Expert Discusses Next Steps With Immunotherapy in Lung Cancer

Hossein Borghaei, DO

Results of studies of immunotherapy as a frontline therapy choice for patients with non—small cell lung cancer (NSCLC) are causing much excitement in the field, along with their potential use as part of combination strategies, reported Hossein Borghaei, DO, during his presentation at the recent 11th Annual New York Lung Cancer Symposium™.

OncLive: What do oncologists need to know about the use of immunotherapies in the frontline setting?

Borghaei, who is chief of the Division of Thoracic Medical Oncology, director of Lung Cancer Risk Assessment, and associate professor in the Department of Hematology/Oncology at Fox Chase Cancer Center, sat down with OncLive at the Symposium to discuss what lies ahead for immunotherapy in lung cancer, and what changes may be on the horizon for such agents as pembrolizumab, nivolumab, and ipilimumab in the frontline setting. He also stressed the importance of the patient’s quality of life when considering new agents and ensuring that the efficacy of the drug outweighs any increased toxicity.Borghaei: I think it is well-established that all of these immuno-oncology drugs have an active role in treatment of patients for recurrent NSCLC. Head-to-head, versus chemotherapy, all of these are a lot more effective and a lot less toxic. I think in the second-line setting, we've established that.

In the frontline setting, up until recently we didn't have any data. But at the ESMO meeting just 6 weeks ago, the results of a frontline study using pembrolizumab in patients with really high expression of PD-L1 in their tumor, over 50% basically, were extremely encouraging and practice-changing, to the extent that, at least at my institution, we now routinely check everybody's tumor expression for PD-L1, and if they fit this study's criteria, we use pembrolizumab.

In that study, pembrolizumab was compared head-to-head versus standard platinum doublet chemotherapy. And both progression-free survival (PFS) and overall survival (OS) were superior with pembrolizumab. There were no additional safety signals above and beyond what we've previously seen with pembrolizumab, suggesting a highly active drug with an acceptable side effect profile. That study, at the time of reporting, changed clinical practice in lung cancer, as far as I'm concerned, regardless of histology.

The question then is: what do we do for patients who have a lower expression of the PD-L1 marker in the frontline setting? As far as I'm concerned, in the absence of clinical trials, standard chemotherapy is the viable option there. That has led to a number of investigations.

I am a co-investigator on a study of pembrolizumab in combination with platinum doublet chemotherapy. This was a sub-arm of a larger study, a randomized phase II trial reported by Corey Langer, MD, where adding pembrolizumab to a backbone of carboplatin and pemetrexed actually did improve both response rate and PFS.1 Overall survival was the same at the time of reporting. But this study did not have adequate follow-up, so we have to wait and see what happens. There were no significant safety signals—a little more in terms of side effects, as you can imagine, adding a third drug to any platinum doublet. But overall, nothing significant above and beyond what we had expected.

What about combining immunotherapies?

The question is: Is that going to be a viable option for patients? The study was small, because it was a randomized phase II. We did look at PD-L1 expression. The signal is a little bit difficult to interpret, I think, because of the smaller number of patients in each subgroup. It is a possibility that the phase III study that's already ongoing with the same combination might show us that, for instance, in patients with low expression of PD-L1, maybe the combination with chemotherapy will be the way to go. We just don't know that yet. We have to wait for the trial results. So I would not combine chemo with an immuno-oncology agent outside of a clinical trial at this moment.And then we started talking about immuno-oncology combinations. There have been a couple of studies that have been published already, including one in Lancet Oncology looking at durvalumab plus tremelimumab.2 Again a smaller number, but a study, after going through several different dosing and schedule of delivery of the agents, was able to come up with a combination most of us would consider fairly tolerable. Based on the published results, hopefully, it will be very effective.

I also discussed the data that we have available for the combination of ipilimumab and nivolumab, a study that I also participated in. A slightly larger patient population, but again, multiple cohorts of patients with different dosing and schedule of the drugs. The most recent reporting at ASCO by Dr. Hellmann was the combination of a standard dose of nivolumab with one milligram of ipilimumab, either every 6 weeks or 12 weeks. Looking at the side-effects, and looking at responses.3

There's a lot of discussion about whether response is an appropriate endpoint for immuno-oncology drugs. Nonetheless, it is of interest in this disease. And with the combination, there definitely was a higher response rate compared to single-agent nivolumab, toxicity as I alluded to before, was more with the combination, but most of them, manageable.

