Narjust Florez, MD, and Suresh S. Ramalingam, MD, on EGFR-Mutated NSCLC: Update on Osimertinib and Chemoradiotherapy

Narjust: Thank you, for joining us and thank you for a wonderful presentation. So let's talk about the LAURA trial. Can you summarize the design of this trial for us? Suresh: LAURA Trial was designed for patients with stage three non-small cell lung cancer who have an EGFR mutation that's not surgically resectable. For them, we currently do chemotherapy and radiation. And the question is, what's the best next step? In the LAURA study, we enroll patients who had not progressed after concurrent chemo radiation within six weeks of completing treatment and randomized them to osimertinib or placebo in a two to one manner. And then the treatment was continued until they had disease progression or had some toxicity issues. Primary endpoint was progression-free survival. Narjust: And the importance this trial comes because we know that patients that were receiving immunotherapy after chemotherapy radiation when an EGFR mutation didn't have a good response. So this was a very large need. Suresh: That is absolutely right. In the PACIFIC study, when we look at a subset of patients with EGFR mutation, there was no difference between placebo and durvalumab. And you know that regardless of the PD-L1 expression, if patients have EGFR mutation immune checkpoint inhibitors, whether you give it alone or with chemo, doesn't work. Narjust: So that was extremely important. We had a large, many, many of us were doing chemotherapy radiation followed by nothing. Suresh: Yes. Narjust: We are high recurrence rate. Now that you brought up PACIFIC, let's talk about brain imaging. How was brain imaging required for LAURA that wasn't done at PACIFIC. Suresh: Absolutely. So we were obviously aware of the fact that EGFR mutated lung cancer has a higher risk of progression to the brain. So at the time of study entry, patients had an MRA of the brain and then for the first year they had MRA of the brain with every staging interval. And then once they completed 48 weeks, scans were done every 12 weeks. So we had a very clear longitudinal perspective on new lesions occurring in the brain. And in fact, the study showed that patients who got osimertinib had a much lower likelihood of progression to the brain. 8% versus 29%. Narjust: So as we continue to talk about the design of the study, the patients when they were randomized, was any type of biomarker or anything that was done, or was just a randomization one-to-one? Suresh: Well, randomization was two-to-one and patients had to have EGFR exon 19 or 21 mutation. We have of course a lot of exploratory biomarker analysis built in, including longitudinal plasma collection, which we hope to analyze and report in the upcoming meetings. Narjust: So the results were impeccable, impressive. Only a few times I have tear up at a plenary session. So could you summarize for us some of the results from the LAURA trial? Suresh: Absolutely. The independently assessed progression-free survival was 39.1 months for patients treated with osimertinib, compared to 5.6 months in the control group. And the hazard ratio here was 0.16, statistically significant. And we saw that the benefit was distributed across all key subgroups of patients. So we felt that this was a compelling result that would change the standard of care for patients with this particular condition. Narjust: It was impressive. And after your presentation, we saw a lot of changes in the graphs before were putting GRAFs in between the graphs because it separates so much. Somebody put a truck because the separation in the GRAF is so impressive. So we always are seeing EGFR as a whole disease. But there are differences with the two more classical mutations. Do you notice any difference in outcomes of the deletion versus a translocation? Suresh: Well thankfully, we didn't see a difference in hazard ratios in a substantial manner. We saw exon 19 patients benefit, exon 21 patients benefit. So for patients with the activating mutations, we would feel comfortable using osimertinib. Narjust: So as we were worried about toxicity when we add new regimens, there was a concern about radiation pneumonitis. We know that osimertinib can cause pneumonitis on its own. Do you see any significant radiation pneumonitis in these patients? Suresh: The good news is we did not see a major problem there. We definitely see chemo radiation related pneumonitis in 38% in the control group and 48% in the osimertinib group. But these were primarily grade one or two. The grade three pneumonitis rate was very, very low, less than 2%. And these can be managed with appropriate treatment interruptions and adjustments. When we look at interstitial lung disease, once again, it was 8% in the osimertinib group. We measured ILT as a group term. And again, these were grade one or two. So we feel that this treatment can be administered to patients without major pulmonary sequences. Narjust: And we need to remember that you're comparing to placebo compared to all the trials. So the toxicity needs to be taken with grain of salt because we are comparing to placebo. Suresh: That's right. And the fact is when patients come off of chemoradiation, they have lingering side effects, even for a few months after completing treatment. And that's what we see in the placebo group. On the other side, we also see responses in the placebo group because late responses do happen with chemo RT. Narjust: And it's true, because radiation continues to provide benefit and help us understand the disease as well. Suresh: Yes. Narjust: So we're almost coming to the end of our conversation and I would like to ask you to summarize the results of the LAURA trial. How will you explain this to your patients and their family members? Suresh: Well the key message here is for patients with stage three unresectable non-small cell lung cancer with an EGFR mutation, the disease biology is aggressive. So chemoradiation is the first step of this multistep treatment program. And the second step of their treatment will be osimertinib. I would explain to them that there is improvement in progression-free survival. There is lower likelihood of progression to the brain and even to other sites in the body. The side effects of osimertinib are consistent with what we have come to know. So our physicians would be comfortable managing them through this. The big question is, would there be an improvement in overall survival? We are anticipating those results in the next 18 to 24 months. At this point, there is a favorable trend towards improved survival with osimertinib, but that's not statistically significant. So we will be looking to present those results in the upcoming meetings as well. Narjust: Yeah, because you have less than 20% material, the data or so. Suresh: The maturity is only 20%. And I would also point out that over 85% of the patients in the control group went on to get a third generation EGFR inhibitor. 81% got just osimertinib alone from the control group after progression. So we're happy to see that patients are getting additional therapies. That was always a concern when you treat patients on clinical trials. Narjust: And I just want to mention that as we come to the conversation. I really like that because a lot of the criticisms we have for ADORA was the crossover. And I think for LAURA, that issue is less significant and patients were able to get access to the appropriate drugs. Suresh: Yes. Thank you. Narjust: Well thank you so much for your time and we can't wait to talk to you, probably in a year or two years, with that overall survival data. Suresh: I look forward to that. Thank you for having me.