Lung Cancer Treatment - 2015 Update - Episode 7
Transcript:Mark A. Socinski, MD: Let’s switch gears yet again. We’re transitioning from targeted therapies and targeted populations. You brought up the question, Geoff, of whether EGFR TKIs have any merit in an EGFR wild-type population, and we asked Mary Jo to comment on this.
We saw the LUX-Lung 8 trial this year where in a second-line squamous population, which is almost universally wild-type EGFR, a comparison between erlotinib and afatinib with actually, at least to me, surprisingly positive overall survival data that was reported; secondary endpoint, but yet survival was better. Your thoughts.
Mary Jo Fidler, MD: It’s true the survival was better, and the progression-free survival was better too using afatinib, which is an irreversible tyrosine kinase inhibitor directed against EGFR, versus erlotinib which is a reversible first-generation EGFR-targeted therapy.
The numbers themselves were a little bit underwhelming. I’ve had wild-type patients, I know they’re wild-type and they have benefitted from a first-generation TKI, sometimes for a year or two. But the problem is we have no way currently to select who’s going to benefit, and if you look at all-comers, the progression-free survival data is still not so high.
My take from this trial was that if you’re going to try using an EGFR-targeted agent against squamous cell cancer, then afatinib is a winner and pick that over erlotinib because there was a PFS benefit, and there was an overall survival benefit that was statistically significant.
Mark A. Socinski, MD: Roy, do you use EGFR TKIs in the squamous second- or third-line space?
Roy S. Herbst, MD, PhD: Not often. I’ve traditionally been a believer that these agents really work best in the EGFR-mutated patient. But the data from that trial I think were compelling. We actually wrote the editorial on it. I think the clinical trial showed a benefit and there are very limited options in the squamous cell space.
We have our Lung-MAP trial where we’re looking for new targets, but even with that it’s hard to find genetically driven targets in that setting. So, certainly, now we have immunotherapy that I guess we’ll talk about later in our panel, but people fail that too or they’re not eligible. I think if someone has a reasonable performance status, afatinib is your drug.
Mark A. Socinski, MD: I was just going to ask you, would that be your TKI of choice in this setting based on LUX-Lung 8?
Roy S. Herbst, MD, PhD: Based on LUX-Lung 8, yes, and dose reducing it and treating the skin and the GI toxicities as need be.
Mark A. Socinski, MD: One of the surprising things was that we had the general sense that we may expose patients to a bit more toxicity with afatinib versus erlotinib. At least in this phase III trial, I didn’t think there was major differences.
Roy S. Herbst, MD, PhD: It was not that dramatic.
Geoffrey R. Oxnard, MD: Partly it’s because they were only on the afatinib, on average, for a couple months and some of the side effects do accumulate over three, four, five months; it is when you start developing the paronychia. So that’s a slightly different population than we’re used to.
Patients I think of for oral therapy for squamous are those who don’t want to be showing up weekly for gemcitabine or vinorelbine. "Come on, is there some way I could just come home and take my pill?" And that’s not most of my patients in Massachusetts, but I appreciate that there are some practices who have those patients who aren’t looking to travel weekly; that’s where you create an oral therapy option.
Roy S. Herbst, MD, PhD: Right. This is why patient-reported outcomes are so critical. Some people say, “Why do we need any more of this?” But in drugs like this where the differences are really small, you have to look at quality of life, how patients are feeling, and how they’re doing.
Mark A. Socinski, MD: And, as Roy mentioned, we’ll get to immunotherapies in a second, certainly for the squamous subset of patients there is a real advance. But we don’t have a lot of options in the second-, third-line options.
Roy S. Herbst, MD, PhD: Mark has a slide where he shows new drugs for squamous cell lung cancer and he puts up a blank slide.
Naiyer Rizvi, MD: Not anymore.
Roy S. Herbst, MD, PhD: That’s what it was like a year ago.
Mark A. Socinski, MD: Times are changing. And speaking of that, I want to get Roy’s perspective. I think you also wrote the editorial on the FLEX trial and you’re P.I. of the SWOG trial looking at cetuximab.
Roy S. Herbst, MD, PhD: Right. We actually presented it at the World Lung Conference.
Mark A. Socinski, MD: Good. So we now have data for another EGFR antibody, necitumumab, which was recently published. It was an agent that was explored both in nonsquamous tumors, in the INSPIRE trial which was negative, and in the SQUIRE trial in squamous tumors in combination with cis/gemcitabine. That was a positive trial for overall survival. Maybe you could argue it’s a little more robust than FLEX, but not markedly so. Give me your thoughts on necitumumab.
Roy S. Herbst, MD, PhD: I so much want to like this drug. The development of this has been over a decade—it’s the ImClone drug, the full human EGFR antibody, and it’s made its way to a number of phase III trials. Of course, the SQUIRE trial was positive. I’ve been involved in some of the ASCO meaningful outcomes work, and the hazard ratio I believe here was what, about 0.8.
Mark A. Socinski, MD: 0.84.
