Advances in Testing and Targeted Therapy for NSCLC: Translating Evidence to Clinical Practice - Episode 9

Neoadjuvant Strategies in Resectable Non–Small Cell Lung Cancer

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Comprehensive review on various neoadjuvant strategies under review in the setting of resectable non–small cell lung cancer.


Benjamin Levy, MD: Neoadjuvant chemotherapy/IO [immunotherapy] has been the news for 2022 in early stage lung cancer. Let’s talk about these data. Let’s just move past the targeted therapy neoadjuvant that we were going to talk about, but for the sake of time, talk about the role of neoadjuvant chemotherapy/IO. Keep in mind that there are still some institutions that thought before these data came out, that the benefit of neoadjuvant chemotherapy is relatively similar to the benefit of adjuvant chemotherapy. You’re not wrong to do neoadjuvant first, but now we’ve got data layering in immunotherapy to this approach in the neoadjuvant setting. We have the CHECKMATE 816 study, and then we have 2 trials that’ll be presented at the oral session tomorrow. Jonathan, you have the privilege to go over these data, and I also want Jessica’s input as well from the surgical perspective. You’ll be discussing, I believe, some of this tomorrow. Jonathan, do you want to talk about these 3 trials?

Jonathan Wesley Riess, MD: I think the CHECKMATE 816 trial was pivotal in the treatment of non–small cell lung cancer. Patients receive 3 cycles of neoadjuvant chemoimmunotherapy followed by surgical resection. The event-free survival [EFS] difference was quite substantial and positive. There was an increase in pathologic complete response [CR] compared to chemotherapy alone, which kind of undergirded the event-free survival benefit that was observed. More data on that will be presented at ASCO [American Society of Clinical Oncology annual meeting] this year, on Monday. It was a practice-changing trial for me, and I have been using it more and more. We still await the OS [overall survival] benefit, although the trend looks very good. Both the EFS and the increase in pathologic CR rate were really impressive to me. I thought there were some interesting nuances as pointed out. PD-L1 [expression of] 50% or more seemed to do the best in the subset analysis. Although they included PD-L1 0%, which I think was something different from IMpower010, where you saw a benefit clearly in the 1% or more.

Heather Wakelee, MD: But more in the higher [expression of PD-L1].

Jonathan Wesley Riess, MD: But more in the higher, so it tracked with that too, but it’s approved for PD-L1 0%. I would note it’s FDA approved for PD-L1 0% as well. You do 3 cycles, and right now, you’re done. After 3 cycles and surgery, there’s no adjuvant immunotherapy after. But there are trials ongoing looking at neoadjuvant chemotherapy/IO, surgery, and adjuvant immunotherapy, and I think it’ll be really exciting to see, does that add to the benefit or not? I think the further trials being presented at ASCO this year go along with that kind of increase in pathologic CR rate and so forth.

Benjamin Levy, MD: NADIM-II, a randomized phase 2 trial, building on the NADIM-I, which has been published in Lancet Oncology in 2020, had a higher pathologic complete response of 50% in stage IIIA, that original NADIM, which I didn’t believe. The NADIM-II will be a bit more modest pathologic complete response, around 30% or 35%. Then the other data, the neoSCORE, is looking at 2 vs 3 cycles, trying to answer the question, is it 3 cycles of chemotherapy/IO, or is it 2 cycles? It looks like 3 cycles are better than 2, but the 3 cycles is already kind of there from the 816 and the NADIM-II trials. Jessica, I’m really curious, [what is] your take on this as a surgeon? How does this impact flow of patients, communication, and the overall data?

