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Dr. Justin Gainor: Welcome to The ASCO Post Roundtable Series on Updates in Lung Cancer. I'm Dr. Justin Gainor, the director for the Center for Thoracic Cancers at the Massachusetts General Hospital. Joining me today are two of my colleagues, Dr. Ibiayi Dagogo-Jack and Dr. Jyoti Patel. I'd like to ask each of them to introduce themselves now. Dr. Dagogo-Jack?
Dr. Ibiayi Dagogo-Jack: Hey everyone, I'm Ibiayi Dagogo-Jack. I'm a thoracic oncologist at Mass General Hospital, and it's a pleasure to be here.
Dr. Jyoti Patel: Hi everyone, I'm Jyoti Patel. I'm a medical thoracic oncologist at Northwestern University, and I direct the thoracic oncology program. Thank you.
Dr. Gainor: Great, thank you both for joining me. Today, we'll be discussing recent updates in lung cancer, including data from recent clinical trials and integrating these new developments into four patient case studies. Our fourth installment, we'll focus on therapy for PD-L1–positive, non–small cell lung cancer.
So we'll begin with case number four, and this is a 65-year-old man with a history of coronary artery disease, hyperlipidemia, and a 55 pack-year history of tobacco exposure, who really presented with an incidentally noted right lower lobe lung mass, that was identified during a workup for nephrolithiasis. So he basically had an abdominal CT that caught this and then prompted additional imaging. The dedicated chest CT confirmed a 4.5-cm right lower lobe lung mass and right hilar adenopathy. He had a PET-CT that showed just FDG avidity in the lung mass, as well as that right hilar node, but there was no mediastinal adenopathy or distant disease. A brain MRI was negative.
The patient subsequently underwent invasive mediastinal staging, which was negative for mediastinal lymph node involvement. And therefore the patient was taken for a right lower lobectomy, and final pathology showed a 4.5-cm, moderately differentiated adenocarcinoma with negative margins. There was a lymphovascular invasion present, and two 10R nodes were positive for malignancy, and all remaining lymph nodes were negative.
So this case, I would say more than some of our others is, I would say, a bit more controversial, but at the same time, timely. So I'll begin with Dr. Patel, and with the question of, is there a role for molecular testing in this patient? And if so, what testing would you perform?
Dr. Patel: So certainly given that he has had no carcinoma histology, I would, at the very least, do EGFR. We tend to, again, do full multiplex testing on all of our patients. And now, I would do PD-L1 on this patient based on some recent data. And I think that this would be appropriate for patients with IB to resective IIIA disease. Historically, we've been doing it as part of a research effort, but now I would argue that it's standard of care to at least do EGFR and PD-L1.
Dr. Gainor: Much to the chagrin, at least for me, but others, the staging system has changed in the last several years. And it's particularly relevant for when we're looking at many of the adjuvant studies that we're going to be discussing, right? Because when you're looking at the eligibility for those studies, they were really done under the seventh edition. And we're now using the eighth edition lung cancer staging.
And particularly, when we think about stage IB disease versus II disease, there are some changes there, right? And what we used to think of stage I, greater than 4 cm as our threshold for adjuvant chemotherapy, and in the new system that's stage II. So I just highlight that for our viewers, that it is important when you're looking at these recent adjuvant studies to pay attention to what staging system was being used at the time.
Dr. Dagogo-Jack, would your approach be any different for molecular testing for this patient?
Dr. Dagogo-Jack: It would not. I think that with an adenocarcinoma, irrespective of smoking status, with the recent approval of osimertinib, based on the donor data, I think you have to, at minimum, do EGFR testing. And internally here, we would do a PCR-based approach or a single gene assay. And I think PD-L1 testing is also important. We don't have any approved drugs in that setting, but I think it's becoming increasingly relevant.
Dr. Gainor: Yeah. And so to go on into this case, so this patient did have EGFR testing done. That was wild-type. PD-L1 immunohistochemistry was performed, showed a tumor proportion score of 25%. So depending on your threshold, positive or not. And so Dr. Patel, would you recommend adjuvant chemotherapy in this case?
