PD-1 Inhibitors Make Tremendous Impact in NSCLC, But Questions Remain

Renato Martins, MD

With both nivolumab (Opdivo) and pembrolizumab (Keytruda) approved by the FDA as treatments for patients with nonsquamous non—small cell lung cancer (NSCLC) across all histologies, oncologists now have their choice of PD-1 inhibitors in the second-line setting.

However, many questions still remain regarding PD-L1 as a biomarker, sequencing, and how the 2 agents compare head-to-head.

OncLive: Who is the ideal patient to receive nivolumab?

For insight into these questions and more, OncLive spoke with Renato Martins, MD, medical director for Thoracic/Head and Neck Oncology and Outpatient General Oncology and Hematology at Seattle Cancer Care Alliance.Martins: Nivolumab is approved as a second-line therapy for all patients with NSCLC. This is not restricted by any expression of PD-L1—which is different than pembrolizumab—which is also approved for this indication.

As of now, I don’t believe any patient is clearly not a candidate for either PD-1 agent. We have seen responses in patients who are supposedly negative for PD-L1.

In one presentation, I put together a list of patients who would be considered negative and the response rate was still 8.9%, which compares to how chemotherapy would perform in this setting. Even for those patients who are so-called “negative,” it seems that the quality of their responses is as good as the quality of responses that we see in patients who are PD-L1—positive.

Is there any possibility of moving it to the first-line setting?

With both pembrolizumab and nivolumab approved in the second-line setting, how do you determine which treatment to use with your patients?

We have other examples in lung cancer where perhaps a patient here and there can respond to a targeted agent if they are EGFR-negative, but these results don’t seem to be of the same quality as patients who have an EGFR mutation. Here, the patients who are PD-L1—negative seem to have very good quality response. That reinforces the concept that PD-L1 expression may be a biomarker, but it is certainly not the biomarker that will answer the question regarding these agents.There are a number of trials looking at the issue of combining PD-1 agents with chemotherapy. They may be showing higher response rates than one would expect with chemotherapy alone; the data is still very immature. My take on it is, until we have a very reliable biomarker—which we will in the future—it is going to be hard to move into the first-line setting.There may be some advantage to using pembrolizumab in terms of the convenience of it being an every 3-week treatment, as opposed to an every 2-week treatment. The per infusion cost of each drug is about the same, so if you are giving it every 3 weeks as opposed to every 2, there is a significant cost savings, overall.

However, for us, the companion test used with pembrolizumab would have to be sent out; we would not be able to do it in-house because we don’t have the right equipment. Because of that, we are not using it right now.

How much of an impact have PD-1 agents had in lung cancer?

I am skeptical that there would be substantial differences in efficacy and toxicity between these agents. If someone were to propose a study comparing 2 PD-1 antibodies in the second-line setting, I don’t think I would support that. I don’t think that would be a valid question.I think these agents have had a tremendous impact in lung cancer. We are seeing things that we have never seen before. We have patients who stopped therapy years ago and the disease has not become active. That is unprecedented. The combination of the positive side effect profile and the quality of the responses is what has made us so enthusiastic about these agents.

What challenges remain in understanding how to use these agents?

These drugs are here to stay. They make a huge difference in a subset that we cannot characterize very well, at this point.We are seeing these responses in 15% to 20% of patients, so there is a lot of room for improvement. I think we will get better. We just started to recognize lung cancer as a disease that responds to immunotherapy. We are going to be busy for a very long time, trying to understand and perfect these therapies.