Immunotherapy in Lung Cancer

Roy S. Herbst, MD, PhD

The Food and Drug Administration (FDA) approved the first immunotherapy for lung cancer in March of this year. The drug, nivolumab (a monoclonal antibody against programmed cell death 1 [PD-1]), was approved for metastatic squamous non–small-cell lung cancer (NSCLC) that has progressed following platinum-based chemotherapy. Nivolumab and other immune-checkpoint antibodies are currently in development for other types of lung cancer including the more prevalent non-squamous non–small-cell tumors. Today we are speaking with Roy S. Herbst, MD, PhD, director of the thoracic oncology research program and associate director for translational research at Yale Cancer Center in New Haven, Connecticut, about these recent developments and what this means for lung cancer patients.

Cancer Network: First, could you place the approval of nivolumab for these advanced lung cancer patients into context? What does this mean for these patients?

Dr. Herbst: I think it’s a tremendous benefit for patients with squamous NSCLC. The approval was specifically for that tissue type. Squamous lung cancer occurs almost exclusively in people who have smoked one time in their life and it’s about 20% to 30% of the lung cancer cases. This now is the go-to therapy in the refractory setting, meaning people who have had their first-line therapy for advanced, metastatic disease, now have the option of nivolumab. Previously, the drug that was being used was docetaxel, and it will still be used in those who don’t benefit from nivolumab but it’s toxicity profile is worse than that of nivolumab. So I think the fact that there is a survival benefit of this proportion (with a hazard ratio in the 0.5 to 0.6 range)-that is just a huge advance for patients with squamous lung cancer and it’s great for patients that this is now available.

Cancer Network: There are some clinical trials in lung cancer now testing whether anti–PD-1 and anti–PD-L1 antibodies are more likely to elicit a response in patients whose tumors express the PD-1 ligand. From what we know so far, how reliable could this be as a biomarker for response?

Dr. Herbst: We clearly need a biomarker. There was some biomarker work done on the nivolumab CheckMate 017 trial that resulted in its approval. At least from the data we’ve seen so far (publications in the New England Journal of Medicine and presentations at ASCO), it doesn’t look like the biomarker helped predict which group might benefit most. But certainly for the non-squamous patients, it’s looking quite real that a biomarker could help. There is clearly a group of patients who are not benefiting from this therapy and without selection I’d say the response rate is somewhere in the 20% range and long-term benefit is very similar. You don't have to have a response to have long-term benefit, but clearly my feeling is that a biomarker, some way to determine who will benefit, is needed so that those individuals can get the drug right away and those that are not likely to benefit can get other combinations.

Perhaps combinations of nivolumab with another drug is going to be essential. The problem is that the biomarker being investigated most now is measuring PD-L1, the ligand on the tumor cells or on the immune cells, it’s present both in the tumor microenvironment and on the tumor. And that biomarker has been somewhat problematic for a number of reasons. It is heterogeneous within tumors, it’s an inducible biomarker by interferon gamma, so it actually gets upregulated by the tumor microenvironment. So it’s very hard to catch when you should sample it, and how do you know that you have a true reading? And even when those things are worked out, there are many different assays that measure it, using different antibodies, measuring it in different compartments whether that is the tumor, the tumor microenvironment, the cytosol. So, really there are some variables on how this works.

That said, it does look like these assays do help predict who will benefit most, and we are beginning to see some data emerge to help us determine who maybe need not get treated. There are several studies being performed that are not yet revealed that I think might shed some light on this. For right now, the biomarker, is a tool one can use, but it’s not being used for nivolumab in patients with squamous cell carcinoma. 

Cancer Network: So, as you mentioned, there are many other trials with immune-checkpoint antibodies in lung cancer, are there any trials you are particularly looking forward to reading out, the first-line trials, the non-squamous NSCLC?

Dr. Herbst: Well, we’ve heard about nivolumab now in squamous lung cancer and of course, nivolumab also met its endpoint in non-squamous lung cancer. But as we speak, it is not yet approved for non-squamous lung cancer, although it does get some use. There are other agents. Atezolizumab (an anti-PD-L1 agent), which I have been quite involved with, is being developed now with a biomarker that measures PD-L1 not only in the tumor cell but also in the immune microenvironment-there are some phase III trials on that that are ongoing. Pembrolizumab is another anti–PD-1 antibody that had some very nice data reported by Dr. Garon and colleagues in the New England Journal of Medicine last April showing that the biomarker, in a phase I study, could really determine which population benefits most. There is a phase III study exploring that which is currently ongoing. Then, of course, there is nivolumab, where biomarker development is occurring as well and combinations are being looked at too. 

My sense is that biomarkers will help with all these drugs that are being studied in the refractory setting. But I am really excited about the trials going on now in the front-line setting, meaning patients with advanced, metastatic lung cancer who have not yet had chemotherapy. Wouldn’t it be great if these antibodies could be used instead of chemotherapy from the get-go? I think in that setting, selection is going to be even more important, and it will be exciting to look at these trial results as they emerge.

Cancer Network: Thank you so much for joining us today, Dr. Herbst.

Dr. Herbst: Thank you very much.