Expert Discusses 2-Year Nivolumab Data and Other Immunotherapy Developments in NSCLC

Hossein Borghaei, DO

In a 2-year follow-up of the phase III CheckMate-057 and -017 trials, second-line treatment with nivolumab (Opdivo) was found to significantly improve overall survival (OS) versus docetaxel in both patients with nonsquamous and squamous non—small cell lung cancer (NSCLC).

Results of the follow-up, which were presented at the 2016 ASCO Annual Meeting, confirm that the immunotherapy agent is superior to chemotherapy in this patient population, explains lead study author Hossein Borghaei, DO.

In the CheckMate-057 trial, which looked at the combination in patients with nonsquamous NSCLC, the 2-year OS rate was 29% with nivolumab versus 16% with docetaxel. In the CheckMate-017 study, the 2-year OS rate for squamous patients was 23% in the nivolumab arm compared with 8% in the docetaxel group.

OncLive: Can you give an overview of the updated CheckMate-057/-017 results you presented at the 2016 ASCO Annual Meeting?

In an interview with OncLive, Borghaei, chief of Thoracic Oncology, director of Lung Cancer Risk Assessment, associate professor in the Department of Hematology/Oncology, Fox Chase Cancer Center, discusses the significance of the 2-year follow-up results, the evolving role of PD-L1 as a biomarker and others that are in development, and emerging immunotherapy agents in the field of NSCLC.Borghaei: This is a 2-year update of the results of 2 separate phase III studies that have already been published in The New England Journal of Medicine. The CheckMate-017 study was done in patients with squamous NSCLC in the second-line setting, and the CheckMate-057 study was for patients with nonsquamous NSCLC. We clearly showed that nivolumab was superior to docetaxel when it comes to overall survival.

What we have at the 2016 ASCO Annual Meeting is a poster presentation where we showed 2-year survival data for patients with squamous and nonsquamous NSCLC. It showed that survival is still superior in favor of nivolumab. This gives us confirmation that the drug is active and that patients do truly benefit from immunotherapy.

We fully acknowledge that this is not for every patient—clearly, unfortunately—but we are hoping that we can learn more and expand the patient population that can benefit from this drug. As far as 2-year survival goes with a monotherapy in the second-line setting, for a very difficult patient population and disease, we think the data are very exciting and very much confirmatory in favor of nivolumab.

What do we know about patients who are appropriate to receive nivolumab? What kind of criteria do they need to have?

We are also presenting a unique set of cytokine data as part of this abstract. The cytokine data doesn’t necessarily indicate to us which patients will benefit from nivolumab; however, the data does point to a specific population that seemed to do better in general—in patients that have a high expression of cytokines versus those who don’t have much of a cytokine expression. That requires more research, and we’re hoping we can test it in a more prospective manner.That’s a fair question, and it’s not necessarily easy to answer. As far as nivolumab is considered, we don’t really have a good biomarker selection, so to speak, because the study was done in all comers. In a retrospective manner, we have PD-L1 expression and the data that has come out suggest that in patients who have higher expression of PD-L1, they will benefit more from nivolumab therapy.

However, it also appears that at least a certain number of patients who don’t have a specific biomarker or PD-L1 expression still draw some benefit from nivolumab. As it stands, the population that I think benefit the most from this immunotherapy are patients who have gone through frontline chemotherapy, who have progression of disease, who still have a good performance status, who don’t have any evidence of autoimmunity, and have more of a smoking history. That is not something that has been proven, but we do see the data in multiple clinical trials.

Do you consider PD-L1 to be an appropriate biomarker?

One point that should be emphasized is that I don’t think patients who have an EGFR mutation or an ALK rearrangement are benefiting as much on nivolumab yet, so we need more research in that particular area. This is my personal opinion, and there are arguments on both sides on whether it should be used or not.This is also a very difficult question and kind of an emotional question. I don’t think it is an appropriate marker; I honestly don’t think it’s a good marker. First of all, we are having difficulties because almost every company that’s developing a checkpoint inhibitor has their own specific way of testing the antibody. I believe there is an effort to unify the testing, which I think should be supported because that is exactly what we need.

We now have nivolumab and pembrolizumab (Keytruda) in this space. How do you choose between the 2 for a patient with NSCLC?

At this point, I would say it is an inadequate marker; however, the totality of data out there seem to suggest that if patients have a higher expression of PD-L1, then the responses are better and maybe the survival can be better. On the other end of the spectrum, there are clearly patients who don’t have as much of an expression but are still drawing some clinical benefit. Again, in a disease where the options are limited, you hate to eliminate a patient population based on a marker that’s inadequately studied or that might not be necessarily predictive of everything we expected in oncology to do. It’s a hot topic.There really aren’t any strict clinical criteria. First of all, physicians seem to use the drugs they have the most familiarity with. I work a lot with nivolumab; I feel comfortable managing its side effects, so I have a tendency to use nivolumab a little bit more.