Dr. Patel: Absolutely. So I think for the past 15 years, we would recommend four cycles of adjuvant chemotherapy for an estimated survival benefit of over 10% for someone like this. Right? And so his risk of recurrence is pretty significant. And so at the very least, we would say the survival benefit for smaller tumors up to stage IIIA is probably between 5% and 15%. And he's probably with the hilar nodes rated about 10%. So absolutely. I think that would be a level one recommendation for me.
Dr. Gainor: Dr. Dagogo-Jack? Your thoughts?
Dr. Dagogo-Jack: I completely agree. I think the recurrence risk, even with kind of a basic stage II is like a 50-50 shot. So I think that anything we can do to improve the chances of being cured, we should be pushing for.
Dr. Gainor: Yeah. I agree with both of you, and while this may be old data that is familiar to most, I think it is important to reaffirm that, that as we start thinking about the newer adjuvant data, that really there's still a role for adjuvant chemotherapy. In these studies, patients got adjuvant chemotherapy. And so, especially when we're going to be focusing on adjuvant PD-1 pathway blockade, all of those patients got between one and four cycles of chemotherapy. So, my personal view is we shouldn't be de-escalating therapy until we're curing more people with early-stage lung cancer.
Okay. So next up, and I'll let this go to either of you, would you recommend adjuvant PD-1 pathway blockade in this patient, assuming it was FDA approved?
Dr. Patel: So I would. Again, in the hope that we cure more people, but certainly I think Dr. Wakelee's presentation of IMpower was certainly interesting. And it was a study that gave us confidence on multiple levels based on PD-L1 expression, based on stage, for this patient that I would absolutely recommend immunotherapy at this juncture.
Dr. Gainor: And Dr. Dagogo-Jack, would you recommend adjuvant chemo in this, or adjuvant PD-1 pathway blockade if FDA approved?
Dr. Dagogo-Jack: I would, I think this is a perfect patient for it, based on the data. So PD-L1 positive, stage II to III.
Dr. Gainor: Okay. Okay. Just to be a little controversial. Does the degree of PD-L1 expression – this patient had 25% PD-L1 staining. Now IMpower010, just to walk people through this study a little bit. So this enrolled patients completely resected IB to stage III disease, under the seventh edition, and after patients underwent surgical resection and patients received one to four cycles of platinum doublet chemotherapy, they were randomized 1:1 to either atezolizumab, PD-L1 inhibitor, or best supportive care. And there was this hierarchical design in terms of the statistical plan, right? First it was focusing on patients who are PD-L1 1% or higher with stage II to IIIA disease, and then went down to all randomized patients with stage II to IIIA disease, and then, after that, looking at the whole population.
So I guess thinking about the metastatic and the results there, showed a hazard ratio in the PD-L1–positive patients was 0.66. And so – PD-L1 positive in stage II to IIIA, I should mention that. So, I guess the question I'd have for both of you, in the metastatic setting, most of us think that, in that 1% to 49% range, we typically don't use PD-1 monotherapy. It's really 50% and above who are driving the most benefit. So how do you think about the absence of subgroup analysis here?
Dr. Dagogo-Jack: Yeah, I think it's a challenge. I think that when they did the subgroup analysis, according to the cutoff of 50% or greater, we saw a very nice hazard ratio in that setting. So 0.43, and then basically greater than 1 was that 0.66 that we talked about, and then people who are PD-L1 negative, it really did not seem to benefit those patients.
It would be nice to see the data parsed out according to that 1% to 49%. I think if you did the math in your head and it estimate it, you would presume it was quite a bit higher than 0.43 for you to settle that 0.66 by including the entire population. But I think that we think in terms of metastatic lung cancer, that 25% is better than 1%. So, this person is in the middle. So I think that they probably would benefit better than someone who had very low PD-L1 expression, but you're exactly right. These are the things we have to think about, and these are the data we need.
Dr. Patel: I agree that certainly that there's a variance, and you imagine sort of this bell-shaped curve from low to higher, but even in the greater than 1% population, if you take out the 50s, there's still a true benefit. And if you think about what we know from like the LACE meta-analysis and how that shaped treatment for the small number of people that we cure, my sense is, again, that until we have OS data that would negate this, I think that we should be offering this for most of our patients.
