In an interview with Targeted Oncology, Heather Wakelee, MD, discussed what community oncologists should know about the newly approved combination of pembrolizumab with platinum-containing chemotherapy as neoadjuvant treatment, and with continuation of pembrolizumab monotherapy as post-surgical adjuvant treatment.
The FDA approved pembrolizumab (Keytruda) in combination with platinum-containing chemotherapy as neoadjuvant treatment, and with continuation of pembrolizumab monotherapy as post-surgical adjuvant treatment for patients with resectable non–small cell lung cancer (NSCLC) on October 16, 2023, based on data from the phase 3 KEYNOTE-671 clinical trial (NCT03425643).1
In the study, the primary end point of event-free survival (EFS) was met with pembrolizumab plus chemotherapy. The 24-month EFS rate was 62.4% with pembrolizumab plus chemotherapy and adjuvant pembrolizumab compared with 40.6% for placebo plus chemotherapy (HR, 0.58; 95% CI, 0.46-0.72; P < .00001). While the overall survival (OS) data were immature, at 24 months, the OS rate was 80.9% among patients in the pembrolizumab arm vs 77.6% in the placebo arm (HR, 0.73; 95% CI, 0.54-0.99; P = .02124).1,2
According to Heather Wakelee, MD, these data build upon findings seen in other trials, including the CheckMate-816 trial (NCT02998528) of neoadjuvant nivolumab (Opdivo) and chemotherapy in patients with resectable lung cancer and show the potential of perioperative checkpoint inhibitors for the treatment of patients with lung cancer.
“The use of perioperative checkpoint inhibitors is an exciting area. When we think about what we're able to offer patients with early-stage lung cancer, we obviously are trying to cure, and have an impact on what's going on with the disease and hopefully make sure that the disease is at bay as much as possible. When we look specifically at KEYNOTE-671 and at those numbers, we have to put it in the context of the other trials,” Wakelee, Stanford University School of Medicine and the Stanford Cancer Institute, told Targeted OncologyTM, in an interview.
In the interview, Wakelee discussed what community oncologists should know about the newly approved combination of pembrolizumab with platinum-containing chemotherapy as neoadjuvant treatment, and with continuation of pembrolizumab monotherapy as post-surgical adjuvant treatment.
Targeted Oncology: Can you provide background on the KEYNOTE-671 trial?
Wakelee: KEYNOTE-671 is a randomized, phase 3 trial which enrolled patients with stage II and III non–small cell lung cancer which was felt to be resectable. Patients on the trial received up to 4 cycles of cisplatin-based chemotherapy with either pembrolizumab or placebo and then went to surgery and went on to up to 1 year of adjuvant pembrolizumab or placebo. The trial was designed with dual primary end points of event-free survival and overall survival.
Can you discuss the patient population that was evaluated?
KEYNOTE-671 enrolled patients with stage II and III non–small cell lung cancer. We did not mandate testing for EGFR or ALK, but patients who were found to have those mutations were allowed on the trial. The numbers were relatively small. We also had no mandates as far as the PD-L1 status of the tumors. We did expect that patients were felt to have resectable disease based on a surgical evaluation before they went on study. We did mandate surgical staging so that we knew for stratification, what stage the patient had of their tumor.
What were the main efficacy findings from the study?
The KEYNOTE-671 trial had 2 primary dual end points, and the first is event-free survival. Event-free survival is a little different from disease-free survival, which we talk about a lot. Disease-free survival is a time point you can only have when you have no known disease. Since the trials start before surgery events are also included in an event that would be something that prevented the patient from going to surgery. It's defined a little bit differently in all of the neoadjuvant and perioperative trials, but essentially, it is the same and that is important for people to know. So event-free survival or overall survival were both the primary end points and the first interim analysis, we actually had hit the event-free survival, which had a hazard ratio of .58, which was highly statistically significant.
Now, the overall survival curves actually looked quite good with separation, but not enough events had occurred for that to be statistically significant, so we can't really call it at this first interim analysis, but that will continue to be followed. The study also looked at major pathological responses and complete pathological responses and in both of those, it was much better when you added the pembrolizumab vs on the placebo arms. Those numbers were keeping with what we've seen with other neoadjuvant and perioperative trials with checkpoint inhibitors and chemotherapy prior to surgery.
What about the safety data?
With all the trials that have looked at immune checkpoint inhibitors, we always have to worry about autoimmune disease. That was seen in this trial, as well some patients developing endocrinopathies [gastrointestinal] toxicities, but really not in any excess of what we would have expected. The predominant toxicities that we're seeing in the neoadjuvant period were related to the chemotherapy. Then there were surgical issues related to surgery, and then in the adjuvant setting, when it was the pure use of the checkpoint inhibitor or placebo, some additional autoimmune toxicities were seen. Again, in keeping with all of the trials that we've seen with checkpoint inhibitors in metastatic as well as earlier stages of disease, it is an important thing to be mindful of as we talk about these options with patients. It's important that they understand about the autoimmune and other toxicities that can happen with treatment, and that we're making sure we're really approaching patients who we think we're going to potentially benefit.
What advice do you have on how to mitigate or manage these toxicities?
