This transcript has been edited for clarity.
H. Jack West, MD: I'm Dr Jack West and I'm a thoracic medical oncologist at the City of Hope Comprehensive Cancer Center in Los Angeles.
Julia Rotow, MD: I'm Dr Julia Rotow. I'm a thoracic medical oncologist at the Dana-Farber Cancer Institute in Boston, Massachusetts.
West: We're here at ASCO 2023 in Chicago, where we've been seeing some blockbuster presentations in thoracic oncology. Many of these have brought up important questions and clinical implications that we need to discuss a little further.
One of the most important trials, as you would expect based on its status in the plenary session, was ADAURA, which tested adjuvant osimertinib, a third-generation EGFR inhibitor that we've overwhelmingly come to use as our first-line standard of care for more than 5 years. This was initially presented back in 2020 at a plenary session as well.
The trial was designed to test the value of 3 years of adjuvant osimertinib or placebo, generally, but not mandated to be after adjuvant chemotherapy for patients who had resected stage IB to IIIA EGFR mutation–positive non–small cell lung cancer. We've known for years that the disease-free survival benefit is overwhelmingly positive, and this led to an FDA approval that has really made this approach essentially a standard of care, if not a mandate. It is very widely practiced, at least in the US.
This year, Roy Herbst presented the data again, but now focusing on overall survival. We knew from a press release a few months ago that it was positive for this, but the question was, how positive? We saw that it's pretty substantial, with a hazard ratio of 0.49 and an absolute improvement at 5 years in the broader population of stage IB to IIIA of 12%.
It was definitely substantial, but one of the issues with this is that the control arm did not have everyone get osimertinib at progression if they had relapse, and only 43% of the patients who got subsequent treatment at all ended up getting osimertinib, with the others getting another EGFR TKI, which we know is a little inferior — if not a lot inferior — or chemotherapy, which would not be our choice.
I just put it to you: What do you think is the clinical significance of this finding with the context that this was already a standard of care but many people have been holding out to see the overall survival to really clarify what it does or doesn't do for patients?
Rotow: I agree. This was, I think, very exciting, compelling data, but also very important data to consider in the broader context. For many of us, our standard of care had shifted based on the disease-free survival data. Of course, the gold standard in any adjuvant setting is the overall survival. That's really what we're trying to modify when we're treating after curative-intent therapy.
These data, I think, were particularly important because of what we know about earlier-generation EGFR TKIs in the adjuvant setting. Erlotinib and gefitinib, first-generation TKIs, had been looked at in the adjuvant space where they prolonged disease-free survival but did not prolong overall survival.
So there was an open question: Will we see an overall survival advantage with osimertinib in this setting? This is the third-generation TKI with better CNS activity. It was a longer duration of treatment at 3 years instead of 1 or 2 years. These may have impacted some of the results.
And we've seen now the overall survival analysis showing an improved overall survival.
My takeaway is that this reinforces my own practice at this time, where I am using adjuvant osimertinib for 3 years after resection in stage IB through IIIA lung cancer.
West: The trial went to 3 years, and it's interesting that the follow-up disease-free survival data presented and published last year showed that, while there was still a big DFS benefit, it was pretty clear that the DFS curve was dropping off as soon as you ended that 3-year period, which is the same pattern that we've seen with the other EGFR TKIs. It raises the question, are we curing anybody or are we just deferring the relapse?
If the latter, can you make it up on the back end by just treating the people who need it if or when they relapse, and sparing everyone else years of a therapy that costs a large amount of money and has toxicities and must be sustained for years at a time?
We have a significant survival benefit at this point in time, but will that also be clearly attenuated, starting with another 9 or 12 months of follow-up?
Rotow: I agree. You can see the shape of the disease-free survival curves. They absolutely do begin to come together, mirroring what we've seen in older drugs after that end of 3-year treatment. What I suspect long term is, as you have said, probably some patients need a very prolonged course of TKI therapy, such as those who really have residual microscopic disease, not radiographically apparent disease.
There are those patients who are cured by surgery who generally need no adjuvant therapy at all. Of course, it's a challenge to know the difference between these two patient populations.
Now, we do have those tools emerging, right? We're going to have minimal residual disease assays available, which continue to demonstrate in prospective and retrospective studies that the presence of minimal residual disease — for example, within the plasma on a blood test — predicts for very high relapse risk, and the absence in an adequately sensitive test predicts for relapse-free survival.
