Interview with Professors Fred and Zhou

Mechanisms of  PD-1/PD-L1 checkpoint treatment

Dr. Fred: Well， that is a very complicated process. What we are talking about here is that the cancer is recognized as a foreign body and， of course， the immune system will try to fight it. However， the cancer is very smart and the cancer will try to escape from the immune system through very， very complicated mechanisms. The T cell lymphocytes play a major role in the fight against cancer—the immune system fighting the cancer. And， of course， what we are leveraging on—in terms of immunotherapy today—is the connection between the receptors on the cancer cell and the connection to receptors on the T cells. PDL-1 is the receptor on the cancer cell. PD-1 is a receptor on the T lymphocyte. When they go together， as loving partners， that actually leads to a suppression of the T lymphocytes. That is not what we want. We want to stimulate the T lymphocyte and the immune system; we don’t want to suppress it. So， what the drugs do is actually to cut the connection between the T cell receptor and the receptor on the cancer cell. And if you do that， you cut the suppressor effect of the receptor and， instead， you stimulate the T cell lymphocyte. And that is what we want. And that is where the encouraging results have come so far.

Now， I have to say this is very simplified. And this is just one mechanism in a very complex system. There are a lot of other cells playing a role. There are a lot of other receptors playing a role. There are also what we call cytokines， which are in some senses at least in the immune process. So， we need to learn much more about those processes. But believe me， in the future， there will be drugs which target other mechanisms—not only the PD-L1 and PD-1， which we are currently talking about. So， in my opinion， we are only on the tip of the iceberg in terms of understanding and in terms of immunotherapy treatments. But， it is very， very encouraging what we have seen so far.

Dr. Zhou: Yes， I agree. The PD-1 and PD-L1 signaling pathways play an important role in the immune escape for the solid tumor. The binding of the PD-L1 to PD-1 will produce energy for the T cells. That means the T cells have lots of functions to kill the cancer cells. So， usually， PD-1 and PD-L1 inhibitors work in the solid tumor in the second line—maybe in the first line. Actually， immunocheckpoints—there are many right? PD-1 and PD-L1 are just one of them. We have LAG3， TIM-3. How about immunocheckpoints in the future for treatment of cancer?

Dr. Fred: And there are drugs already developed against other checkpoints， so we will see much more of those results in clinical studies in the years to come. That’s for sure.

Combinations of PD-1/PD-L1 and others

Dr. Zhou: Okay. So how about a combination of PD-1 inhibitors as immunocheckpoint inhibitors? It could increase the efficacy of immunotherapy in solid tumors.

Dr. Fred: Yes， I agree with you. Synergy between immunotherapy combinations—I think we are starting to learn something about it. We have clinical trials， also， with CTLA-4 inhibitors and PD-L1/PD-1 inhibitors and we will see other combinations. I will make a personal comment and that is that these days， the drug companies are lounging. Many， many， many combination studies—it can be combinations with other immunotherapies; it can be combinations between immunotherapy and chemotherapy; it can be combinations between immunotherapy and targeted therapy—in my personal opinion， a lot of large studies are lounged without sufficient scientific background.

 Dr. Fred: We don’t know exactly the science behind those combinations. Should those combinations be given concomitantly? Should they be given sequentially? We lack this type of information， in my opinion， and hopefully in the future， we will see some smaller studies which also can have a clear scientific approach—not only just a clinical efficacy approach.

Dr. Zhou: Yeah， I agree， you know because this area is very hard. The pharmaceutical industry could lose in this area. They just try to move to get a lead. That’s what they do， right?

Dr. Fred: And the safety profile could be an issue， particularly when you combine (Immune Oncology， IO) I-O with I-O. We know that this combination can give quite a serious toxicity. We might overcome that in the future with dose modifications and schedule modifications， but that is something we’ll need to work out.

Dr. Zhou: Right. And that’s why the combination IPI and nivolumab works in non-small cell cancer. At first， the combination is intolerable in most cases. Now we know that the dose of IPI is important in terms of toxicity. When we decrease the dose of IPI， that combination works in non-small cell lung cancer.

Dr. Zhou: I agree. We know that PD-1 expression is important. We also know that immunoscore is important. Now， we know some data about tumor mutation burden， neoantigen. We don’t know which biomarker is more important in predicting efficacy of immunotherapy. We need to study. Neoadjuvant immunotherapy is one of the best ways to solve such kinds of problems.

Dr. Fred: Well， in first line therapy， pembrolizumab is approved with PD-L1 with defined cut off. Nivolumab is not approved in first line therapy; it is approved for second line therapy. So， it depends on the clinical situation. In first line therapy， pembrolizumab is the answer. For second line therapy—particularly for those patients who have not received immunotherapy in first line—you have some choices. No， I would hope that we would better understand the predictive biomarkers， because I think that we can agree that these therapies are not cheap; they are expensive therapies， and at this stage， only a certain subgroup of patients will benefit from it (about 20 percent of the patients). So， I think， for many reasons—also financial reasons—it is important to find the right selection of patients for these therapies.

