DR GOVINDAN: So this is actually a patient of mine, 49-year-old never-smoker, worked as a statistician. Presents with cough, shortness of breath, has this large mass in the right upper lobe with biopsy-proven mediastinal nodal disease, multiple-station disease, excellent performance status. So he was deemed not to be an ideal surgical candidate because of the bulky disease and multistation N2 disease.
We actually decided to treat him off protocol with chemoradiation. The test somebody ordered. Actually the genotype came back as EGFR-mutant disease, L858R. And this actually is interesting. This is about three and a half years ago. And so there are a couple of questions I have for David. What chemotherapy is your choice, and would you give this patient erlotinib?
DR LOVE: I’d like to tag on: What about postchemoradiation consolidation?
DR SPIGEL: Yes. So, I mean, these are the issues we face every day. I mean, this is probably one of the hardest things I struggle with, because we’re still talking about things that we were talking about a decade ago. And there’s no clear way forward. I’ll tackle the EGFR one first.
Yes. I don't know. I mean, it’s tempting and I get calls about this frequently, because our patients are getting tested for these markers now. And the right answer is that erlotinib doesn’t have a proven role in any part of Stage III care, whether it’s postchemo/RT or concurrently. And the only data we have, right, is with gefitinib, where there was a suggestion from a SWOG study it may be increased mortality with that approach.
In terms of chemotherapy, I think there’s a lot of options. You said this patient has an adeno?
DR GOVINDAN: Yes.
DR SPIGEL: A person obviously with an EGFR mutation. So I think certainly the standard out there, or a standard, would be a cis/etoposide regimen, certainly very popular outside of the US. I’m not so sure in our community network that that regimen gets used at all. In fact, we were involved in a trial comparing cis/pemetrexed with cis/etoposide and we had a very difficult time randomizing to that study in the community because of the control arm. Carboplatin/paclitaxel with radiotherapy is a very commonly used regimen, despite all the problems we have with large randomized data sets with that combination.
Consolidation therapy, the data set we have is from Nasser Hanna and in the HOG group that suggested that there is no role for consolidative docetaxel following platinum/etoposide. And yet it still is done a lot in the community. In fact, the pemetrexed randomized trial I was referring to, the registrational trial, it was originally designed without a consolidation arm. But the FDA asked if that would be included as an option for doctors who wanted to give it. So I think consolidative therapy with all its pitfalls is still something that is probably more commonly done than not, just because doctors feel more comfortable giving a little bit more, even though we don’t have data, really, that tells us that’s the right approach.
So for this patient, the approach I would have taken would have been carboplatin/paclitaxel and radiotherapy. And then depending on how well they did — if they got too beaten up with that, I would stop and just observe. Or if they did beautifully with that, I might give them 2 additional rounds of carboplatin and paclitaxel at full dose.
DR LOVE: John?
DR HEYMACH: I agree with David’s points. We don’t have an established role yet for EGFR inhibitors with chemoradiation. But there is a decent amount of Phase II data out there. So we conducted a study of erlotinib with carboplatin/paclitaxel and radiation. And there was about 60ish patients, actually extremely well tolerated and very high response rates, as you might imagine, particularly in the EGFR mutants.
Now, there’s an RTOG study, the RTOG 1306, an Intergroup study for EGFR mutants and ALK mutants. Unfortunately, from my perspective, it’s going to use just induction erlotinib for the EGFR mutants instead of keeping it going through chemoradiation. There’s a wealth of preclinical data supporting that EGFR inhibition can synergize the radiation. In head and neck cancer, we know cetuximab adds benefit with radiation. So I think it’s a shame that we’re probably missing the opportunity to be including EGFR inhibition with radiation, but we don’t have randomized data at this point supporting it, and it looks like all we’re going to be looking at in the near future is this RTOG 1306 with induction erlotinib.
DR LOVE: So, just to clarify, though, in this situation outside of a protocol setting, would you be integrating erlotinib into this patient’s treatment?
DR HEYMACH: No. With all that said, I would do just what he said there at this point.
DR LOVE: Ram?
DR GOVINDAN: So I just want to defend this. I’m the principal investigator for RTOG 1306, along with Hak Choy, so we debated at great length: What is the right strategy? We didn’t want to combine that with radiation. We didn’t have that much data with crizotinib and radiation. And we weren’t so impressed when we reviewed the literature in the clinical setting, the combination of erlotinib or EGFR inhibitor with radiation really gave that much benefit. We had done a study in CALGB before with gefitinib along with radiation treatment.
And then the postchemoradiation setting — there were a lot of concerns about using the drug in that consolidation phase, because of the SWOG study with gefitinib. So that’s why we decided to go with the major tumor bulk. And it was the best of all the options we thought. And we didn’t want to hurt our patients. That was the rationale for that.
DR HEYMACH: I mean, just a point about that, we certainly know the SWOG S0023 study showed harm for gefitinib when it was given after, but, of course, that was in the wild-type — it was in the overall population, not EGFR mutant selected. And so I think —
DR GOVINDAN: We couldn’t be certain such a thing would not happen here. That’s why we tried to play it safe.
DR LOVE: I mean, when you first told me about this, to me it seemed very logical. I mean, it seemed like it had low potential for having anything adverse happening. And just the idea of just shrinking the thing down before you get started kind of makes intuitive sense. What did you actually do with this man?
DR GOVINDAN: So I treated him with cisplatin/etoposide and radiation treatment, my standard regimen. I give only 2 cycles of therapy. And we did not give any consolidation treatment. And I don’t think we should be using EGFR TK inhibitors off protocol in these things.
And I just want to quickly say that by killing the mutant population in some other curative setting, we may give those resistant clones a growth advantage. So we are to be careful about doing these things off protocol unless we really follow them and learn that it is safe. And in the previous study we did in CALGB, we gave patients 8 cycles of pemetrexed and carboplatin — 4 cycles of pemetrexed/carboplatin followed by 4 cycles of pemetrexed maintenance in this previous CALGB study. And we saw the overall survival around 22 months, median survival, not that different from the study that Nasser and I and a few others did comparing docetaxel versus observation.
So I feel that these regimens are compatible, and the case for consolidation treatment in this setting is…
DR LOVE: So he did not get erlotinib?
DR GOVINDAN: No.
DR LOVE: And I’m hoping he’s still free of disease?
DR GOVINDAN: Yes. Very much so.