do it optimally? But to me, there’s no question the immunotherapy sooner or later should be playing a role in earlier stage disease and moving up more and more toward frontline therapy.

Mark A. Socinski, MD: And there’s even an adjuvant trial with durvalumab being planned in the Canadian Cooperative Group.

John V. Heymach, MD, PhD: That’s correct.

Mark A. Socinski, MD: Howard, in melanoma, what’s the role combinations play, immunotherapy combinations?

Howard L. Kaufman, MD: I think they’re quickly becoming the mainstay of treatment. I think the ipilimumab/nivolumab combination is considered the first-line therapy for many patients if they can tolerate the treatment. And the other thing I would say in melanoma is we’ve already conducted several trials in the adjuvant setting. So, we are moving both ipilimumab/nivolumab and pembrolizumab in the adjuvant setting. And I think it’s going to be very interesting to see the outcome of that. We’re going to have to wait a few years to see what happens, and then that may change our approach in the metastatic setting if these patients are getting these agents earlier on. That’s going to be something to keep an eye on.

Transcript Edited for Clarity