Eric Kumar Singhi, MD: Hello, my name is Eric Singhi. I’m a thoracic medical oncologist at the University of Texas MD Anderson Cancer Center. We’re back for another episode of Leading Thoughts: Lung Cancer. I’m joined by my friends and colleagues. Dr. Sandip Patel, if you want to introduce yourself.
Sandip P. Patel, MD: Hi, I’m Sandip Patel, professor of medical oncology at the University of California San Diego. Great to be joining you guys.
Dr. Singhi: Great to have you, Sandip. We’re also joined by Dr. Maya Khalil.
Maya Khalil, MD: Hi, Eric and Sandip. I’m Maya Khalil, one of the thoracic medical oncologists at University of Alabama at Birmingham, and happy to be here.
Dr. Singhi: Great. We’ll jump right in. I know there has been a very exciting topic of debate, and that is the evolving treatment landscape for our patients with early-stage resectable non-small cell lung cancer (NSCLC). As you guys know, historically, the only meaningful systemic therapy that we’ve had for our patients in this setting has been cisplatin-based chemotherapy for almost two decades. That provided a modest benefit at best.
But fast-forward to 2021. That is really when immune checkpoint blockade entered the paradigm in this setting for our patients. We saw adjuvant immunotherapy. Fast-forward a year later, we saw neoadjuvant immunotherapy. And then a year later, we saw perioperative [immunotherapy]. A lot of excitement [accompanied these advances]. It means we have a lot of different options, but also a lot of choices. And so we’re faced with difficult decisions in clinic. We’re also filming this after the recent U.S. Food and Drug Administration (FDA) approval that was just announced this month, in August 2024, and that was for perioperative durvalumab. So like I said, a lot of choices.
Maybe, Sandip, we can kick it off with you? When you’re in clinic and you’re thinking about which treatment setting and which option to discuss with a patient and to pursue with a patient, walk us through what you think of these three different settings.
Dr. Patel: Yeah, I think, and maybe even slightly upstream, it is important to understand the host factors and then the tumor factors before we consider these types of localized curative-intent immunotherapy approaches. A couple of things to think about. One is discussion with a multidisciplinary tumor board. Is this patient resectable? This is important because it is different than what is called conversion therapy. For someone who is borderline resectable, [if I] give this patient a little bit of treatment upfront, then I can resect them. We actually don’t know if these approaches work in that conversion setting. So at the point at which you meet them, that patient could go for resection right then and there. That is where we have these FDA approvals. Is the patient amenable to surgery based on tumor factors and based on host factors? Are their pulmonary function tests, cardiopulmonary function tests, six-minute walk tests indicative of whether this a patient who can tolerate a lobectomy?
Then the next question is, is their tumor going to be sensitive to immunotherapy? There are negative factors and positive factors there. If the patient has an EGFR mutation or ALK rearrangement, we know that immune checkpoint blockade does not benefit those patients. Those patients in the localized setting are better treated with resection followed by adjuvant chemotherapy and then targeted therapy.
Let’s say we have that discussion at tumor board. The patient is resectable, they have EGFR ALK wild-type NSCLC. Then we have the discussion on which approach makes the most sense. We don’t have data that a pure neoadjuvant approach is better or worse than a perioperative approach. We have two, as you highlighted, perioperative approaches: chemotherapy-pembrolizumab, where you get four cycles upfront and then pembrolizumab for a year afterward, and then durvalumab with a very similar design, although maybe a little more flexibility on the platinum choice.
We don’t know what’s better. We do know that the pembrolizumab combination from KEYNOTE-571 has an overall survival benefit. Just hot off the presses, as you mentioned, the AEGEAN study with durvalumab. We have event-free survival, but we have yet to see overall survival there.
So you have these as options. And in my clinic, it’s a lot about what the patient wants. Right? There’s no law that if you choose chemotherapy-pembrolizumab and someone gets a pathologic complete response (path CR) and has an immune-related adverse event that you can’t stop at four cycles, either. I think there’s a little more flexibility in the real world than in clinical trials. I’d love to hear how these discussions happen in your clinic, Maya and Eric, as well.
Dr. Khalil: Yeah, so this always comes up, right? It is part of our daily discussion with patients and with our tumor board discussions, all the time. Another thing that comes up, besides deciding whether we want to go with neoadjuvant purely or perioperative, is do we even want to go the adjuvant route? Just resect your patient first and move forward to adjuvant therapy with chemotherapy and then adjuvant immunotherapy.
I think for very early-stage lung cancer, stages I, maybe IB, maybe node-negative stage II, I don’t think all the surgeons of the world are sold on doing perioperative treatment there. I think it might be worthwhile to resect these patients and then move over to the adjuvant therapy.
