Roundtable Discussion: Fontaine Debates the Practice- Changing Implications of the ADAURA Trial for NSCLC

Jacques Fontaine, MD

Treatment of patients with EGFR-mutant non–small cell lung cancer in the phase 3 ADAURA clinical trial resulted in practice-changing disease-free survival with tolerable safety.

During a Targeted Oncology Case-Based Peer Perspectives event, Jacques Fontaine, MD (Moderator), senior member, Departments of Thoracic and GI Oncology, director, Mesothelioma Research and Treatment Center, program director, Robotic Thoracic Fellowship Program, Moffitt Cancer Center, and professor, University of South Florida in Tampa, FL, spoke with 6 other clinicians about how the ADAURA data will impact the field.

FONTAINE: [Is this a barrier to testing] because you believe it’s a medical oncologist who should be sending it? Or should it be after a tumor board? Or is it up to the surgeon to send it? Is it OK to send it within the first 14 days? Are you encountering any insurance issues?

VILLAMIZAR: With the new data, if they have invasion, we’re asking the medical oncologists to do molecular testing. If they have the driver mutation to receive osimertinib [Tagrisso], that’s what we are advocating for. Then, any tumor that is above 4 cm, they are not that hesitant to do regular adjuvant chemotherapy. The other categories of high-risk patients may be a little more hesitant. For any tumor more than 4 cm, most of our medical oncologists would go with it if [the patient’s] performance status is good.

FONTAINE: I think that’s the same thing that we experience here, that for [patients with] stage IB, based on tumor size, we talk about adjuvant systemic therapy or basic chemotherapy, but few patients end up going for it. But if their tumor is EGFR positive, seeing that there’s much less toxicity with the tyrosine kinase inhibitor [TKI], a higher percentage of them will end up taking it. As the stage goes up to stage III, I think we all see that a higher percentage of patients are willing to do it for that 20% relative risk reduction for standard chemotherapy.

FONTAINE: Are you more likely to send them if they’re a stage IB, just based on size? Do you wait for them to have N1 disease? Do you look at lymphovascular invasion? What are some of the criteria apart from performance status?

SCHWARTZ: All the above. So if somebody has [a tumor] greater than 4 cm, I’m clearly sending them to have a conversation with our medical oncologist about adjuvant therapy. If they have lymphovascular invasion, all these are important markers for systemic disease.

FONTAINE: Are you more likely to send them if they have N1 disease? Does the fact it’s stage II—because stage II can be stage II just based on size without N1 involvement—[affect the decision more?] What’s your likelihood to send them to medical oncology if it’s a large tumor, a 5-cm tumor, but node negative, versus a 1-cm tumor with a level 10 lymph node N1 disease? Does that change your perspective, if it’s large size but all nodes negative vs small size but node positive, both stage II?

SCHWARTZ: No. I refer all those to medical oncology for adjuvant therapy.

PETTIFORD: [At my institution], many of these patients are discussed in a multidisciplinary lung tumor boards, pre and post operation. So we have a plan going into surgery as to whether this individual will require adjuvant therapy. For a large-sized tumor, I will discuss with the patient the need for adjuvant treatment, and it’s not uncommon for patients to express some reticence, regardless of whether it’s a large tumor or a smaller tumor with N1 disease. It’s the reticence about undergoing treatment. I reassure them that at a minimum they should engage in the discussion with their medical oncologist.

Once we have the final pathology reports, we will re-present those patients at our multidisciplinary tumor board and come up with some type of a consensus on our treatment. I think that when the patients hear from the surgeon that “Hey, I’m not the only one driving the bus, we’re going to discuss this in a forum,” that’s a little bit more reassuring for them.

FONTAINE: One item I get from some of our medical oncologists is that when they see these data, they say, “Well, we really need to look at overall survival [OS], because that’s what patients want to [know]: if they’re going to live longer.” That’s true and that’s important, and we don’t have those data yet. However, my rebuttal is that disease-free survival [DFS] is equally important for these patients, especially in terms of quality of life.

[For example], if you have 2 patients that are going to live the same amount of time—2 patients that are going to live, let’s say, 60 months, but the first patient [has a disease recurrence] within the first 12 months and they recur in the brain and have headaches, seizures, they need to get treatments, they’re in and out of the hospital very often, and their quality of life is terrible. Even though they’re both going to live 60 months with treatments, one recurred earlier and they have a poorer quality of life. So I think that, yes, it’d be important to wait for OS, and I think OS is very important, but it’s not that we should downplay an increase in DFS, because that impacts a lot in a patient’s quality of life, anxiety levels, and everything else.

RAMSAY: I couldn’t agree more. I had a similar discussion recently with someone on a different medication for metastatic liver cancer, and again, this medication did not increase OS, but it did increase the progressionfree survival. There’s always going to be a cost-benefit and everything’s not right for every patient. You have to look at each patient individually. But, if you can offer improved quality of life for certain patients, that is absolutely a benefit.

TROTTER: Just to step back a second, we typically operate on these patients, and then they go to the oncologist. [This treatment] is practice changing in the sense that we may be stepping over to participate even more with the tumor board, but I see this as probably opening up that dialogue with our oncologists that we work closely with.

Now, is it going to make a huge difference? I don’t know the answer to that question. Quality of life is important; I’ve seen patients who have quit adjuvant therapy because their quality of life was so bad. Their quality of life until they died was a lot better without the chemotherapy. I’m not saying I have a jaded view, but I have seen a lot of this over the years. Overall, I think it’s hopeful, and as we move ahead, this is going to be more applicable to our surgical practices than it has been in the past.

