Benjamin P. Levy, MD: Let’s talk about some of the data, Dr Salgia, that came out of ESMO [European Society for Medical Oncology Congress]. Although maybe not as promising of activity from the trials that Dr. Leal went over, but let’s get your take on the ESMO presentations.

Ravi Salgia, MD, PhD: Thanks, Dr Levy. Beautifully summarized, Dr Leal and Dr. Naidoo. I enjoyed that discussion. There were 2 abstracts that were presented. One was by Dr. Marie Wislez, and this was the IFCT-1601 IONESCO study looking at durvalumab. This was given on days 1, 15, and 29, and it was relatively very well tolerated. The partial response rate was 8.7%, with a major pathologic response [MPR] rate of 18.6%. There were about 46 eligible patients, but the issue was it was stopped early. The trial was stopped early because 9% had observed deaths. This was most likely related to not the immune checkpoint inhibition but comorbid disease, and that’s what the author stated.

The second study, PRINCEPS, was presented by Dr Benjamin Besse and colleagues. This study looked at using atezolizumab. Only 1 dose was given, and then surgical resection was 4 weeks later. That’s an important end point. They looked at 30 patients. Four of 30 patients had MPR. That was 14%.

This summarizes that for these 2 abstracts that were presented, I don’t negate what’s been done in the past, but we always tend to come back, with the pendulum coming back to normalcy. The initial trials may show a great response rate, but this one is showing major pathologic response. But these ones, not necessarily. I agree with all of you that it may be about not just using an immune checkpoint inhibition strategy by itself, but is it a combination? Let’s say nivolumab with ipilimumab gives you better outcomes, or is it chemotherapy plus immunotherapy?

My only editorial comment here is that we have to be cautious. We have seen patients who have gotten immune checkpoint inhibition or chemotherapy combinations and have had hyperprogression. We have to really consider whether we should do next-generation sequencing on those patients up front to see if there’s a negative predictor, like STK11 or MDM2 or something else, that will help us prevent that. It would be a terrible shame, even if 1 patient had hyperprogression in our clinical trials or in our clinical experience. That would really negate a lot of things. I do think we need some predictive values as well.

Benjamin P. Levy, MD: Yeah, I think you’re right. Understanding the underpinnings of the tumor as well as trying to understand end points for these trials and harmonization of end points is going to be important. I’ve kept a tally in my head as everyone has gone over all this data. My head is spinning. Dr Patrick Forde’s data are around a 40% to 45% major pathologic response. The other single-agent immunotherapy neoadjuvant trials elicit a major pathologic response rate somewhere between 15% and 20%. From the NEOSTAR data, it looks like dual-checkpoint blockade elicits a major pathologic response, around 18% to 20%; maybe a little bit higher—30%. And with chemotherapy and I/O [immuno-oncology] as neoadjuvant therapy, we have a pathologic complete response of close to 60%.

Dr Zhang, you’ve been quiet, but I know you’re taking notes. I see you’re ready to distill all the confusion and simplify this. What is your take on all these trials? What do you think about them? How do we put this all together?

Jun Zhang, MD, PhD: These are really good summaries. I have learned a lot from everyone’s comments. My take-home message is that we’re seeing a similar trend like what we’ve seen in the metastatic setting. Single-agent immunotherapy has some response but is pretty limited. When we combine that with chemotherapy, the response is higher, especially when we use the major pathologic response. When we combine with another I/O therapy, I/O plus I/O, it seems like the response is higher as well. I would say that if we’re really serious about considering this in the neoadjuvant setting, if we are going to use MPR as 1 of the end points, then the combination of I/O plus chemotherapy might be something that I would favor.

Having said this, what we also know from the NADIM trial is that when we combine chemotherapy and immunotherapy, we have a higher incidence of grade 3 and 4 toxicities. Whether those things would really delay surgery in the real world is another question.

Another point Dr Salgia mentioned is that we actually need to know the molecular profile of those cancer cells as well. For example, if a patient has an MDM2/MDM4 application, EGFR application or mutations, there’s a chance of hyperprogression. In clinical trials this would be rare, but we cannot really afford for any patient in our lives to get to hyperprogression. Certainly, these are things that need to be investigated as well.

Benjamin P. Levy, MD: Yeah, it’s getting exciting and complex at the same time.

Transcript Edited for Clarity