Treating Advanced Squamous Non-Small Cell Lung Cancer - Episode 3
Transcript:Benjamin Levy, MD: Before we move on, quickly, testing EGFR and ALK in a squamous patient, is there a role, just briefly, Paul?
Paul K. Paik, MD: So the NCCN does support now limited testing. It has for the past couple of years based on some retrospective analyses of EGFR-mutant lung cancer patients that happen in what appears to be squamous lung cancer, and also ALK rearrangements. The recommendations are in never-smokers, so patients essentially whose clinical presentation suggests that this may not be a typical squamous lung cancer and small biopsy specimens. And so it does recommend and support testing for that because the data are that at least a fair number of these patients will have some degree of benefit to these inhibitors, yeah.
Edward S. Kim, MD, FACP: The mantra that we try to adhere to, and I agree exactly with what Paul said, is that we’re all lung specialists here. I’m probably less specialized than you guys are now, but it’s a matter of we can go through that process. We can think about it intuitively. Just like the peripheral nodule that’s a squamous, we’re going to think differently about that patient. When you have a general oncologist out there who has to cover all the different tumor types at less than a depth level, they need something that’s a yes or a no. They cannot spend time interpreting things, and so the message I would give to them is, just as you said, if it’s a never-smoker or a light smoking history and an atypical presentation, then test them. And I think reimbursement, as you mentioned, with the NCCN, will be covered. I think that’s one of the big worries out there is that they’ll do a test that’s not reimbursed.
Benjamin Levy, MD: Yeah, I agree. Patients who fit the right clinical phenotype who are squamous, we are testing. So let’s move on. We’re going to stick to this theme of identification of relevant genetic alterations in squamous cell and talk a little bit about the Lung-MAP study, an umbrella study that’s currently evaluating different targeted drugs with distinct genetic alterations in a chemo refractory setting as a second or third-line now in squamous cell lung cancers. It’s unique not only in its design in terms of it being an adaptive study design but also in its ability to bring certain people together to try to make this happen. We brought together cooperative group, industry, diagnostic companies, as well as advocacy. It’s been through a few iterations that may be reflective of the pace of drug discovery and implementation in routine clinical practice. Ed, you want to tackle this and talk a little bit about the Lung-MAP study.
Edward S. Kim, MD, FACP: I think the Lung-MAP discussion is very parallel to the discussion we had when we first launched and reported BATTLE, and BATTLE was a study in lung cancer where it was not a squamous, it was anyone coming through the door with a previously treated lung cancer. You had to have a biopsy, and that was really one of the big paradigms of BATTLE was we were mandating biopsies and were utilizing that information, not just to store, but also to use it to randomize patients or sign them into specific treatment arms, and that was our hypothesis.
I think too many people get into the actual nuts and bolts of the therapeutics of BATTLE. It was a phase II study and BATTLE was biomarker-based approaches of targeted therapy for lung cancer elimination. So it was a DOD grant. Waun Ki Hong was the grant holder. I was the PI of the study, and in less than three years we enrolled 250 patients. That’s amazing. MD Anderson is good but they’ve never been that good. And so Lung-MAP sort of borne out of this, and the need in lung cancer was squamous. So, if you go back to about 2011, 2012, this is when we first started talking about it. Where could you project squamous cell cancer treatment would go in several years? And I think one of the ideas behind it, just as you mentioned, Ben, was that it brought together groups that had never been there before.
And so we had Friends of Cancer Research, you had the FDA and the NCI involved, and you had the InterGroups involved led by SWOG, but it brought together these types of groups, as well as industry including, Foundation Medicine. And the goal was very nicely clearly and articulately outlined. Let’s try and learn something about squamous cell cancer patients and give them opportunities to receive therapy. And there have been multiple drugs and targets that have been involved in the study. It has undergone changes. I think one of the biggest changes was the fact that the control, the default arm was an immunotherapy, PD-1-based arm and that drug obviously has, which we’ll talk about later, made remarkable progress in squamous cell cancer patients.
And so that threw a wrench into that design. They are editing now and changing it, and I think it speaks to the fact that in order to successfully do these types of umbrella studies, you have to be very clear on what you want. I think they’re learning. We’re going to learn a lot about these patients because we’re going to have a large platform of information in hundreds of patients that have been screened. Will we learn something about some of the therapies? Hopefully, but I think that’s a secondary goal. I don’t know if the pharma partners like to hear that but it’s tough. You’re going to have a tough time enrolling small percentages of mutations into these types of tumor types. But mostly, again, the collaborative spirit. The way the InterGroup has come together with government industry I think has really been reflective of Lung-MAP, and hopefully we will learn something whether it’s through serendipity or science.
Benjamin Levy, MD: I agree with you. I think it’s a wonderful effort and a proof of principle that people can come together and come up with this design and also try to answer multiple questions with targeted therapies. Will we get our answer? I don’t know. My one concern is just with the implementation of immunotherapy as a second-line. One of the new iterations of the study is that this may move to third-line as well, and whether patients who have received platinum chemotherapy then immunotherapy will make it to this study is a question mark in my mind. Paul, do you think this will answer questions in terms of targeted therapies? Will we get a drug out of this that maybe is approved?
Paul K. Paik, MD: I think it will answer some questions. I think the important thing to keep in mind is while the TCGA data set is rich and has 178 patients, these are all early-stage patients and we have very little clinical annotation to these patients, very, very little. What that results is in we have a lot of genomic data without knowing what the clinical manifestations are. The platforms like, Lung-MAP, will provide that information, so that’s one very important thing. And that goes to what Ed is talking about in terms of the amount of information that’s not necessarily related to treatment that we’ll obtain. I think because some of these things are low frequency alterations also, it’s going to be very difficult to get away testing these things on a rigorous basis outside of a larger platform. That then involves a lot of different institutions and players, so I think that’s the other part. And I think the third part is because it’s so large, changes are a little bit slower to happen than if you were just doing it by yourself as a single center. And I think that’s something else we have to keep in mind.
While the pace of phase I discoveries is going to be faster, it’s going to take longer for Lung-MAP to make these adaptations. Now, they are to their credit and they’re trying to adapt as we get additional information. But I think, overall, the complexity of the disease, the fact that what we do know is that combination therapy probably is going to be needed. This makes any effort like this a lot more difficult to put into action.
Benjamin Levy, MD: I agree. I think there’s a lot of challenges with this study, as I’ve said before, and that’s not just because the study is complex, but squamous cell is a genetically complex disease, and I’m not sure we have that story of a predictive biomarker with a drug that is going to be gangbusters in this type of disease.
Edward S. Kim, MD, FACP: I will say we should mention both NCI Match here, that isn’t just squamous lung but it is covering a lot of different rare tumors. And to Paul’s point, when you are large and have multiple sub-protocols, the unwieldiness becomes a little bit more difficult. ASCO is also launching their first trial to do, it’s called TAPUR. We will be one of the three sites that will open hopefully in February with this. We’re very excited and these are approved drugs and there’s a little more flexibility in this study as opposed to some of the very strict lines that are in some of these other studies. But, I think it’s great to have these types of efforts where we’re trying to learn about the science but gather that clinical information.
Transcript Edited for Clarity