The treatment of immune-related adverse events is a whole field in and of itself. Most of the academic centers now have immune-related adverse event tumor boards where we're able to bring together people from different disciplines. I think out in the community, people are doing that as well, because these toxicities can hit any organ system, so some of them are rheumatological, or endocrine, or neurologic. Whereas general oncologists, we've had training, but it's not something that we have gotten used to seeing all the time. It is important to have a multidisciplinary team, or at least colleagues, that one can call and consult at the time that a suspected adverse event is happening that we think is immune-related.
What does this approval mean for patients with NSCLC?
The use of perioperative checkpoint inhibitors is an exciting area. When we think about what we're able to offer patients with early-stage lung cancer, we obviously are trying to cure, and have an impact on what's going on with the disease and hopefully make sure that the disease is at bay as much as possible. When we look specifically at KEYNOTE-671 and at those numbers, we have to put it in the context of the other trials. CheckMate-816 is the only pure neoadjuvant trial with nivolumab, and that trial was clearly positive. It set a standard and it's something that is utilized today. The questions that come up then with the perioperative trials are, how much is that additional adjuvant component adding and do we need that or not? We don't have the answers to that data yet, but we had a very good outcome from event-free survival for CheckMate-816. We're waiting for the definitive overall survival data, but it is certainly trending positive.
With the perioperative trials, all of which read out in the spring of 2023, we had the AEGEAN trial [NCT0380013] with durvalumab [Imfinzi], again, looking quite positive with event-free survival, and it was too early for OS, and it was pretty early overall, I think they had less than 12 months of follow-up at the time of the data that they presented. Then there was a study with toripalimab [Tuoyi], Neotorch [NCT04158440], which looked at event-free survival and had robust outcomes, but with a slightly different patient population. They excluded patients who had EGFR mutations. The study was mostly done in China, so they ended up with a group of patients who mostly had squamous cell histology, and they've only presented the stage III data. In all of the trials, the patients with stage III tend to have the most benefit from the addition of a checkpoint inhibitor. It's hard to really compare it to the others, but looks to be in the same ballpark. Then we have KEYNOTE-671.
Trying to figure out which one's the best is not something we can do at this time, because they all had slightly different patient populations. When we look at what was the major pathological response, complete pathological response, event-free survival, there's some numerical differences. But I think the big picture is not that different. The questions are going to be who needs neoadjuvant and who should just go straight to surgery because in all of the trials, there's about 20% of patients who don't make it to surgery. Some of that's toxicity, a lot of it is maybe they weren't patients who were destined to be able to get surgery anyway, and maybe shouldn't have gone on the trials. I think there's more to explore there.
We have questions about who should go straight to surgery and not get neoadjuvant [treatment], and for those who do get neoadjuvant, who should get additional treatment? There are arguments saying, if you've had a great response, maybe you're gonna do better with even more. And then there are arguments saying, those who haven't had the best response are those who potentially need even more treatment. There's some data for melanoma arguing that if the patient's hadn't had a great pathological response before surgery, with the chemo and IO, they're the ones who did the best when they had additional immune therapy in adjuvant settings in different disease melanoma. But, you know, we try to extrapolate sometimes.
We have a lot ahead of us to try to determine the question of who should go to surgery, who needs neoadjuvant, who needs adjuvant, as opposed to looking at all of the different options that we have. But we do have a wealth of opportunities, assuming approvals, and there are a lot of steps forward for our patients. These results look pretty encouraging, so I think we are going to be making an impact.
For a community oncologist, what are the key recommendations when using this combination for patients with early NSCLC?
For a community oncologist who is seeing a patient with stage II or III lung cancer, there are a lot of questions that come to mind. I think it's important that a multidisciplinary tumor board does evaluate the patient so that you get input from radiation oncology and surgery before any treatment is started. The importance of that is emphasized by the fact that many of the patients who went on the neoadjuvant and perioperative trials didn't make it to surgery. Some of them probably should have been considered for definitive chemoradiation and not surgery. We want to make sure that that is discussed and the appropriate path is chosen for a patient. We also want to make sure we have got biomarkers, and by that I mean PD-L1 status is important.
When we look at the level of benefit in all of the trials, patients with the highest PD-L1 levels have the best benefit. But in the neoadjuvant with chemotherapy plus IO, there's been benefits seen even without PD-L1 one vs in adjuvant [trials which] is a little more complicated. It's important to have that information to help them with the decision process. The other important part is knowing the driver mutations that might be in the tumor for the patient. We know if there's an EGFR mutation, osimertinib [Tagrisso] is probably going to be a better choice in the adjuvant setting based on data. If there is ALK translocation or ROS1, we know that immunotherapy does not really help. We've seen hints of that in these trials.
Then with other drivers, there's variability of what we know for metastatic and the likelihood of immunotherapy working and I think that all needs to be weighed. Of course, looking for the resectability that is part of that multidisciplinary tumor board. Then you've got to make a decision with the patient about the neoadjuvant therapy or not. For me, if a patient has stage III, I think we should be thinking about neoadjuvant. If a patient has stage II, it's somewhat debatable, and it will be the right approach for some patients, but we're not sure if we are going to be giving neoadjuvant or perioperative chemotherapy plus and immune checkpoint inhibitors definitively. There are going to be a lot of decisions that go into that. The data from KEYNOTE-671 are positive, but the data from the other trials have also been quite positive. We need more trials to help with the answer to those questions about who needs that additional adjuvant treatment or not, and are there any differences between the different agents?