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DR. RAMALINGAM: Hello. Welcome to The ASCO Post Roundtable Series on the Appropriate Management of Challenging Cases in Lung Cancer. I'm Dr. Suresh Ramalingam, Deputy Director of the Winship Cancer Institute of Emory University. Today I'm joined by two esteemed colleagues, Drs. Heather Wakelee and Julie Brahmer.
DR. BRAHMER: Hello, I'm Dr. Julie Brahmer. I’m a professor of oncology at the Johns Hopkins Kimmel Cancer Center in Baltimore, Maryland.
DR. WAKELEE: Hi, I'm Dr. Heather Wakelee. I'm a professor of medicine and the interim chief of the Division of Oncology at Stanford University in California.
DR. RAMALINGAM: Thank you for joining us. Today we will be discussing adjuvant EGFR inhibition in early-stage non-small cell lung cancer. So I'll set the backdrop, Heather. About 15 years ago, or even a little longer, at the ASCO plenary session was the first adjuvant trial that showed survival benefit in lung cancer. That was the IALT study. That was four cycles of platinum-based chemo after patients had undergone surgery for stage I, II, or III. And the results were practice changing. Five-year survival rate was improved by about 4.2% in absolute terms, and the hazard ratio for overall survival was 0.86. And that clearly led to adoption of chemotherapy. Now fast forward. Just this year at ASCO, a few weeks ago, at the plenary session once again, we heard the results of the ADAURA trial, specifically focusing on EGFR TKI therapy. Can you talk to us about the ADAURA trial and the results, and what you think are some of the important learning points from that study?
DR. WAKELEE: Well, sure. Probably most of the audience knows, but ADAURA was looking at the use of osimertinib third-generation EGFR TKI in the adjuvant setting. The study was restricted to patients with exon 19 deletion or L858R mutations, so the majority of our known activating EGFR mutations, but not everybody. And it included patients with stage Ib, II, and IIIa non–small cell lung cancer, which had been resected. Fairly well balanced as far as which patients, which stages went on the study. And patients were randomized after receiving chemotherapy, if they got chemotherapy, and about half of the patients got chemotherapy, a little bit less than that. They were then randomized to get three years of osimertinib or not.
And then the results that we saw were actually presented earlier than we were expecting to see them because the hazard ratios were so good that the Data Safety Monitoring Committee felt that the data needed to come out. So we only have data with two years. It was looking at two-year disease-free survival as the endpoint that was really the focus. And many of the patients had not reached anything beyond that, so I think about half the patients had even gotten to that two-year mark. So there were a lot of patients earlier on, and very few who had reached a longer timepoint. And that becomes relevant as we have the conversation.
There is absolutely no doubt that the data was quite compelling. The hazard ratio separated out strikingly from early on. With hazard ratios, if you looked across the board, it was amazing. So, with stage IIIas, hazard ratio was 0.12 for two-year disease-free survival, 0.17 for the stage IIs, and then 0.5 for the s3tage Ibs. So – and if you looked at that disease-free survival rate at two years, it was close to 90% for all of the stages – all of the stages. It was the difference – the reason those hazard ratios vary so much is because of the difference with the chemo alone or nothing, right? Some of the patients even with IIIa never had chemotherapy before their randomization.
And so when we look at those numbers for chemotherapy alone, of course it varied by stage, about three-quarters of patients in stage Ib were still disease free at two years, but it dropped down to only about a third of patients with stage IIIa. So that's expected. But it led to these huge differences in hazard ratio. And then a lot of debate about, what do we do? We've seen significant disease-free survival benefit with adjuvant EGFR TKIs in the past. We've seen it with erlotinib. We've seen it with gefitinib. And yet those really hadn't changed practice.
