Fred Hirsch, MD, PhD: Roy, what kind of trials should we do in the future? What we see, today, is that the industry is throwing in large phase II trials and phase III trials with a large number of patients. Earlier in this program, we said that there is a lack of science behind those trial designs. But I personally think it is important, in the future, to conduct much smaller trials where we can try to figure out proof of principles and try to get some scientific rationale to build upon for further, larger trials. I think we see too many of those big, big trials out there today.

Roy Herbst, MD, PhD: Well, yes and no. I think that in the last year or two, they’re all coming back positive. I think there’s been a large push to identify areas of unmet needs in non—small cell lung cancer—the chemotherapy combinations which, intuitively, one wouldn’t have thought would be the way to go. But in the absence of these, other IO-IO (immune-oncology and immune-oncology) combinations are coming forward. They have looked good, and these have moved forward. But, you’re right, Fred. What’s happened is the bar is getting higher and higher. And in lung cancer, we’ve gone from no patients getting an IO in lung cancer in second-, third-, or fourth-line treatment, to almost everyone’s going to get an IO, frontline.

Then, we really have a much higher bar. Now we have to find activity in the second-line setting. And there, Fred, I think we are going to have, probably, smaller trials. We’re going to be looking at either the very primary refractory patients who are PD-L1 high and didn’t benefit from pembrolizumab. In fact, they grew. So, what’s going on there? And then, we’re also going to be looking at, maybe they need chemotherapy? And then, also, the patients who are PD-L1 low or PD-1 high who’ve had some activity and then progressed. I think we’re going to have to test these combinations in rational ways.

I agree with you. They all can’t go to phase III. I’d love to see some investigator-initiated trials—adaptive trials. At Yale, we have a trial for ipilimumab/nivolumab. You might say, “Why? That’s already in phase III.” But this is a trial where every patient gets a fresh biopsy at the beginning. We’re doing imaging for PD-L1. We’re looking at tissue. We’re looking at sequencing. We’re looking at RNA. We’re collecting stool. We’re doing microbiome work. We’re really casting a wide net. So, that’s going to be a reverse translation. We’ll have an existing regimen that’s gone to phase III.

And then, for some of the newer agents in the phase I setting, we have 1 trial, as an adaptive design, where we have 3 combinations in the frontline setting. We treat a certain number of patients and then move forward. I think these are challenging designs. They require extensive statistical work and a large number of biopsies. But we need to do some of those.

I also think that if something is looking reasonably promising, we should take a swing at it in the phase III setting. We have to have these drugs available for the patients. The quicker we can get drugs to the patients to benefit them, that’s the goal.

Fred Hirsch, MD, PhD: Absolutely.

Everett Vokes, MD: The MYSTIC trial was mentioned. Naiyer, can you just briefly describe what that is and tell us what the status is?

Naiyer Rizvi, MD: Sure. There’s a lot of interest to extrapolate the experience of ipilimumab and nivolumab to other tumor types beyond melanoma. Certainly, lung cancer is an area of interest. The initial trials with combining the PD-1 pathway with CTLA4 were encouraging. The ipilimumab/nivolumab combination or the durvalumab/tremelimumab combination are both in phase III trials to see if a combination or a dual PD-1 pathway and CTLA4 blockade can be more effective than chemotherapy in the first-line setting.

The initial look at the MYSTIC trial revealed that it did not meet its progression-free survival primary endpoint. The coprimary was overall survival. So, the trial is continuing to mature, and we will look into it in the future for an updated dataset. I think both CheckMate-227 and MYSTIC are highly anticipated trials that look at the potential for combination immunotherapy, and we’ll see.

Transcript Edited for Clarity