FONTAINE: Do you send off molecular testing on all patients that you resect? Do you wait for the medical oncologist to send it? What’s your practice?

TROTTER: We pretty much get our marching orders from the medical oncologist. We’re not as bad as some places doing [coronary artery bypass grafting] where they say “I want this, this, and this grafted.” Let’s face it, we do what our referring doctors want us to do. So we let them guide that part of it.

BHATIA: Well, I agree with what Dr Trotter said, and I think that this has become a much more multidisciplinary approach than it has been in the past. We used to just go in and resect the tumor, and then we’d send the [patient] back to the oncologist or the referring physicians, and then you basically never saw them again. Now, we see these patients more than once and weigh a decision in terms of how they’re going to be treated. Quite frankly, patients are getting smarter about this, too, and they’ll come in and even ask us what we think. If we can garner a good multidisciplinary approach and instill confidence in the patients, it’s a win-win for everybody.

FONTAINE: I think for me, the way it’s really changed is with the patients that are resected where I work…come straight to the surgeons, and then it’s up to the surgeons to refer them to the medical oncologists, unless they come with stage IV disease or very advanced disease.¹ In the patients where we find a lesion, and it turns out that it’s stage II disease and all the lymph nodes are negative, but it’s a large lesion and the patient has a borderline performance status, I would be hesitant to recommend to the patient adjuvant standard chemotherapy. Even though it’s a 4-cm lesion, if the lymph nodes are negative, there are significant adverse effects from chemotherapy in terms of quality of life, and the relative risk reduction is only 20%.

With these data that I’ve seen, only for DFS, [osimertinib is] much easier to tolerate; only 20% grade 3 or more [adverse events], most of them being diarrhea or stomatitis. Second is that the relative risk reduction is 60% and not 20% for DFS. I think that would be very useful, and that’s how it changed my practice.

FONTAINE: How do you predict you will use osimertinib in patients with [EGFR-positive tumors] who’ve been resected? Would you use it now, or do you think it’s important to wait for OS data?

I can tell you that’s controversial because some of our medical oncologists would not do it until they get OS, and they feel that they want to wait for the data to mature. Although DFS is increased, they feel it’s not warranted yet.

SCHWARTZ: It begs the question, “How important is traditional adjuvant chemotherapy going to end up being for these patients?” Do they need to get both traditional chemotherapy and this new medication, or can we forgo the previous chemotherapy?

FONTAINE: I think my take on that is that standard cisplatin doublet therapy has been proven to work in the adjuvant setting for these patients. The data from the ADAURA trial show that patients who got chemotherapy did even better. The patients who got chemotherapy did better than patients who did not, but if you look overall at the group, the groups were a balance in terms of how many got chemotherapy or not, and both derived a benefit.

I would not withhold chemotherapy for patients who can tolerate it and in whom it’s indicated. I would give it, but that doesn’t mean because you give chemotherapy that you can’t give osimertinib afterwards and vice versa; just because you give osimertinib does not mean that you should not give chemotherapy before. So the indication for chemotherapy has not changed. Whether or not you give chemotherapy should just be based on your clinical decision, not whether you’re going to give osimertinib.

If you think that a patient has an indication for chemotherapy, will tolerate chemotherapy, then in my opinion, that patient should receive chemotherapy and then be considered for osimertinib afterwards. If they decide not to go with chemotherapy, that doesn’t mean that you shouldn’t give them osimertinib afterwards either. Especially as you’re looking at stage III disease, I think that’s where chemotherapy really has the most benefit, as does a TKI. The higher you go in the stage, the more you should be prescribing or recommending chemotherapy, as well as a TKI.

PETTIFORD: I think [these data from the ADAURA trial] are extremely compelling and, quite frankly, exciting when you look at the DFS. I noticed that about 60% of the patients in each arm were of Asian descent. What subset of those patients had adenocarcinoma with a lepidic growth pattern, especially the IA and IB stage patients? Did they have a solid tumor arising within an area of ground-glass opacity, and what implications does that have on DFS and OS, if a substantial number of those patients maybe had a solid tumor?

FONTAINE: Most patients on the trial [were Asian because most sites from the clinic were in Asia.] The vast majority also had adenocarcinomas. Now, whether they were lepidic pattern and minimally invasive, we don’t know. These data in the trial are not that granular to [let us] know what percentage were lepidic or not. However, we do know that the more lepidic they are, the better they’re going to do. The more lepidic they are, the higher [percentage of Asian patients had an adenocarcinoma, so the more likely] they are to have an EGFR mutation in their tumor. Those patients do better than if they don’t have an EGFR mutation.

However, to answer your question frankly, I don’t have the number of patients in each arm. All we know is that both arms, whether they got osimertinib or a placebo, were balanced in terms of a percentage who were Asian. They were balanced in terms of the percentage who had stage I vs stage II vs stage III disease and were balanced in terms of histology as well; but, as lepidic vs not, we don’t know.

TROTTER: Is there any information out there about third-party coverage for this? Because that’s going to come up relatively quickly.

FONTAINE: I don’t have the answer to that. But I can tell you that if it’s not covered by insurance, there are different ways. If you speak to your AstraZeneca representative, they can point the patient to different ways to pay for it or have it covered. There are many, many resources, and your local representative can help you with that, but I can’t tell you in terms of insurance coverage.

_REFERENCE

_{Wu YL, Tsuboi M, He J, et al. Osimertinib in resected EGFR-mutated non–small cell lung cancer. N Engl J Med. 2020;383(18):1711-1723. doi:10.1056/NEJMoa2027071}