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Melanie Cole, MS (Host): Welcome to UF Health MedEd Cast with UF Health Shands Hospital. I'm Melanie Cole. And joining me today is Dr. Aaron Franke. He's an Assistant Professor of Medicine in the Division of Hematology/Oncology at the University of Florida College of Medicine. And he's a research co-director of Thoracic Disease Site Group, and he practices at UF Health Shands Hospital. He's here to highlight neoadjuvant immunotherapy for resectable non-small cell lung cancer and the current challenges facing the shifting paradigm of early stage management.

Dr. Franke, it's a pleasure to have you join us today. Can you start with a little background on the evolution of treatment for non-small cell lung cancer in the case of mortality? What has been the standard of care?

Aaron Franke, MD: Sure. And thanks for having me here to talk about this very timely topic. So just to give a little background, you know, lung cancer, again, remains the leading cause of global cancer mortality. And non-metastatic, so early stage non-small cell lung cancer, is going to account for about 12% of all newly diagnosed cancers and about 20% of that mortality annually in the US.

So when about a third of patients present with early-stage tumors that are amenable to surgical resection, you know, despite this curative intent, surgery and systemic therapy that has been the standard of care that we'll talk about, the five-year overall survival, so the long-term survival, still remains poor. With about 65% if you have stage IB or II, that drops to about 41% in stage III. So the majority of these patients, as you go up in stage, still end up having recurrence, usually with distant metastatic disease.

I should say, based on a lays meta-analysis of all the randomized trials that showed, I guess, a minor benefit to the addition of platinum-based adjuvant chemotherapy for stage II to III non-small cell lung cancer, you know, based on a 4%, 5% benefit at five years, this has been our standard for, well, longer than I've been a doctor, Melanie.

And you know, the problem is that following curative intent treatment with surgery and chemotherapy are surveillance imaging, you know, what we use to detect recurrence, CTs, MRIs, they remain limited as they can really only identify macroscopic recurrent disease. And when this happens, it's most often advanced, incurable and usually metastatic. And historically, this has been associated with pretty poor outcomes.

Now, I said the standard of care had not changed for decades. Now, this shifted last year, when we saw the recently published IMpower010 results. So this was the first reported phase III study of adjuvant. Now, again, we're talking about neoadjuvant or preoperative therapy today. But to get there, we just need to highlight that adjuvant immunotherapy was kind of the first to change this paradigm last year in resectable non-small cell lung cancer. So the addition of atezolizumab, a PD-L1 immune checkpoint inhibitor gave us an improved disease-free survival for patients with stage II to IIIA resected non-small cell lung cancer whose tumors expressed PD-L1 at least 1%.

Now, we can dive into the subsets another time. But you know, looking at this, it seems the PD-L1 expression, the higher it went, as we see in most of the metastatic trials, really seem to be the driver of this benefit. And a similar trial with pembrolizumab, the KEYNOTE/PEARLS trial, we saw that they also had an improved DFS benefit or disease-free survival improvement regardless of PD-L1 for the stage IB to III resected non-small cell lung cancer.

So now, we dive into the story of today, right? There has been no direct trial level assessment of whether perioperative systemic therapy, chemotherapy or chemoimmune therapy is more beneficial either before or after surgical resection. Now, theoretically, the reason a lot of people live in the neoadjuvant camp, I'll say, is that there are several theoretical advantages, including leveraging systemic therapy in the preoperative neoadjuvant setting. And this helps us prioritize early sterilization of micrometastatic disease, tumor downstaging, increased rates of complete or R0 surgical resections, reduced surgical time and complications and decreased need for more invasive resection procedures like pneumonectomies.

In addition, giving the immunotherapy or chemoimmune therapy with the primary tumor still in place really maximizes your immune system exposure to the neoantigen burden of the tumor. So this ostensibly is what is leading to these deeper pathological responses. So there have been several neoadjuvant immunotherapy trials, most of them non-randomized, early phase or single arm to date, and they were designed using treatment response assessments. And we'll keep going over this as we go through the data and these include major pathologic response, so less than 10% viable tumor cells or a complete pathologic response or a path CR as we'll say today. And these were the primary study endpoints and the proposed surrogates for relevant oncologic outcomes. So having said that, that is where the standard has been. And we'll kind of talk about where it has shifted to just in the last six months or so.

Melanie Cole, MS (Host): So why don't you do that for us? Discuss the current challenges facing that shifting paradigm for us.