And I think it is important to mention that the CTONG1104, otherwise known as the ADJUVANT trial, was also updated at ASCO this year. That was the Chinese study using adjuvant gefitinib in the EGFR patients. The difference? It was almost all stage III patients. It also showed a disease-free survival benefit that was pretty striking, but when you got to the three- and four-year mark, the disease-free survival curves came together, and there was no overall survival benefit. So we hadn't used that as our standard practice. But because the osimertinib data was so striking, there's been a lot of discussion about that becoming a standard of care, and a lot of discussion because we don't yet know what is the three-year, what is the four-year data? Are we actually changing survival, and yet with such striking differences of disease-free survival, it's hard to argue not to give osimertinib. So again, lots of controversy here.
And when I’m talking to my patients, and I've actually had a couple already who have come in, who have already had their surgery, who have already had their adjuvant chemotherapy and are now trying to decide do they start osimertinib or not? Some of them are nine months, 12 months after surgery. So these conversations are happening in clinic. Of course we're letting all of our patients know who have EGFR-mutant lung cancer that has been resected about this data, but I'm not uniformly starting it on everybody at this time. I think that disease-free survival is very comforting, to know that your cancer is not going to come back. Osimertinib is usually well tolerated. But it is not universally well tolerated.
And so we have to really weigh for patients with stage Ib where we don't know if we're doing anything than postponing when their cancer comes back, and more than half of them might be cured already, is it worth it? For stage IIIa, it's a different story perhaps, where the risk of recurrence is so high, but does everybody need it? Probably not. So to me, the story is not over. It's a really exciting chapter, and it changes the conversation, but I still think it needs to be an individual conversation. I'm not of a mindset of osimertinib for all at this point after resection for EGFR. I know that some colleagues are. But I think osimertinib discussion for all is where I am at this point.
DR. RAMALINGAM: Thank you, Heather, for that excellent overview and summary. Julie, when I look at the ADAURA results, you have the hazard ratio of 0.17 favoring osimertinib in the adjuvant setting for the stage II/IIIa patients with a highly significant p value. Those are the kind of hazard ratios we're not used to seeing lung cancer. Now, Heather pointed out all the caveats. The data have maturity of only 33%, even for DFS, and the survival data are a long ways away. Assuming that this is going to be available to our patients if approved by the FDA, how would you approach it in your clinical setting?
DR. BRAHMER: I think I'm enjoying my conversations with patients in this setting, and I've just had my first one with a patient. You know, someone who is otherwise healthy who has a high chance of dying from their lung cancer when it comes back, you know, that discussion is a very heartfelt and can be a difficult one. And certainly it depends on the patient. I think the potential but rare long-term complications from taking a drug for three years has to be weighed in to this. There are some risks, such as a rare complication of cardiomyopathy, as well as interstitial pneumonitis. Again, that's rare but has to be part of that conversation.
And really, we don't know some of the long-term complications of this drug because we typically only give it in the metastatic setting, where at some point, these patients' disease would become resistant. However, I think in the adjuvant setting, particularly in patients with stage IIIa disease, I think I'd push someone harder to undergo the three years of osimertinib, but we talked significantly about what does the data mean? This is disease-free survival. It's not overall survival. And that's – it's hard for folks to wrap their heads around that anyway, let alone a patient who's trying to figure out, you know, do I need to take this so I could see my children's graduation, or you know, how am I gonna feel while I'm taking this every day? So, you know, but I think the data is very amazing. Like you said, we've never seen this before, and it does regard, like Heather said, everyone needs this discussion if they have an EGFR-mutant lung cancer after surgery.
DR. RAMALINGAM: So definitely some important pieces of information for us to discuss with our patients based on this. And again, we should emphasize to our audience that for patients with a resected stage Ib, II, and IIIa, first step after surgery would still be adjuvant chemotherapy, four cycles of platinum-based chemo, and then whether you give osimertinib or not or enroll patients to do a clinical trial if they have targeted mutations, these are conversations that happen while the patient is going through chemotherapy, so you can set them up for the next step in their care journey.
So a lot of excitement with these results. We'll wait to see if this is also an FDA approval, in which case, we will have that option available for patients who want it, and also eagerly anticipate the survival data.
This has been very helpful and informative. I want to thank both Drs. Wakelee and Brahmer for joining us, and you, our audience, for watching this. Please don't forget to watch the other videos in this ASCO Post Roundtable Series. Thank you.