In terms of how to select the patients for perioperative versus neoadjuvant alone, I don’t think we have data to derive that. We don’t know ahead of time, or before surgery or before neoadjuvant therapy, how a patient is going to respond to treatment and who is going to achieve path CR. I think what’s encouraging is that for patients who achieve path CR with neoadjuvant therapy on the neoadjuvant nivolumab trial, really a vast majority of those patients did not receive adjuvant immunotherapy, and they still did phenomenally well. That’s a group of patients where you might feel more comfortable not doing this adjuvant immune therapy part. But for the rest of the patients, I think adjuvant immunotherapy actually has some improvement in their outcomes.
Dr. Singhi: Yeah, these are excellent points from both of you. I really appreciate it. I think it’s a very nuanced conversation, so I really appreciate the way you highlighted this, Sandip, saying we need to have multidisciplinary discussion but also shared decision-making with our patients, and really talking them through what to expect, potential toxicities, and what they’re signing up for before surgery and potentially after surgery.
Maybe Maya, I can ask you to elaborate more. When we’re thinking about molecular characteristics, disease characteristics, some of the things we talk about are achievement of path CR and PDL1 expression. How do you use those things to guide your decision-making in this process or in this setting?
Dr. Khalil: I think the first thing we need to do on all these patients (any patient who is diagnosed with NSCLC) is learn about their molecular characteristics. Of course, for patients who have EGFR or ALK mutations, these patients are going to be excluded from this conversation altogether. Then comes the characteristics of the patient. PDL1 expression being higher might sway us more into delivering immunotherapy, maybe neoadjuvantly, and trying to engage the immune marker environment while still in the patient before removing it surgically.
Also, some of the toxicities that we expect with patients… Some of the patients who don’t make it to surgery might not make it to surgery just because of going through neoadjuvant therapy. It’s kind of a litmus test. One thing that always comes up in all of these neoadjuvant trials is that there is about 13% to 17% of patients that don’t make it to surgery. The question is, "Why aren’t they making it to surgery?" I think the trial that had the highest percentage of patients that actually made it to surgery is the pembrolizumab trial, and they mandated for everybody to have cisplatin. So that is probably a different patient population than the average patient population that we see. I think a lot of it has to do with if the patient actually can handle neoadjuvant therapy, go through surgery, and move over to the adjuvant side. And a lot of that comes down to comorbidities of patients.
Dr. Singhi: That’s a fantastic overview. I’ve heard both of you talk a little bit about platinum therapy and tolerance, and also thinking about which platin drug we want to use. We started to see some variances in these data. So maybe, Sandip, what are your thoughts in clinic now? How much are you pressing for cisplatin-based therapy versus considering carboplatin therapy?
Dr. Patel: I’ve never been of the view that cisplatin is a must. Now, are all our studies designed that way historically? Absolutely, in the adjuvant setting. But if you actually look at the neoadjuvant data and some of the adjuvant targeted therapy data, the patients who got carboplatin did just as well – a lot of confidence interval overlap – even the point estimate was maybe a bit better. When we think about this, we’re thinking about agents that enhance our cure rates. The goal is for more people to be alive.
So my logic is, “Is cisplatin so much better that potentially permanent neuropathy, ototoxicity, and nephrotoxicity are worth it, when in the modern era, the platinum isn’t the main course, it’s the side dish?” The main course is the immunotherapy. It is the targeted therapy, in my opinion. Although I think with targeted therapy some of the cure rates are really driven by the chemotherapy. We don’t know how much of the targeted therapy is suppressive versus actually permanently killing the cells. I agree with that point.
I don’t think carboplatin is worse than cisplatin. I probably use carboplatin in my clinic maybe 80%–90% of the time because I offer both to my patients who are eligible. If your creatinine level is 3 mg/dL, we’re not even discussing cisplatin for very long. They’ll often ask me what would I do? Or, if you’re my family, what would you do?
I tell them, I would take carboplatin-pembrolizumab if I was nonsquamous, with an immunologic. A lot of this gets into – as I think, Eric, you highlighted nicely – the discussions with the patient. If I have someone who lives three hours away, they have EGFR ALK wild-type NSCLC, they have PDL1 of 80%, they have a smoking history, and they really don’t want to come here for a whole year, they want to try to see what three or four cycles will do, then the social determinants of health play a role in which treatment we make as well. And for many centralized health systems, there is a big cost differential. So some of these may be the only options. Thinking about those social determinants in the context of these patient discussions is key. But it really starts with the multidisciplinary tumor board discussion on what the options actually may be that are reasonable for that patient.
Dr. Singhi: Absolutely. I agree with that. I’ve really opened up my thought process and my discussion with patients about carboplatin versus cisplatin, that exact sort of scenario. Asking “what would you do if you were in my shoes” has come up multiple times in my clinic. I appreciate that conversation and sort of framing that conversation.
