At the 2020 American Society of Clinical Oncology virtual scientific meeting, over 100 sessions and thousands of abstracts on the latest emerging topics in cancer treatment were presented in an all-online format. MedPage Today brought together three expert leaders in their field — Sara Tolaney, MD, a breast oncologist at Dana-Farber Cancer Institute; H. Jack West, MD, a thoracic oncology specialist from City of Hope; and Shilpa Gupta, MD, a genitourinary oncologist from the Cleveland Clinic — along with moderator Hope S. Rugo, MD, of University of California San Francisco’s Comprehensive Cancer Center, for a virtual roundtable discussion on the new and potentially practice-changing data from the meeting.
In this second of four exclusive MedPage Today episodes, the discussion features West and Rugo on the latest advancements in treatment of lung cancer.
Episode 1: Advances in Breast Cancer
Following is a transcript of their remarks:
Hope Rugo, MD: Hello. Welcome to this virtual roundtable, where we will be discussing some of the key data that emerged from this year’s ASCO meeting. I’m Hope Rugo, professor of medicine and director of breast oncology and clinical trials education at the University of California San Francisco’s Comprehensive Cancer Center.
Today I’m joined by three expert leaders in their fields: Dr. Sara Tolaney, a breast oncologist at Dana-Farber Cancer Institute, Dr. Jack West, a thoracic oncology specialist from City of Hope, and Dr. Shilpa Gupta, a genitourinary oncologist from the Cleveland Clinic. Welcome and thanks for joining me.
Now, we’re going to turn our focus to lung cancer and we’re fortunate to have Dr. Jack West here, a thoracic oncology specialist from City of Hope. We’re going to start in talking about one of the most controversial areas from ASCO that even I know about — because it was all over Twitter and my email, which is interesting — the ADAURA trial that looked at adjuvant therapy with osimertinib in patients with non-small cell lung cancer. Can you tell us a little bit about that trial design, and also the results?
H. Jack West, MD: Of course. Thanks for having me, Hope. I’ll say that ADAURA was really, I would say by a pretty good margin, the most well-recognized and discussed trial in the lung cancer setting from ASCO. It was in the plenary session and I would say it deserved that visibility as a very positive trial for adjuvant osimertinib in patients with stage IB-IIIA resected EGFR mutation-positive non-small cell lung cancer.
It was a randomized trial of osimertinib versus placebo and it showed a very strong benefit in disease-free survival — which was the primary endpoint of the study — with a hazard ratio of 0.17 for patients with stage II and IIIA disease, which was actually the defined primary endpoint. They added in stage IB, and when they added that, the hazard ratio was 0.21 for DFS. There is really no question that this was a very impressive result.
The osimertinib or placebo was given up to 3 years, and so I would say that the questions were largely around the clinical significance of disease-free survival versus what many of us would have hoped for in trying to get overall survival as the ultimate arbiter of what should define postoperative therapy, at least historically has, in resected lung cancer.
Really, one of the challenges is that osimertinib is so effective — and I would also say well-tolerated enough — that it does lend itself to longitudinal administration. That the question is, “Could these patients who relapse potentially do just as well by getting osimertinib upon relapse, and then do well for years and years, and still have a very good overall survival?”
That’s a question that we don’t have an answer to. Those of us who are, at least, questioning the clinical significance of it really center on the question of, “Is this really that surprising?” Anybody would have known that patients on ongoing osimertinib for years are going to have a significantly improved disease-free survival. That’s just not the key question to us.
I think we have also some debate about what our role should be as oncologists in terms of concern about the societal impact in terms of cost of therapy. I don’t think we would be having much debate if this was a much less expensive treatment. But the fact that it’s over $200,000 a year for 3 years and potentially patients would continue on it beyond that if they could, I think this is something we’re struggling with as an oncology community. How much should we focus just on the patient in the exam room? How much should we be shepherds of limited societal resources? This is where I think the debate comes from. It’s not that it isn’t a very impressive difference in disease-free survival. It’s really just a question of whether disease-free survival is the question we should be focused on.
Rugo: Let me ask you two questions about that because it really has huge potential to be practice-changing. Do you think that the survival benefit might not be seen as early because patients can be rescued with other drugs, although they are likely to progress and eventually die of their cancer more than if you treated, maybe, in the adjuvant setting? It’s hard to know. Or is it more the population of patients, where there’s a lot of competing mortality? Then the second thing is which patients are you going to be treating with this agent? If it was approved now and you could give it as adjuvant therapy, who would you give it to?
West: With the question of potential outcomes with overall survival, I think it is likely that this dramatic difference in disease-free survival will ultimately translate to an overall survival benefit over… I would say this is a population where the risk of the cancer is much greater than the risk of any competing comorbidities. But there are mechanisms where there could be a much greater efficacy from adjuvant osimertinib. The first being that there is a greater efficacy by treating a much lower burden of micrometastatic disease than even the opportunity to treat, it becomes macrometastatic later.
Then the second is that we know there is some fallout of patients and attrition, potentially patients developing significant brain metastases — or worst of all, leptomeningeal carcinomatosis — who may not get that opportunity to get treated with the best treatments that we have. I think that’s a pretty low number, but that, I think, is the two mechanisms that we might see, and very likely would see, an improvement in overall survival. But we’ll follow the results of the trial and see what happens.
