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DR. RAMALINGAM: Hello, I'm Dr. Suresh Ramalingam. Welcome to The ASCO Post Roundtable Series on the Appropriate Management of Challenging Cases in Lung Cancer. Today I'm joined by my two esteemed colleagues in thoracic oncology, Dr. Julie Brahmer and Dr. Heather Wakelee. We'll have them introduce themselves.
DR. BRAHMER: Hi, I'm Dr. Julie Brahmer. I’m a professor of oncology at the Johns Hopkins Kimmel Cancer Center in Baltimore, Maryland.
DR. WAKELEE: And I'm Dr. Heather Wakelee. I'm a professor of medicine and the interim chief of the Division of Oncology at Stanford University in Stanford, California.
DR. RAMALINGAM: Well, thank you both for joining us. Today we'll be discussing the latest in emerging data on combination approaches involving chemotherapy and immunotherapy, or immunotherapy-based combinations for non–small cell lung cancer. Julie, I'll start with you. At ASCO 2020, we saw some exciting updates on immunotherapy combination approaches, but before that, give us a background on where we stand for treating patients in the frontline setting or candidates for immunotherapy.
DR. BRAHMER: Well, I think currently the standard of care really depends on the patient. We base it on histology, as well as mutation testing, and then also PD-L1 status. So, you know, if a patient has adenocarcinoma or squamous cell carcinoma, that does play into which chemotherapy we pick, and that hasn't changed for almost a decade.
Certainly we also base our frontline treatment based on mutation testing, so particularly for adenocarcinoma patients looking for a driver mutation where we may have a tyrosine kinase inhibitor set to have a great response and long-term improvement in overall survival in most of these patients, and then lastly, in those patients without a driver mutation, looking at PD-L1 status. If patients have high PD-L1 in their tumor, 50% or greater, certainly they have an option of single-agent pembrolizumab, but also for all patients, regardless of PD-L1, combining immunotherapy plus chemotherapy does increase the chance of response rate and improvement in survival over chemotherapy alone. Unfortunately, particularly for those patients with high PD-L1 or a tumor of 1% or greater PD-L1 status, we don't have head-to-head combining single-agent pembrolizumab versus pembrolizumab plus chemotherapy.
We also now have in PD-L1–positive tumors, single-agent atezolizumab that is now approved for use as well, so that is an option for some of our patients. I think now with recent FDA approvals of nivolumab and ipilimumab based on the CheckMate 227 data, and then even more recently, the combination of nivolumab, ipilimumab, and two cycles of chemotherapy is also an option, and really, that's what we need to talk about today, is where do we fit those combinations in for this patient population? Clearly, the recent data basing the FDA approval for nivolumab and ipilimumab is positive PD-L1 status. So PD-L1 status of 1% or greater in the CheckMate 227 study has led to the approval of that IO-IO combination.
DR. RAMALINGAM: Great. Just a few years ago, we just used chemotherapy for all patients. The start of sub-sectioning patients to personalize therapies to achieve best outcomes is really exciting. So Heather, Julie touched on the two key studies at ASCO with regards to immunotherapy, CheckMate 227 and CheckMate 9LA. Can you share with our audience the key takeaway messages from those trials and your impressions on those data?
DR. WAKELEE: Sure. So CheckMate 227 I think most of our audience has probably heard about before, as we have had a lot of updates on that trial over some years now. It's a very complex trial. There were six arms, though really not quite six.
So, the study divided patients based on PD-L1 status using just some or none as a cutoff, so just 1%, and in both of those groups, patients could get the combination of nivolumab and ipilimumab together. In both of those groups, they could get chemotherapy together. But then there was a difference based on PD-L1 status. So if you had expression of PD-L1, then you could get single-agent nivolumab. And if you didn't, then you were going to get the combination of chemotherapy plus nivolumab. So the decision was made that if there was zero PD-L1 expression, single-agent nivolumab wasn't what they wanted to give people, it needed to be the combination. And this made it so that there were a lot of different comparisons that could be made. And so if you looked at the whole trial, you had this nivolumab/ipilimumab versus chemotherapy.
And there was a lot of really interesting outcomes from that trial, some of which were updated, which showed that the nivolumab/ipilimumab combination seemed superior to chemotherapy. And that was regardless of PD-L1 expression, and if anything, we were seeing better outcomes for patients who were getting nivolumab/ipilimumab alone, and that was sort of unexpected.
Where we were getting some updates are in the questions around which patients need to have PD-L1 expression and which patients don't. We know that the FDA approval now for nivolumab and ipilimumab based on [CheckMate] 227 is for patients who have PD-L1 expression of at least 1%, and yet the data that we keep seeing out of that trial and as it was updated by you, Ram, at ASCO this year, 2020, was that in the group of patients that had zero PD-L1 expression, the hazard ratio looked even better for patients who got nivolumab/ipilimumab versus those who got chemotherapy.
So, it continues to be more robust in finding that combination nivolumab/ipilimumab data. It also continues to get a little bit more confusing. In previous years with that trial, there has been a lot of hope around tumor mutation burden as being a way to distinguish who was going to benefit and who wasn't, regardless of the PD-L1 status, and as that story has continued to evolve, we've realized maybe that doesn't really matter so much.