This is something I brought up: as physicians we keep saying the side effects are manageable. They're manageable from a physician point of view, but it's not clear if they are manageable from a patient point of view. That is something that we have to pay attention to.

Were you surprised by the results of CheckMate-026 study, with nivolumab in the frontline setting? Do you think nivolumab is going to have a role in the frontline setting?

By and large, personally, I've been happy with the response and side effect management that I have seen with my patients. And I think the study, which hopefully will be published soon, bears that. We'll see if we can continue that more.At this point, I have to say, no. There is no role for nivolumab in the frontline setting, because that study did not show a benefit. There were major differences between the CheckMate-026 study and the pembrolizumab study, KEYNOTE-024. For instance, CheckMate-026 with nivolumab used a lower cut-point for PD-L1, about 5%. Can we argue that 5% expression is not adequate? We don't know. That has to be investigated.

What about the future of PD-1 as a biomarker?

I think, clearly, at this point, I would not use nivolumab in the frontline setting, in that patient population. There were many issues with the study in terms of imbalances, so we're trying to dissect now and see what really happened. But at the end of the day, it is a negative Phase III study. And I think more work needs to be done before we can move that agent into the frontline setting.Based on the KEYNOTE0-24 study, now you have to accept and argue that it is a marker that can select a patient population that would respond to pembrolizumab preferentially better, compared to a platinum doublet. I think it is an imperfect biomarker. There have been many papers and discussions and abstract presentations about it. I think we do need to do a better job of finding a marker that truly identifies patients who would or would not benefit from immuno-oncology drugs.

Do you think we’ll get to the point of triple regimens for lung cancer, as we’re seeing with hematologic malignancies?

At this point, I think PD-L1 expression in the frontline setting is an acceptable marker for selecting a very specific patient population for frontline immuno-oncology. I don't think I can argue with that data. Although, as I said, I do have many issues that I can raise with the biomarker. I think the field is complicated enough, and there's no need to further complicate it.I think we're already there. There are active clinical trials with triple drugs and it would be interesting to see what happens. I think this is going to be a place where we have to ask: What's the balance? How many more side effects, how much more efficacy? As physicians, how much are we willing to accept? And as patients, how much are the patients willing to accept?

I think if you get to a combination where the efficacy is significantly better than what we have, but yes, there are side effects, I think the balance is tipped toward using a triple drug. But if it is modest to minimum improvement and the toxicity is still kind of high, then you have to question if that's the appropriate way to go. I think future clinical trials, coming in with different combinations, are going to have to address some of that.

And then we have to decide as a community with patients, patient advocacy groups, and everybody else: is this really worth it? And also, remember, these are going to be expensive. There is a societal cost that comes into it. Again, not just for the drug delivery but what happens when patients have side effects?

What do you think is the main message for this that you want to get across to oncologists?

It really has to be significantly better than what we're doing right now for it to move to the frontline setting. But it has to be investigated. We're not curing our patients with lung cancer. We do need to find better treatment options for them. I don't think anybody would argue with that. But it shouldn't come at the cost of causing more harm.The main message is that we are extremely excited and hopeful for the future of lung cancer therapy. In a patient population for whom, over the last 20 or 30 years, we really haven't had a whole lot, if you take out the patients with molecularly subtypes—EGFRs and ALK. For the majority of patients, we haven't had this much excitement and this much development and improvement for survival, which I think is the key factor here.

We are very hopeful. We have to continue along this line. But managing side effects and selecting patients who are appropriate, I think, is going to be the key challenge that we have to face.

References

1. Langer CJ, Gadgeel SM, Borghaei H, et al. Randomized phase 2 study of carboplatin and pemetrexed + pembrolizumab as first-line therapy for advanced NSCLC: KEYNOTE-021 cohort G. Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark.
2. Antonia S, Goldberg SB, Balmanoukian A, et al. Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study. Lancet Oncol. 2016;17(3):299-308.
3. Hellmann MD, Gettinger SN, Goldman JW, et al. CheckMate 012: safety and efficacy of first-line nivolumab and ipilimumab in advanced NSCLC. J Clin Oncol. 2016;34(suppl; abst 3001).

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