Where things have changed the most in the past year was the first-line indication. The KEYNOTE-024 trial was for patients with high PD-L1 expression [via] the IHC 22C3 pharmDX assay used for pembrolizumab. For those over 50% or at least 50%, patients were randomized to either get chemotherapy or pembrolizumab. There was superiority not just in survival, but in response, PFS, and OS with pembrolizumab in that setting. That rapidly changed practice.
We had some follow-up at the 2017 ASCO Annual Meeting by Dr Julie Brahmer looking at how many people were still doing well. It was pretty high numbers around 18 months. They also were looking at the PFS2, which are patients who responded, stopped responding, and then went to chemotherapy. However, the benefit from chemotherapy seemed to be higher than one would have anticipated, so there are questions about perhaps there is some sensitization toward chemotherapy that can happen. A lot of investigation is happening there. A lot of work is also looking at what else can we do to rev up that response; what drugs can we add to it? Can radiation play a role? There are many studies. How many different angles are we looking at?
At this time, there is not really a clear winner there. One of the IDO inhibitors was talked about at the 2017 ASCO Annual Meeting, but those were pretty small numbers and careful selection, so I don’t know if that is going to be the answer. There is a lot looking at the CTLA-4 inhibitor plus the PD-1 inhibitor combination, and that data is evolving and looking promising. However, we are not clear about where that is going to go—first-line, second-line, third-line—and what toxicity questions we have.
We are also looking at chemotherapy and, of course, there was an FDA approval for chemotherapy plus pembrolizumab. However, that was a pretty surprising approval for most of us because it was based on a randomized phase II study that was small, and while there was a PFS benefit in some of the subgroups, there was no OS benefit. In some of the subgroups, especially if you look at the PD-L1 expression between 1% and 49%, chemotherapy was actually better than the combination. So, we were really surprised by that indication.
Also, there is the fact that the label doesn’t exclude patients with EGFR
mutations, and that is one of things we feel is critical. If you look at who actually went on those trials, first-line patients with EGFR
abnormalities were not allowed on those trials, and first-line patients with EGFR
mutations or ALK
translocations really should get a focused targeted drug, even if they have high PD-L1 expression. Many of them do, but that doesn’t mean they’re going to respond the same way as someone who didn’t have a driver mutation. That is a really important point, and one that most, but not all, of the community knows. It’s hard because the patients really push to get immunotherapy if they have PD-L1 expression; they have heard that message. However, they don’t always put it in the context of understanding that if they have an EGFR
abnormality, that is a better pathway to start with.
We have heard so much about pembrolizumab in recent months. What about some of these other PD-1/PD-L1 inhibitors?
With atezolizumab, we are waiting for the first-line data. It has its second-line approval and third-line approval for patients. If they have high PD-L1 expression, they are going to get pembrolizumab in the first-line setting but, in the second-line setting, atezolizumab is being used. It is something I am prescribing for my patients.
Nivolumab still has a role in the second-line setting. The data are just as good as it is with any of the other drugs; it was just the first-line trial where things didn’t go quite the same way. That has raised some questions; whether they are warranted or not is another study. The combination trials that are being done are involving various different combinations of all those drugs.
We haven’t heard much about durvalumab (Imfinzi), but there is going to likely be more this fall with the PACIFIC trial, which was the first one in patients with stage III disease. It was for patients who had chemoradiation, and then went on to get durvalumab or not. We have only seen that little press release that said it was positive, but we don’t know any of the details yet. The expectation is we will be hearing more about that in the fall, and that could get durvalumab to be talked about it quite a bit more.
Avelumab (Bavencio) is available but not in lung cancer. It’s on the market for other indications and, certainly, there are ongoing trials in lung cancer, so we'll find out more about it. There are many others being developed by other companies. As far as how are we going to pick which one to use, I don’t know yet. As other first-line trials read out, we perhaps won’t all be giving pembrolizumab in the first-line setting for the high PD-L1 patients; maybe we still will. As far as toxicity differences, we haven’t seen those very clearly. It is different than with the TKIs.