Dr. Gainor: And I guess, but all of us now are, we've jumped into the fact that this is disease-free survival. So it's sounding like across the board, we don't necessarily need to see an overall survival here in order to adopt this. In that PD-L1 50% and above, I think it's a much easier decision for me. I think in the 1% to 49%, I would have loved to see that data included in the presentation. To Dr. Dagogo-Jack's point, if you just kind of eyeball it, I worry that in that 1% to 49% range, it may cross one. In which case, then I think it's going to be a harder, more personalized decision in that setting.
So really interesting, and we'll see when this manuscript comes out we can parse the details a bit more. In the closing minutes, I did want to just mention the neoadjuvant setting because really contemporaneously with the IMpower010 data, we're now seeing neoadjuvant PD-1 pathway inhibition data come out with CheckMate 816.
Dr. Patel, maybe you could just walk us through briefly the CheckMate 816 data?
Dr. Patel: Sure. CheckMate 816 was a neoadjuvant study that was done internationally. Again, AJCC version seven, but IB to IIIA patients were enrolled, and there were actually three arms, one was nivo plus chemotherapy. The other arm was chemotherapy. And then an arm of nivo and ipi, which hasn't been presented. So the 350 patients that were in the chemo plus or minus nivo have been presented. Patients ended up getting three cycles of therapy, and the primary endpoint was pathCR rate. And so it was substantially higher. So we think about the difference in pathCR, so no evidence of tumor in the nodes or the primary tumor. It was only 2% in patients treated with chemotherapy but it was 24% with three cycles of nivo. More patients – and that had been presented at AACR.
The ASCO presentation, a more recent presentation, looked at surgical outcomes to see if more patients went to surgery because of a deeper response. And they actually found that that was the case, that fewer patients had open surgery. So more patients could have minimally invasive surgeries, a higher number of patients could have R0 resections, but we also talk about major pathologic response, which is the end result. So how much viable tumor is there. And we look at whether it's 10% or not. So in patients that got nivolumab and chemotherapy were 10% versus 74% in the chemotherapy arm. So really a huge difference.
So certainly this is exciting, and to me, game changing. This trial enrolled a lot of patients with advanced disease, with stage IIIA disease. And seeing this depth of response was what really, I think, caught my eye and biologically. It makes sense to treat with immunotherapy when the antigen is still there. And seeing that real early response gives me real excitement about subsequent studies that we'll see with even immunotherapy out back.
Dr. Gainor: And I'm really glad you brought up the ASCO data on CheckMate 816, because I've found it a little surprising just in talking to our thoracic surgeons, there was this concern that there would be more complications, longer OR times. And really now we've seen this big randomized phase 3 study, really, we weren't seeing excess OR times. If anything, it seemed shorter because you were seeing more down-staging, as you alluded to.
In the closing minute, I'll just ask Dr. Dagogo-Jack. This is impressive data, but is it ready for prime time?
Dr. Dagogo-Jack: Yeah, I think the pathCR endpoint is tough, but it's new to us in lung cancer, right? But breast cancer has been using it. And so I think one would hope that pathCR in the context of immunotherapy is a meaningful endpoint, in the sense that, hopefully that this initial regression, now you have enhanced immune surveillance afterwards, and that would lead to cures. But I think we have to see where things are, personally.
Dr. Gainor: Great. So in terms of key clinical takeaways, I would say that based upon the success of checkpoint inhibitors in the metastatic and the locally advanced setting, we're really now seeing checkpoint inhibitors move to both the adjuvant, as well as neoadjuvant settings in non–small cell lung cancer. The IMpower010 data showed that adjuvant atezolizumab led to significant improvements and disease-free survival among patients with PD-L1 positive at 1% or greater stage II to III non–small cell lung cancer with a hazard ratio of 0.66. And this is data that may be the basis for regulatory approval, which we hope to see sometime soon.
I think what you're hearing from all of us is that we'd be more ready to adopt adjuvant PD-1 pathway blockade, despite seeing some promising new adjuvant data, using the combination of chemo plus PD-1 pathway blockade. Most of us now are wanting to really see event-free survival data, rather than just pathCR data at this point, but very exciting area. And we eagerly await long-term follow-up for all of these studies.
This brings us to the end of this case. Please see the other segments for further discussion about the latest data in lung cancer, or visit ASCOpost.com. And I'd like to thank both of my panelists for an excellent discussion.