In terms of what to do in the clinic, I personally feel that even though I am less than thrilled by the lack of overall survival and the early presentation of disease-free survival as what we need to work with, with a drug that I strongly suspect is going to be FDA-approved, and with such compelling results even for a surrogate endpoint, I’m going to talk about it with all of my patients.
I think it is most compelling for patients with stage II, IIIA disease. The patients with stage IB non-small cell have a disease-free survival hazard ratio in that isolated group of 0.5, which is good, but not as high-risk, and also a group that very well may have an equilibration of overall survival.
But I would present it to everybody. I would very likely softly recommend it for my patients with higher-risk disease. And I just think we need to be mindful as we discuss this of how to present it so that we don’t overstate the benefits and what we know versus what’s still speculated.
Rugo: It’s really interesting. It’s such a fascinating trial and very exciting results, and of course it’ll be interesting to see what happens with survival over time. We have time just briefly to talk about three other studies with — it’s kind of interesting — looking at immunotherapy and radiation. The CheckMate-9LA trial looked at nivolumab and ipilimumab with 2 cycles of chemotherapy in advanced non-small cell lung cancer that didn’t have a driver mutation and showed an overall survival benefit, but that hasn’t been the standard of care. Would you now start using that FDA-approved regimen as opposed to some of your other standard approaches?
West: CheckMate-9LA did show a significant benefit of 2 cycles of chemo with nivo and ipilimumab over chemotherapy alone, for up to 6 cycles, and that was clearly a positive study. It is now FDA-approved. It was actually FDA-approved days before we actually saw the data at ASCO. I think it will struggle to find a footing because the true competition for this is not chemotherapy, which is a comparator arm from 2015, 2016, but not over the last 2 years, where we have overwhelmingly used pembrolizumab, commonly with a chemotherapy doublet, sometimes as monotherapy, in patients with high tumor PD-L1.
Many of us have been, really, quite happy with the utility and efficacy of these choices. Without a direct head-to-head comparison, we’re left with a cross-trial comparison. There is a hint that maybe the tail of the curve is higher on the nivo-ipi combination trials like CheckMate-9LA or CheckMate 227, but again, this is a kind of apples to oranges comparison.
There is also a questionable value of still having a chemo doublet to go to as a second-line treatment when patients subsequently progress and we weigh that versus the general mantra of, “Give your best treatments upfront, because we really cannot count on what’s going to happen afterward.”
I think it could have a place. It’s definitely an option, but it doesn’t bubble up clearly as anything incrementally better than what we’ve been using for the last few years.
Rugo: Of course, it’s always good to have options, but it’s so interesting that some of these studies compared to something, but in the meantime another treatment gets approved, and so you end up with a trial that shows great results, but is compared to something you’re not going to do. That’s a big problem.
There were also of couple of trials that looked at radiation therapy, trying to alter radiation therapy, to try and improve outcome. A trial from Scandinavia that looked at twice-daily radiation therapy for limited disease small-cell cancer, which I think is very interesting, showed an improvement in overall survival.
Then a trial from China, the SINDAS trial, looked at treating oligomets… which is a great interest, I think, across malignancies… with SBRT-added EGFR inhibitor therapy in China. What is your take on these two? How would you put them into practice?
West: I think that the trial by Grönberg and colleagues out of Scandinavia that looked at escalating twice-daily chest radiation, along with concurrent chemotherapy for patients with limited disease small-cell, that compared 45 to 60 Gy on a BID schedule and demonstrated a very impressive improvement in overall survival at 2 years. It was 73% at the higher dose versus 46% in the lower dose. It did not show any increase in toxicity.
Frankly, I think some of us are just scratching our head thinking, “That’s almost too good to be true.” But overall survival is a hard endpoint and it’s really hard to argue a substantial improvement and not want to factor that in when you’re talking with your patients about the treatment approach.
I think there are challenges about a twice-daily, just in terms of the practical issues and spending much of your day, if you’re a patient, getting your radiation in the morning and then again in the afternoon, particularly, maybe, in a world of coronavirus risk. On the other hand, we have to prioritize the disease we know they have over the potential risk of something they don’t. I think that this is an approach that really deserves to be carefully considered moving forward because results are quite impressive.
Then with regard to the question of the SINDAS trial, which was a Chinese study in EGFR mutation-positive patients who received a first-generation EGFR inhibitor, and then could either get stereotactic body radiation therapy to up to 5 sites of disease or not… and this was at their initial presentation, not as consolidation after several months of treatment. This trial showed a significant improvement in progression-free survival, as well as overall survival.
The control arm that just got the EGFR inhibitor alone didn’t do quite as well as we’d have hoped, but these results build on the data we’ve seen in many other trials, many of them still pretty small. But when you look at the aggregate, the consistency, and the magnitude of benefit, I think it really argues at least for careful consideration of this kind of approach, maybe upfront, but especially as a consolidation for those with very limited residual disease, especially in a setting where we have very effective systemic therapies for these patients, whether it’s driver mutations and targeted therapies, or immunotherapy, and especially if there’s a very limited extent of disease of just a few sites.
We’re going to see more work on this including in larger randomized trials, but it’s all building toward similar conclusions that I think should force us to revisit the role of local therapy in metastatic disease.
Rugo: That’s really interesting. It’s so fascinating to hear about these tremendous advances at this year’s ASCO. I really appreciate you sharing the data and your perspective in our ASCO update. Thanks again.
West: It’s a pleasure. Great talking to you.