Roy S. Herbst, MD, PhD: 0.84, so a modest benefit but again, it’s in the frontline squamous cell lung cancer setting comparing it to cis/gem. Part of the issue also is that there was concern about pulmonary embolism and toxicity because the other trial was stopped. The trial in the nonsquamous population was stopped. That said, there is a benefit.
I’d love to define some biomarker that could help us determine a group where the hazard ratio is in the 0.7 range. Those data are emerging now, looking at maybe EGFR gene copy number by FISH. We’ve run a large trial through the South West Oncology Group, SWOG 0819. I’m sure you put patients on it yourself.
Mark A. Socinski, MD: Yes. Still have people on it.
Roy S. Herbst, MD, PhD: I still have people on it, and this was looking at cetuximab plus chemotherapy versus chemotherapy, that being carboplatin/paclitaxel. And we used EGFR FISH. Actually, Fred Hirsch spearheaded this from his work.
One of the main analyses looked at those patients. With 1300 patients with an EGFR FISH rate of about 40% positive, there will be a large population now to actually look at that and hopefully answer the question whether it can that be used as a predictive biomarker.
As far as what we have now, this is under review by the FDA. Hard to know which way this will go, but certainly as someone who sees a large number of patients, as do you, to have something again with immunotherapy on the horizon, realizing that that might be for a specific group of patients. Having something to offer some of the other patients, certainly deserves consideration.
Mark A. Socinski, MD: And I must say when you looked at the IHC data and the H-score within FLEX, it was promising but never really came to fruition. We looked in the SQUIRE trial at the cut point that was defined in the FLEX trial, the 200 cut point for H-score. There was no interaction with treatment in that particular sense, so I agree with you. With an antibody you should be able to identify a biomarker that tells you who the patients that benefit will be, and more importantly, who are the patients that will get no benefit from this drug above that of chemotherapy.
Geoffrey R. Oxnard, MD: One of my questions is, with nivolumab and immunotherapy coming and changing the care for squamous lung cancer, is that going to move the bar more than this hazard ratio of 0.84? And does that hazard ratio get diluted by such more powerful therapies that are emerging?
Roy S. Herbst, MD, PhD: Maybe, but, again, it’s going to depend if there’s selection. I was going to ask the panel what you think. When was it that FLEX was a plenary at ASCO, was it 2009? It’s a while back and it was a plenary talk by Robert Pirker and the hazard ratio then was 0.87, so a little bit further north. That never moved. We never saw an approval of this, and cetuximab, is being looked at in other settings. Of course, it’s approved for GI cancers, but it never got any headway here. We’re a little bit better with this one, perhaps a little bit easier to give antibody because of some of the issues with toxicity. But it will be interesting to see. But, I do agree, H-score, a bit disappointing here. Could EGFR FISH be a little bit better? It’s slow progress.
Mark A. Socinski, MD: Is there a patient in your practice where you would consider using say cetuximab at this point?
Roy S. Herbst, MD, PhD: I think yes, if I had someone with untreated squamous lung cancer, my first reflex now would be to see if I could put them on immunotherapy. I have to look and see if they meet the criteria. Most of the trials with immunotherapy are requiring patients to be PD-L1—positive, a difficult biomarker in any respect. If they’re negative, to offer them this versus the same chemotherapy we gave in 1998, I’d consider it.
Mark A. Socinski, MD: So this is currently under review at the FDA. The FDA convened an ODAC meeting and interestingly took a different strategy, they didn’t ask for an ODAC vote but if you read the medical letter, it was a thumbs up or thumbs down.
Roy S. Herbst, MD, PhD: Can we do that here now on our panel? Close our eyes and put our thumbs up?
Mark A. Socinski, MD: That’s right. But reading through the medical letter it would seem like most of the ODAC members were in favor of it. Was that your impression?
Roy S. Herbst, MD, PhD: Yes. Again, I read the same letter as you but it was an interesting discussion. But my sense was that there were more in favor than not. The hope will be that we can even find drugs in the future that are more of a home-run so that we don’t have to sort of resort to this.
Mark A. Socinski, MD: Do the yay, nay, thumbs up or thumbs down.
Roy S. Herbst, MD, PhD: It would be right on the border.
Mary Jo Fidler, MD: And I think the frequency of coming into clinic is important for some patients to come in for cetuximab once a week. I’m sure you can stretch it out to every two weeks safety-wise, but I feel like it can be a little bit more toxic. That could be a lot of back and forth for people.
Mark A. Socinski, MD: Yeah, at least necitumumab is not a weekly drug. It’s a day 1 and 8 drug, so that’s a little bit of an advantage. This side of the table?
Naiyer Rizvi, MD: I’m not a fan.
Mark A. Socinski, MD: Not a fan?
Naiyer Rizvi, MD: Yes.
Transcript Edited for Clarity
Geoffrey R. Oxnard, MD: I don’t think it shifts the bar enough to be a standard part of my practice. I want something better, as Roy says.