Latest Overall Survival Analyses in Resected EGFR-Mutated NSCLC

Dr. Zofia Piotrowska: I think it was with great enthusiasm that we were all awaiting the plenary session at this year's ASCO to see those overall survival results. And indeed we did, we did see Dr. Herbst present the updated results from the ADAURA data, including the overall survival analysis at this year's ASCO 2023. And what we saw is that indeed it was positive for overall survival. So, the median follow-up was 62 months in the osimertinib arm and 60 months in the placebo arm, and we saw that, for the primary-study population of stage-2-to-3a disease, the overall survival hazard ratio was 0.49. So, if we look at the landmark, five-year survival, it was improved from 73% in the placebo arm to 85% in the osimertinib arm. And the results in the overall study population bringing in those stage 1b patients were actually very, very similar. The hazard ratio there, again, was 0.49, and the improvement was from 78 to 88 percent. We saw that when we looked across subgroups, that benefit was maintained, really, across subgroups. When we looked by stage breakdown, as we had seen with the DFS, I think, the magnitude of benefit was higher in the higher-stage patients, which we would expect, and in the stage-3a patients, the OS hazard ratio was 0.37. So, really emphasizing the benefit for them. I think that, really, the benefit was maintained, again, across different subgroups, across eGFR mutations although, as we've seen in the metastatic setting, the exon 19 patients tended to do a little bit better. And importantly, and we'll come back to this, we saw that benefit was maintained whether or not patients received adjuvant chemotherapy, which as per the investigator's choice. In the study. There was a little bit of data, although I think it would be interesting to see more about the post-treatment outcomes and the therapies that patients were able to access. We did see that more patients access osimertinib in the placebo arm than in the osimertinib arm, but I think we need to see a lot more granularity to really understand the impact and to see what access looked like for those patients. But overall, I think there was a lot of enthusiasm. And so, maybe I'll ask the same question of everyone on the panel say what was your take on that overall survival data, and did it change your perspective? What do you think was the key take homes? What are you going to talk to about your patients when you see them in the clinic next week with this data in hand? Lyuda, maybe I'll start again with you.

Dr. Lyudmila Bazhenova: I think it undeniably improves overall survival. I think the data is very strong. The absolute benefit is more than 10%. What I think we don't know yet is if we are curing the patients. But in my opinion, the goal of the oncologist is one. Our major goal is to make our people live longer. So, at this point, I was an adopter and it just reinforced what I do, but when I'm explaining to the patients, I don't think we can use the word 'cure' yet, because those patients with eGFR mutations tend to recur later, and so, maybe five years is not enough, but it’s clearly making our patients live longer, and that's- I think the most important factor.

Dr. Zofia Piotrowska: And Benjamin Bessie, I think did a beautiful job of kind of summarizing and making that point and saying we need more time and more follow-up to really know," but it certainly seems to improve outcomes, and there's essentially about 10% of patients that wouldn't have been alive if they hadn't received that osimertinib. So, it was really great. Nick, how about you?

Dr. Nicholas Rohs: I think, definitely, we've reaffirmed that it makes people live longer. It's practice reaffirming what we're doing right now, at least what I was doing in my clinic, but I harbor the same concerns that you have, is this truly curing people? But again, we talked about that's not- We want to have people live longer, we also want them to live better. And I think that most people are living better. I do think that Dr. Bessie did a great job of also highlighting the fact that Tagrisso or osimertinib is not fully benign as far as the side effect profile. So, we do have to take that into account, but I think that this is making people live longer. And as we see the pace of eGFR treatment going at light speed right now, who knows what we're going to have five years from now on a patient who goes on adjuvant osimertinib. So, I think that that's absolutely a valuable time point to get them to.

Dr. Jay Moon Lee: I would just add to it that ADAURA really put the stamp of sealed that DFS is a surrogate for OS for a TKI in the early-stage setting. To me, that was very meaningful and significant from the ASCO presentation with ADAURA OS data. And then secondly, when you look at the time of relapse amongst patients, what's the next therapy that those patients went onto? And the highest percentage 41% went on eGFR TKI, which alludes to everything that my colleagues are saying that patients probably need to be on it longer. And then the other finding that I found interesting is that the second drug that patients most likely went onto was other TKIs, suggesting resistance mechanisms. So, this really leads to the future of, we need combination-targeted therapies in the early-stage setting, a more personalized approach in the importance of testing to figure out the resistance pathways and combination approaches, just as we're doing in the late-stage setting, but we need to bring that to the early-stage setting.

Dr. Zofia Piotrowska: Such an important point. I absolutely agree.