The other part of the trial that is confusing is that in the patients who had no PD-L1 expression—there was a chemotherapy plus nivolumab arm, as I mentioned—we don't have any data for that group who had a higher PD-L1, but for the no PD-L1, chemo plus nivolumab versus chemo wasn't as positive as we would have expected to see. Most of our other trials, not all, but when you look across the board at the numerous trials we've now had of chemo plus or minus immune checkpoint inhibitor, whether it's PD-1 or PD-L1, they've mostly been pretty positive. This is one of the trials where it didn't hit that mark, and so that's where it's also confusing.
So my takehomes from [CheckMate] 227 as it stands today, which I think is close to the final analysis, I'm sure we'll get the five-year updates and things like that, is that the nivolumab/ipilimumab has been very good across PD-L1 subsets and remains an option for patients with high PD-L1 on label, for no PD-L1 off label, and seems to be superior to chemotherapy in many patients.
And I pause there because there is a crossing of the curves, and that's one of the things as we look at all of our immune checkpoint inhibitor studies, is that when you're comparing to chemotherapy, for many of the trials, you do have early on in the first number of months some patients who aren't benefiting and who are looking like they would have done better if they'd had chemo. And we still haven't figured out the best biomarker to distinguish those patients with these IO-IO combinations of nivolumab/ipilimumab. But it is an option that we have.
The chemo plus nivolumab isn't an option that's really emerged as a good choice. Single-agent nivolumab hasn't really emerged as the best choice when we have other options. And the chemo plus nivolumab got then – so from [CheckMate] 227 didn't look great, but now we have more data that came out of the CheckMate 9LA, so that was another update at ASCO.
And the CheckMate 9LA looked at patients and gave them either chemo or chemotherapy plus nivolumab and ipilimumab. So the combination. And that study was a positive study. And so it gives us another option of things that we can consider. And so that trial showed a hazard ratio of 0.66 for the combination versus chemo, and as Julie alluded to earlier, one of the subtle differences of this study, and it's not that subtle, is that all of our other trials of chemo plus checkpoint inhibitors have given four cycles of chemo, and this one only gave two, and still showed the benefit. So that brings a whole other question into the debate.
And I think right now, the first step when we have a newly diagnosed patient is to figure out their driver mutation, and I always like to emphasize that. Julie emphasized that. I think that's such a key takehome. Always know what the driver mutation is as you're making your plans for treatment. And then you've got to look at your PD-L1 status, and if that is high, you have one set of choices, which could include single-agent pembrolizumab. If it is not high, you're probably going to be thinking about a chemotherapy plus checkpoint inhibitor combination, but we also have the nivolumab/ipilimumab option. If you think of a chemo plus combination, then you have to think about how much chemo. Are you going to just give the two cycles and give it with nivolumab/ipilimumab? Are you going to –because we already have that approval – or are you going to give it for four cycles and give it with pembrolizumab? Or are you going to think about an atezolizumab combination? And so it gets more confusing, and there are different reasons we might all have preferences one way or the other.
We do have to talk about additional toxicity when we add the nivolumab and ipilimumab versus single-agent checkpoint inhibitors. Not as overwhelming as I think we were worried about when we first were thinking about those combinations, but it is still an issue. And I do think we, at some point, need to mention that other IO-IO combos were also presented at ASCO this year: the durvalumab-tremelimumab, which were not as positive, shall we say. So I'll stop there and turn it back to you, Ram, because I’m interested in hearing how you sort through all of it.
DR. RAMALINGAM: Right. So a lot of moving parts here, and thank you for that excellent summary. In the interest of time, perhaps we can go to Julie for your sort of takehome messages, given the two new phase III data that have been reported. Not only have they been reported, they both have recently had FDA approvals just a few weeks ago, so how does this fit into your clinical practice, and what are some of the key takeaway messages for our audience today?
DR. BRAHMER: Well, I think certainly there's a lot of interesting data, particularly for nivolumab and ipilimumab on [CheckMate] 227. If you have a response, that response is maintained for a long period of time and does seem to result in some quite interesting, tantalizing long-term survival, you know, at least at three years. I think even looking longer term to five years, really the question is, for which patient do we really need chemotherapy, and for which patient do we need a combination versus a single agent? And, you know, right now, we have no biomarkers that really tell us which patient goes into which bucket, but I think for most of us on a clinical standpoint, if we need a very high response rate, particularly in those patients with high PD-L1, most of us are leaning towards combining the IO with chemotherapy to really get our biggest bang for our buck and try to prevent those patients from ending up on the curve and falling off therapy because of rapid progression of disease.
And so, I think that is really how I'm picking patients, whether or not to add chemotherapy to IO. I myself have not used the nivolumab/ipilimumab/chemotherapy combination. Certainly, nivolumab and ipilimumab does have a schedule, at least from an ipilimumab standpoint, every six weeks that does help, I think, based on some of the early phase I data, to decrease the risk of toxicity. However, I think you do have to have experience in combining the two and actually managing immunotherapy toxicities with that combination. But it is manageable. And I do think without chemotherapy, there is something about the immune system that may—and we'll see if this bears out—may actually result in longer-term outcomes that are favorable for that combination without chemotherapy. But to be honest with you, I myself am struggling trying to figure out for which patient I should use which combination. Certainly, though, if I want to have long-term maintained responses and a significant response rate (i.e., trying to get that patient's disease under control right away), I will combine the three drugs, or four drugs.
DR. RAMALINGAM: Thank you, Julie, and thank you, Heather, for the excellent discussion. Thank you both for joining me, and for our audience, don't forget to watch the other videos in this ASCO Post Roundtable Series. Thank you.