Aaron Franke, MD: Yeah. So, again, we had lots of early phase single arm trials. I was a part of a few of them. I think we had one here at UF Health Shands as well as that Moffitt Cancer Center where I was before. And these were just looking at a few doses of preoperative immune checkpoint inhibitor. And what they saw was a very high rate of pathologic downstaging and path CRs. You know, with chemotherapy, historically, you see about a 1% to maybe 4% rate of pathologic complete response giving neoadjuvant chemotherapy alone. So when these immunotherapy trials were showing 10%, 20% and above and later the chemoimmune therapy trials showing 30%, 40% rates of path CR, you know, we really started to scratch our head and wonder, "Okay, is this a good surrogate for long term survival? And is this a more meaningful approach than trying to give it in the postoperative or adjuvant setting?"

So, the first kind of study to tease this out for us, although non-randomized, was the phase II NADIM study, and this was looking at chemotherapy versus chemoimmunotherapy for three cycles for resectable stage III non-small cell lung cancer. Now, where this becomes a little tricky is, I should say, since 2018, when Dr. Scott Antonia announced the initial results of the PACIFIC, and this was the most practice-changing study in stage III non-small cell lung cancer in decades, our new standard of care for unresectable stage III really became chemoradiation followed by a year of consolidation immunotherapy with durvalumab.

Now, when you look at the NADIM study, this was stage III a and B tumors with 72% of these patients having what we call N2 nodes or pathologic clinical lymph node involvement at the N2 stations. To begin with, most surgeons are not comfortable outside of an academic center routinely operating on N2 nodes without preoperative therapy. You know, high rates of recurrence, high rates of R1 resections and high rates of pathologic upstaging of other lymph node groups once they get in there. And in addition, since PACIFIC has come out, I will tell you that even at our own center and in my own practice, really any patients with contraindication to surgery who don't want to undergo surgery or who have an N2 node or higher, they've really been going straight to the PACIFIC regimen. It has an overall survival benefit that has maintained itself five plus years now. So I think surgery was starting to get taken off the table without even much of a discretion for at least the IIIB tumors and most IIIA's.

So now, we're shifting this paradigm back and saying, "Okay, wait. We're actually having rates between 30%, 40% in the randomized study," maybe 25% of patients having a complete pathologic response, meaning when they go in there to cut the tumor out, there's actually no viable cancer cells left. So, this is a potentially curative population with otherwise thought to be high risk disease. So now, I think we're shaking up a little bit, who really is operative and who is not. And this is where the multidisciplinary team becomes even more crucial than it has always been in lung cancer, where the surgeons, the radiation oncologists, the pathologists, the medical oncologists, and the radiologists really need to be around the same table for, I would say, anybody with stage IIB to IIIB in a discussion of, "Okay, is this patient operable? And do they have clinical and tumoral features that suggest a pre-operative approach may be more beneficial or at least as beneficial? And why or why not should we pursue that as opposed to the standard cut it out and then give chemotherapy and immunotherapy on the back end?"

And these results were confirmed with the CheckMate 816 earlier this year at a AACR. And again, we saw 25% versus I think 3% pathologic complete response rate. This was associated with a prolonged event-free survival. Again, we still await overall survival data. There were less pneumonectomies. The operative time was less. And again, this was associated with higher PD-L1s had better tumor downstaging. There was CT DNA or circulating tumor DNA correlative data that showed higher rates of clearance with the chemoimmune therapy versus chemotherapy alone. And this is what led to the FDA approval of this regimen.

So cut two, okay? Now, we are three-quarters of the way through 2022, right? We now have a preoperative chemoimmune therapy for three cycles that is FDA approved for resectable non-small cell lung cancer, regardless of PD-L1. And now, we have adjuvant atezolizumab approved for stage II and III resectable PD-L1 positive group. And we have pembrolizumab that is probably very soon to get its approval for the same indication in the adjuvant setting.

So we now have two different treatment paradigms for essentially the same patient population. And the problem is that CheckMate 816 was the first phase III study in this realm to publish its results. It was in tremendous effort and a great trial. The problem with this trial is it is the only standalone neoadjuvant trial that was both performed and that will be reported. All of the other neoadjuvant studies that are highly anticipated are periadjuvant, meaning they give pre and postoperative immunotherapy with or without the chemotherapy. So it's really going to muddy the waters and kind of obfuscate who needs more treatment after surgery. And this has been, I'd say, the biggest point of debate, scratching our heads, lack of data, and really probably what I've gotten the most calls about from the community for physicians who are able to actually implement this neoadjuvant strategy and have this multidisciplinary surgical and radiation conversation, yet afterwards, they're wondering, "Do I give chemotherapy on the back end? Do I give immunotherapy on the back end? Is PORT or postoperative radiotherapy still of any benefit in this population?" You know, "Do we gauge it on the pathologic complete response, the circulating tumor DNA?"