Maya, let me ask you a little bit about how you discuss potential toxicity with patients. Now we’re bringing in immune checkpoint blockade into an earlier setting, which of course we know that immunotherapy does not always come without risk, and potentially many of these patients have already been cured. What are your thoughts on having that discussion, monitoring for toxicity, and making sure that patients are truly informed about what they’re signing up for, potentially, one year after surgery?
Dr. Khalil: Absolutely. I always tell my patients it is not a free ride, even if immunotherapy is generally more tolerable than chemotherapy. I’ve had patients in my clinic who have long-lasting hypothyroidism. Although this is not life-threatening, you have to take a pill for the rest of your life for that. I’ve had one patient who actually went into adrenal insufficiency in the perioperative setting. That’s really a life-altering diagnosis.
I make it a point to actually sit down and talk to them about all the potential toxicities that could happen, in terms of the risk for them, in terms of the potential for them to change their quality of life, the potential for them to affect long-term what their day-to-day is going to be. That helps them make an informed decision. If a patient already has an autoimmune condition, for example, they need to understand that if you have a mild lupus or a mild rheumatoid arthritis, you are at a higher risk of developing toxicities with that immunotherapy, rather than lower rates with people who don’t have autoimmune conditions.
It’s a long conversation, usually, to address all their questions about the potential toxicities and what is life-threatening. What is not life-threatening? The percentage of that and the signs and symptoms… The patients are our first line of defense when it comes to figuring out, “Is my symptom important enough for me to report it, and how soon should I report it?” So we go over all of that. [Including] colitis, of course, and symptoms from that.
I think that’s a very important conversation to have very early on to set the stage, because you don’t want to have a patient who is otherwise healthy go through treatment and have something that they did not expect as an outcome down the line with immunotherapy. And they’re signing up for a long period of time, at least three-quarters of them.
Dr. Singhi: That’s fantastic. We’ve touched on a lot of excellent points today. We talked about the need for multidisciplinary discussion. We talked about the need for shared decision-making. We’ve talked a little bit about how you think through all three different settings of incorporating immune checkpoint blockade in the early-stage resectable setting.
One more thing we’ll touch on toward the end is this high-risk disease subset with N2 disease. There was a really nice presentation by one of my colleagues, Tina Cascone, MD, PhD, at the American Society of Clinical Oncology Annual Conference this year that really focused on that N2 subset. Sandip, you alluded to this earlier, this concept of downstaging or conversion. We saw that the patients who had N2 disease, surgical feasibility was definitely achievable. We also saw, more importantly, that the path CR rates, even for patients with multistation N2 disease, which raises a lot of red flags also for our surgeons to go in and do surgical resection, were close to 38%–40% in this subset of patients. What are your thoughts on that subgroup, and are you pushing more for a perioperative approach for those types of patients?
Dr. Patel: We think about these studies, and the study that started it all was NADIM, which was actually isolated at stage III. I think one of the pleasant surprises of immunotherapy is that when you look across studies, it almost, when it works, gets rid of nodal stage as a negative prognostic factor, meaning you could have N2 or N3 disease where you get a path CR, your outcomes are as good as someone who was basically node-negative. And it makes sense. The immune system doesn’t really care where the cancer is, and it is a serial killer in terms of those T cells that are generated.
I think for patients who are resectable but who have N2 disease or N1 disease, I do favor a neoadjuvant or perioperative chemoimmunotherapy approach over an adjuvant approach. I think the adjuvant approach is still reasonable. I think I have a little more equipoise for patients who are node-negative with smaller tumors who are going to get lobectomies. I think for patients who are node-positive, these are patients we can cure. Let’s not forget, for those patients who are unresectable, either because of tumor factors or host factors, we have over five years of high-quality data with the PACIFIC regimen, concurrent chemoradiation followed by durvalumab for a year with cure rates of almost one in three patients, depending on if you select by PDL1 biomarker or not, getting to five years and beyond. So those are cures as well.
Thinking about how we can best increase these durable remission cure rates is key, not forgetting that patients who are not surgical candidates are candidates for radiation and consolidative durvalumab, but also that those patients who are resectable, they can either do upfront with adjuvant immunotherapy, [whether] it be atezolizumab, IMpower010, pembrolizumab in the PEARLS study, or these neoadjuvant or perioperative approaches.
Dr. Singhi: That’s perfect. Very well put. Well, we could go on and on about this topic, and there are a lot of exciting updates that are coming. We’re sure to present and talk about this in future episodes. But Maya, Sandip, always a pleasure. Thank you both for being here and take care.
Dr. Khalil: Thank you.
This transcript has been lightly edited for clarity.