However, there are things to consider in looking at the pembrolizumab data and the amount of responses you could get in patients with high PD-L1 expression. If I see a patient who has a large disease burden, or needs something that works quickly or works really well, I will gravitate toward using pembrolizumab because the data is there.

At the same time, we are beginning to get the same data for nivolumab. Patient preference matters a lot because the dosing schedule is different. If I have a patient who is driving 3 hours to be treated with immunotherapy, I might choose pembrolizumab because receiving the treatment once every 3 weeks is a little bit easier. I have patients who travel quite a distance; therefore, considering the preferences and what is easier for patients has a lot to do with what you choose.

What advice can you give to community oncologists about treating patients with these agents?

From a clinical efficacy, I honestly believe both drugs are highly active. They are very good drugs, and the side effect profile appears to be pretty much the same. I don’t have a favorite, so to speak. It’s a comfort level on what is good for the patient and how often they have to come for treatment.For immuno-oncology, the most important take-home message is that these drugs are extremely active and they’re well tolerated. That’s a huge issue. You don’t want to use a drug that causes a lot of side effects; you don’t want the treatment to be worse than the disease. Both of these drugs are available in the market in the second-line setting.

I would encourage oncologists to get familiar with these drugs because they are here to stay; I don’t think they are going to go anywhere. To some extent, they have to get over the fear of using immunotherapy because the side effect profile is a little bit different. All of us have to learn how to manage the side effects of these drugs and it is really not all that difficult.

You do have to monitor the patients a little bit carefully, because if they do have a side effect, you want to catch it early and manage it appropriately. Every time we have a new class of drugs, such as these immunotherapies, there is a certain hesitance to use it.

What other agents would you like to see studied in combination with these agents?

I would remind community oncologists that nivolumab has been approved and available for melanoma treatment for a long time, and it is better tolerated than ipilimumab (Yervoy). Getting to know them and use them for the appropriate patients are a good idea because, with the way the field is moving, we are going to see more and more immunotherapy agents and different [combinations] being studied, so the more familiar you are with these agents at an early stage, the easier you can manage your patients.There is actually a 2-page table of drugs of which are being studied right now. We are going beyond just nivolumab or pembrolizumab plus ipilimumab combinations. There are some really novel compounds, such as OX40 and 4-1BB antibodies. These are all immune regulators that are being investigated and are compounds that we have known about for awhile. Now that we have these drugs, we know how to manipulate the immune system a little bit better.

How do you see the role of chemotherapy evolving in this field?

This goes way beyond chemotherapy combinations. I am talking really novel immune combinations that are being investigated in these diseases that we will see more of. I suspect to see some clinical data at the 2017 ASCO Annual Meeting for some of these ongoing trials.A lot depends on some of the studies that are ongoing. We are waiting for the results of the frontline immunotherapy drugs; that is going to be in patients who have the highest level of PD-L1 expression. The expectation is that the drug is going to be active, but we obviously do not know. We have to wait and see.

I suspect that, if those studies are positive, we are going to treat these patients with immunotherapy. The rest of the patients, at this point, are going to get a combination of chemotherapy and immunotherapy.

I don’t think chemotherapy is going to go away quickly in the world of lung cancer. We still rely on it. Interestingly, we are beginning to look at different dosing schedules of chemotherapy as a potential immune enhancer. This means that you could actually bring out changes in the tumor microenvironment that would make the tumor more responsive to immunotherapy. That’s an interesting area.

Chemotherapy is not going to completely go away anytime soon, but I can tell you that, in my clinic, there are patients with a diagnosis of metastatic NSCLC who are going on 2 or 3 years and have not seen a cytotoxic chemotherapy yet.

The possibility is that we are going to move chemotherapy down the line so, all of a sudden, the platinum doublet might be a second-line therapy for an appropriate patient. That’s the direction we are heading, but I don’t think we are completely done with chemotherapy. I’ve got to tell you, I am all in favor of not having chemotherapy—as long as we can have effective treatments.

Borghaei H, Brahmer JR, Horn L, et al. Nivolumab (nivo) vs docetaxel (doc) in patients (pts) with advanced NSCLC: CheckMate 017/057 2-y update and exploratory cytokine profile analyses. J Clin Oncol. 34, 2016 (suppl; abstr 9025).