So, while it is amazing that we now have a great treatment for our well-selected high-risk population that will hopefully continue to increase our rates of cure and maybe decrease some of the burden of 16 months of adjuvant therapy that we're used to slating patients too. It's definitely left us with so many questions, intriguing, but still very confusing, I would say, even for us that just specialize in one or two cancers, you know, think about the community oncologist that's treating 15, 20 tumor types in a day, this is a lot to take in and try to sit there and parse through what is the best clinical scenario for each patient and how do we really extrapolate from data that has no historical comparison for us to extrapolate from.

Melanie Cole, MS (Host): Wow, this is absolutely fascinating. And what an exciting time to be in your field, Dr. Franke, and thank you for pointing out the importance of that multidisciplinary tumor board and evaluating treatment approach and the utility of these several parameters as predictive biomarkers for therapy personalization. As we get ready to wrap up, please let other providers know what you'd like them to know about when they're planning therapy for patients with resectable non-small cell lung cancer, based on those individual patient considerations, the expert recommendations and the available clinical data that you've spoken, when you feel it's important they refer to the specialists at UF Health Shands Hospital.

Aaron Franke, MD: Yeah. I would say, for one, clinical trials are always a great option. So, even in the AE trial that I will hopefully be opening here in the coming months. You know, we're looking at circulating tumor DNA to help guide our periadjuvant therapy both in the pre and postoperative setting immunotherapy escalation. So clinical trials are always great. But let's say for the patient that doesn't wanna travel that lives far away and is just trying to get a second opinion, I think all patients in this stage II and III, if preoperative or postoperative therapy is going to be considered upfront, multidisciplinary discussion is I would say paramount and required. The only person who should be able to say operable, non-operable is that oncologic surgeon.

Now, having said that, and these will be the pearls I leave you with, there needs to be some very rational and pragmatic discussions between the surgeon, the med-onc and so forth that need to have realistic expectations. So if the surgeon comes to you and say, "This isn't really resectable, maybe we can give upfront neoadjuvant therapy and make him or her resectable," that is not the strategy that was used in any of these studies. And I will also say that, if you are expecting the tumor in the lymph nodes to kind of melt away from the mediastinum to help clear a plane of dissection, it actually usually involutes towards the mediastinum. So again, these are important anatomical considerations when you're trying to use this therapy to "downstage" a patient to make them resectable.

So these patients should be surgically operable, even if they have N2 disease. So I would say the patient I consider this most for, if you say, "Dr. Franke, who is that patient that you are thinking about this, you know, for the last few months?" And that would be a stage III single station N2 PD-L1 positive. And remember the importance of biomarker testing, EGFR and ALK, and I'll say even ROS1-negative patients, I would say these are not patients who should be implemented in this, regardless of their inclusion or exclusion from the studies. And I will tell you that EGFR and ALK were excluded from almost all of these studies. And remember, we have an adjuvant EGFR targeted therapy that is approved for resectable stage IB to III. So, I'd say the pearls to take away is multidisciplinary discussions are the underlying kind of mantra you want to revisit because it really has become very complicated. And if you don't have that access to that round table, you know, it is nice and easy to have a place like UF Health Shands and the UF Health Cancer Center to send your patient, even if it's for us to tee them up, to send them back to you and your surgeons, you know, to have that access to the multi-D discussion, I think really, one, obviously benefits the patients. It also benefits the physicians out in the community who again are trying to parse through very convoluted data at the current time. Exciting, but convoluted nonetheless.

Melanie Cole, MS (Host): Certainly a time of personalized medicine and therapy personalization. And thank you so much, Dr. Franke, for joining us today and sharing your incredible expertise. To refer your patient or to listen to more podcasts from our experts, you can visit ufhealth.org/medmatters.

That concludes today's episode of UF Health MedEd Cast with UF Health Shands Hospital. For updates on the latest medical advancements, breakthroughs in research, follow us on your social channels. I'm Melanie Cole.