Aspirationally, while we may need to apply these new data to most patients now, I hope in the future that we will use more dynamic measures to predict better who truly needs this therapy.
Now, you mentioned the curves coming together at 3 years. I agree. Why would we choose that number? You either need therapy or you don't. Our older studies, or prior studies, did 1-2 years. There are studies ongoing looking at even more prolonged courses of treatment.
West: In the meantime, we're now 3 years out from the initial presentation of the data. You're going to start having patients where you have to face this decision. Do you stop for good or do you keep it going?
Rotow: Exactly. That decision point is coming. We're just about 3 years out from the original approval in the adjuvant setting, so we're going to have to make this decision with our patients. There are trials looking at this. The target study is looking at 5 years in the single-arm study. We will eventually have more data from that, though of course, not guiding our decisions today or tomorrow.
The stakes get even higher in, for example, patients treated with chemoradiation for curative intent. The LAURA study is looking at indefinite osimertinib as a consolidation therapy strategy. That's a large commitment on behalf of the patient to an ongoing treatment that carries some toxicities over time.
West: And in patients who may be cured without it.
Rotow: Exactly.
West: We don't want to have them taking it as an alligator repellant if they don't need it at all.
Rotow: I will say that with the trends we saw in the ADAURA data showing increasing magnitude of overall survival benefit in our higher-stage patients, I certainly hope that we'll see benefit as well in our post-chemoradiation patients. It does speak to how critical it is to have biomarkers and a more personalized way to select patients for these sorts of very long-term therapies.
West: How concerned or bothered are you about the control arm having such limited access to osimertinib? There was an amendment to the protocol that allowed patients access to osimertinib after April 2020, but this was our standard of care years before that.
I think it's unfortunate when patients don't have access to the best treatments we would routinely use in our own clinics. It makes it a trial that isn't purely about timing of adjuvant vs treating at relapse, if needed. Now it's about access. It's 100% of patients getting treated vs less than 50% of patients on the other arm getting access to osimertinib at any time over the course of their disease.
Rotow: I agree because you want a clean study where you're truly looking at, does it matter starting it first vs starting at relapse? Instead, we have starting it first vs starting at relapse, but maybe not with what is our current optimal standard of care for metastatic EGFR lung cancer. That does make the data a little more difficult to interpret.
I would love to see a subgroup analysis of only those patients who had drug access on crossover and really look at that population. Of course, that biases in the other direction, where we know in routine clinical practice that there's always dropout as you move from one line of therapy to the next. There will always be patients who won't get that first-line metastatic therapy or that second-line resistance therapy.
West: It's not more than 50% of our patients.
Rotow: It's not more than 50% — I agree. That is, I think, a real caveat to put on these data. In my opinion, it doesn't stop me from using this regimen. To me, it's our standard of care at this time, but it is something to be mindful of when interpreting the data.
West: Well, you brought up the issue of minimal residual disease and doing serial testing. I hope that we get to a point where they are with CML, where you can do these assessments and really give bespoke therapy just as needed or withdraw it, monitor, add it back as needed, but not get behind the curve. That's where I hope we get to.
Rotow: I agree. We're not there yet in lung cancer, but we're beginning to have the tools to do it. I think as we get more highly sensitive residual disease testing, hopefully we can again aim for that undetectable status and adjust therapy as needed to continue to achieve it. I hope that's our future in lung cancer.
West: Thanks. This has been a great discussion of a pretty complex topic. Even though the topline story is extremely positive, it's always a little nuanced.
Rotow: Absolutely. Thank you.
H. Jack West, MD, is an associate professor at City of Hope Comprehensive Cancer Center in Duarte, California, and vice president of network strategy at AccessHope in Los Angeles. West serves as web editor for JAMA Oncology, edits and writes several sections on lung cancer for UpToDate, and leads a wide range of continuing medical education and other educational programs.
Julia Rotow, MD, is the clinical director of the Lowe Center for Thoracic Oncology at the Dana-Farber Cancer Institute in Boston, Massachusetts. Her research interests include the development of targeted therapies and immunotherapies for the treatment of oncogene-driven lung cancer.
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Cite this: Jack West and Julia Rotow Discuss ADAURA Trial Takeaways - Medscape - Jun 13, 2023.
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