Expert Discusses Dramatic Impact of Immunotherapy on NSCLC Paradigm

Melissa Johnson, MD

PD-1/PD-L1 inhibitors continue to change the armamentarium of non—small cell lung cancer (NSCLC) treatment, especially with the May 2017 frontline approval of the combination of pembrolizumab (Keytruda) and pemetrexed/carboplatin regardless of PD-L1 expression status.

Although the promising findings of the phase III KEYNOTE-024 trial led to the October 2016 FDA approval for single-agent pembrolizumab in the frontline setting, results of the CheckMate-026 trial—which explored frontline nivolumab (Opdivo) in patients with NSCLC—were disappointing as overall survival (OS) was with chemotherapy and the PD-1 inhibitor, also questioning the utility of PD-L1 as a biomarker.

However, results of an analysis of CheckMate-026 presented at the 2017 AACR Annual Meeting showed that patients who had high tumor mutation burden derived an enhanced benefit from nivolumab compared with platinum-doublet chemotherapy. Of the patients with high tumor mutation burden, the median progression-free survival (PFS) improved to 9.7 months versus 5.8 months (HR, 0.62; 95% CI, 0.38-1.00) and the objective response rate was higher with nivolumab versus chemotherapy (46.8% vs 28.3%).

OncLive: What is the current role of immunotherapy in NSCLC?

What emerging regimens are in the pipeline?

Melissa Johnson, MD, associate director, Lung Cancer Research, Sarah Cannon Research Institute, described the impact of immunotherapy for patients with NSCLC—those with both high and low levels of PD-L1 expression—and how the treatment and the role of PD-L1 will continue to progress in the coming years in an interview during the 2017 OncLive^® State of the Science Summit™ on Advanced Non—Small Cell Lung Cancer.Johnson: Immunotherapy is currently approved for second-line use in all patients with lung cancer, but about 6 months ago, it was also approved for patients in the frontline setting whose tumors express high levels of PD-L1 at 50% or greater. It’s pembrolizumab that is approved for those patients.Pembrolizumab is approved for patients in the frontline setting who have tumors that express high levels of PD-L1 at more than 50%, but that is only about 30% of frontline patients with lung cancer. That leaves about 60% that need to be treated either with immunotherapy plus chemotherapy or PD-L1 inhibitors in combination with other checkpoint inhibitors such as anti—CTLA-4 inhibitors. PD-1 plus CTLA-4 is a strategy that’s already been approved for the treatment of patients with metastatic melanoma, and many oncologists have good experience using that regimen.

How has the frontline approval of pembrolizumab changed the landscape?

We have a number of clinical trials right now that are evaluating that strategy for patients with lung cancer in the frontline setting, across a number of sponsors. Merck is evaluating pembrolizumab plus ipilimumab (Yervoy), Bristol-Meyers Squibb is evaluating nivolumab plus ipilimumab, and AstraZeneca Medimmune is looking at durvalumab (Imfinzi) plus tremelimumab.It cannot be overstated that it has really changed the standard of care for patients with newly diagnosed lung cancer, which is a pretty dramatic statement. However, the idea that you can give patient a single-agent therapy that doesn’t make them lose their hair or give them side effects like nausea, cytopenia, or neuropathy is very significant.

What is the efficacy of PD-L1 as a biomarker?

It has also led to improved survival, which is amazing, and something that is a hope for every clinical trial. It [has] also meant that patients need more tissue at diagnosis in order to know the best treatment. In the past, we needed tissue for molecular testing. Now we also need it for PD-L1 testing. Therefore, we are having more and more conversations with our pulmonologists, pathologists, and sometimes surgeons with getting enough tissue at diagnosis to enable the best treatment decision from the beginning.That is a good question, maybe even a controversial one. In the frontline setting, we use pembrolizumab based on its FDA approval in October 2016 for patients with PD-L1—high tumors. In the KEYNOTE-024 trial that led to that approval, it seemed to be a very reliable biomarker, as the patients with PD-L1–high expression did do better with pembrolizumab.

However, we all have other patients who have PD-L1—high tumors that don’t always do as well with PD-1 therapy. There are an increasing number of oncologists who will tell me that they have patients who are PD-L1–negative but, in the second-line setting, do really well with immunotherapy. There certainly is the suggestion that it is not a dichotomous biomarker or that positive equals benefit and negative equals no benefit.

In CheckMate-026, frontline nivolumab did not improve PFS versus chemotherapy. What are your thoughts on those findings?

At the 2017 AACR Annual Meeting, there was an analysis of tumor mutation burden, which is perhaps an alternative to PD-L1 testing as a biomarker to select patients for benefit. That was a cumulative summation of missense mutations in a tumor, and the authors looked at patients who were treated in the CheckMate-026 trial. Sixty percent of them had enough tumor tissue and DNA to undergo whole-exome sequencing. Those who did undergo whole-exome sequencing were given a tumor mutation score. The authors found that patients who had a tumor mutation score that was high actually did better with nivolumab versus chemotherapy. For patients on that trial, PD-L1 wasn’t a good indication of whether those patients were having a benefit.There have been a lot of critics that have said one explanation or another. It’s not that simple. Between [CheckMate-026 and KEYNOTE-024], they were clearly different trials that enrolled different patient populations. The patients in the KEYNOTE-024 trial were a highly selective group of patients.

They had PD-L1—high tumors, and there is a suggestion that they might have been a healthier population than the patients treated in CheckMate-026, where 40% had radiation therapy before they even went on the trial. There were more squamous patients and never-smokers in CheckMate-026.

Clearly, there were differences in the patients who were treated. Whether or not there is a difference in nivolumab versus pembrolizumab is an interesting question, but it is not one that we have data to support at this time. They do seem to be the same in all of the clinical work that has been done to this point.

What do you think the future holds with immunotherapy in lung cancer?

What should community oncologists take from your lecture on immunotherapy?

These first 2 trials are the tip of the iceberg; they were similar trials with simple designs. The trials that are still maturing, that we hope will be published in late 2017 or early 2018, were more complicated, and it’s going to blow this field wide open in terms of the therapeutic possibilities for patients with lung cancer.That is a good question. I don’t think anyone knows the answer to that yet, but I find myself wondering if there is going to be an immunotherapy strategy for frontline newly diagnosed lung cancer. Right now, it is going to be for patients who express high levels of PD-L1 expression in their tumor. In time, we will know whether those patients who have lower levels of PD-L1 expression can better be treated with immunotherapy plus chemotherapy or if they should be treated with PD-1/CTLA-4 therapy. There are a lot of options, and as we look ahead 1 year or 2, there are going to be a number of different strategies available. Hopefully, we will have better biomarkers to select the best therapy for every patient.I hope they understand that immunotherapy in the frontline setting for patients with lung cancer is very different than second-line therapy. Right now, all patients are eligible to receive immunotherapy in the second-line setting, where we really are limited to prescribing immunotherapy in the frontline to only patients with high levels of PD-L1 expression in their tumor.

I hope that the audience came away with a better understanding of tumor mutation burden; it’s a new concept and perhaps an alternative to PD-L1 testing. We will hear a lot more about it. The analysis was very compelling to me, and it is an important message to start telling both oncologists and other specialists that take care of patients with lung cancer.

Peters S, Creelan B, Hellmann MD, et al. Impact of tumor mutation burden on the efficacy of first-line nivolumab in stage iv or recurrent non-small cell lung cancer: An exploratory analysis of CheckMate 026. In: Proceedings from the 2017 AACR Annual Meeting; March 1-5, 2017; Washington, DC. Abstract CT082.