Dr. Zhou: Right， I understand. How about a combination of I-O and chemotherapy? We have the KEYNOTE-021 trial. G panel， right? Which was published in ASCO and also in ESMO. You know， the combination of pembro plus Alimta carbo produced significant improvement in the tumor response rate as well as in progression-free survival. You know， median progression-free survival is about 19 months. It’s unbelievable， you know.

Dr. Fred: Right. My comment to that is it is a randomized Phase II study， and there is a Phase III trial ongoing. We haven’t seen results from the Phase III trial.

Dr. Zhou: Maybe at the next ASCO.

Dr. Fred: It could be. So， I certainly hope these results will be validated in the Phase III setting. But， in my opinion， we need to see the Phase III data. And another thing， I would like to see all the PD-L1 studies as relates to outcomes. We haven’t seen that yet either.

Prediction of anti-PD-1 treatments

Dr Fred: One area where we have a focus， currently， in the US and in our institution is the neoadjuvant approach. And the neoadjuvant approach gives us an opportunity to study the scientific molecular background for treatment response， treatment assistance， and I think this knowledge will be very important in the future treatment planning.

Dr. Zhou: Yeah， right. So， we just talked about a neoadjuvant study of nivolumab in the adjuvant setting， right? So actually， in that study—a very small sample sized study in which about 22 patients were enrolled into the trial—were given neoadjuvant nivolumab. The cystic tumor response rate was about 22 percent—not so high. When we look at the pathological response， it’s quite good. Many， many patients developed a kind of tumor shrinkage， even major tumor swing-age. So， I think that maybe resisting graft earlier is not good enough for immunotherapy， right?

Dr. Fred: Right. And I agree with you. I think we need to look more into the definition of a “response.” To that end， I can tell you that the organization I represent， the ISOC， will be holding a workshop with the FDA in the beginning of 2018， where we will look into neoadjuvant therapies and we will discuss what will be the right trial designs， what will be the definition of responses. And I think we need to revisit the whole resist criteria—not only for immunotherapy， but also for targeted therapies， for TKIs.

Collaborations between CHN and US

Dr. Zhou:  So， in China， I’m leading a randomized Phase III trial comparing Chinese PD-1 inhibitor plus Alimta carbo versus Alimta carbo in the Chinese population. So， the study was studied a few months ago. About 60 patients were included in the study. We hope to get the results at the end of next year. This is the Chinese KEYNOTE trial.

Dr. Fred: Very exciting. Do you do PD-L1 studies as well?

Dr. Zhou: Yeah， we will， we will do that. We have two primary points: progression-free survival in the IT population and also， in the PD-L1-positive population.

Dr. Fred: Right. That is the beauty with international collaboration.

Dr. Zhou: We work together.

Dr. Fred: Dr. Zhou’s department and my laboratory is working closely together on many biomarker studies.

Dr. Zhou: Right， right.

Dr. Zhou: I’m happy to work with him. We have worked together for many years.

So， I asked you about tumor mutation burden. As we talked a few months ago， you know， the Chinese pharmaceutical industry asked to meet you to discuss the possibility of doing the trial—the TMB-driven study. Is it possible or not?

Dr. Fred: Yeah， I am a little bit skeptical about the tumor mutation burden as a predictive biomarker over a couple of reasons (which I mentioned in my presentation today). One is that there is no standardization of a tumor mutation burden. What should be the sequencing? What is the definition of a high tumor mutation burden? How many genes should be covered? There are several open questions around that. Secondly， we are using two more mutations as a generic term. I think we will learn more and more about differences between mutations. All mutations are not equal. Some are more immunogenic than others， so I think， we will need to learn more about that. So， that makes me a little bit skeptical with the use of tumor mutation burden as of right now.

Dr. Zhou: Okay， I agree. We will try to do a small sample size Phase II trial based upon the mutation burden. We use the target NGS panel and also WES—NGS as control.

Dr. Fred: There were interesting presentations at ESMO this year， where they looked into tumor mutation burdens based on plasma. And interesting data came out when they applied it to the OAK study with atezolizumab. So， I think， mutation burden as a predictive biomarker needs much more validation and much more standardization.

Dr. Zhou: I agree. In that study， they used Foundation Medicine to detect the TMB. You know， Foundation Medicine is just the panel test， not Hujilong. Sequencing， right?

Dr. Fred: But Foundation Medicine is one company. There are several other companies using different platforms， different definitions， and so on.

Dr. Zhou: Especially in China. We have over 200 NGS based companies. Each NGS uses a different platform. That’s our problem. We need standardization.

Dr. Fred: Yeah， I don’t know any around clinical trials—I would think there are collaborative clinical trials. As I mentioned before， Professor Zhou’s department and my laboratory are collaborating on biomarker development and biomarker validation. And that is a collaboration which has been very successful for many years. This type of collaboration is important. I think， both institutions bring a lot to the table and synergize.

Dr. Zhou: So， actually， the preface host—he gave us a lot of help. You know， he took two of my doctors to be trained at his lab. That’s very important. He gave us a lot of contributions， you know. So， I think in the near future， we can work together more in immunotherapy. Now， we have so many trials from the Western (US) pharmaceutical industry performed in China. Maybe in the near future， the Chinese pharmaceutical industry will do the chemical trials in the United States. They also need your help. That’s very important， right?