Jessica Donington, MD: I think the overall data are super exciting. Jonathan Spicer, [MD, PhD,] presenting here at ASCO last year, presenting pure surgical data, really went a long way in surgical acceptance of this. There was no increased risk of attrition or delay. It appeared that the surgeries might actually be technically easier. We don’t have a good marker for technically easier, but if you use things like blood loss and open procedures and extent, they were all just a bit better. I think surgeons were excited. In terms of stage IIIA, this isn’t a new flow for us. These are just new agents, but the flow we’ve always had, so this is an easy acceptance. For stage II, this is a change. For the IBs, it’s a huge change and I don’t know if surgeons are totally super excited about sending their node-negative patients for upfront therapy. I think in the node-positive population, this feels very good, and I think surgeons are genuinely excited. And more and more of the data that are coming out have that surgical stuff included, where it’s looking that it’s not a barrier to a minimally invasive resection or a safe and smooth operation.

Benjamin Levy, MD: Do you think there’ll be some hesitancy on the part of surgeons who evaluate these patients first, to send them to the medical oncologist before surgical resection? Do you think this will be in the community and other academic centers? And do you think that patient buy-in will be tough to sell, saying, “Look, we’re going to pump the brakes on your surgery? We’re going to offer you some neoadjuvant approach first, and then you’ll come back to surgery.”

Jessica Donington, MD: As I said, the stage IIIA patients were supposed to always go to the oncologist first if they had N2disease. I think for most surgeons, that does happen. Again for the N1 patients, who we would’ve operated on first, my discussion with the patient is very clear, “You have stage II disease; you’re going to get systemic therapy. Let’s do it up front. It’ll just be easier and better for everybody if you do this first, and then you come to us.”

Alexander Spira, MD: I agree completely, and I’m glad we’re all on the same page. The challenge is not only is there going to be a delay, but what do you do about the EGFR [mutation testing]?

Benjamin Levy, MD: I was going to ask. What do you do here?

Alexander Spira, MD: Now you have to put the brakes on, but wait, we still have to get the EGFR testing. If there isn’t reflex testing on that original biopsy, and I’m not even going to go into what if you have a liquid biopsy, but what if there’s not enough shedding DNA? There’s a can of worms here. We have a clinical trial for neoadjuvant currently. It’s adding on to immunotherapy, but we need the EGFR back. I made the dumb mistake of not doing a blood-based assay and we didn’t have enough, so now I’m repeating a biopsy because we need the EGFR. Delay, delay, delay, delay, delay, delay.

Benjamin Levy, MD: I’ll go off the record and say we’re having real challenges at our institution putting these people on now that the EGFR and ALK [testing] have to be completed. Sometimes they don’t shed ctDNA [circulating tumor DNA], and we have to wait for the tissue, and that tissue takes a while, even in the best of cases at our in-house assay, and the patients don’t want to wait around. It’s a hard sell sometimes.

Heather Wakelee, MD: Which is good that there’s adjuvant treatment that works too.

Alexander Spira, MD: I feel like we’re bouncing a basketball back and forth here. To go back though, you said before, now you’re sending more patients to chemoradiotherapy before we said that, with the adjuvant durvalumab for stage III. Is this going to shift it back?

Jessica Donington, MD: I think it is going to shift it back and not because surgeons are excited. We’ve always been excited about surgery, but because I think the medical oncologists are excited. I think you guys see the value that surgery may add in this situation.

Benjamin Levy, MD: Chaitali, your thoughts on this, what’s your approach in your institution? Are you doing neoadjuvant chemotherapy? Are you an early adopter or is it still a challenge at your place?

Chaitali Nangia, MD: Again, it depends. I think the community resources, the community referral is kind of tough on it because patients don’t want to wait, and the surgeons don’t want to wait. Everyone wants to jump at it. The tissue is an issue; getting that EGFR testing will slow things down. But I think for the right patients, like node-positive N2 patients, they’re more responsive to neoadjuvant approaches.

Jonathan Wesley Riess, MD: I would just highlight, we’re talking about molecular testing, and there are ongoing neoadjuvant EGFR trials and other oncogene drivers. There’s the NeoADAURA study with chemotherapy, osimertinib. Then we have [Collin] Blakely, [MD, PhD,] from UCSF [University of California, San Fransico]. We have his trial open at UC [University of California] Davis with neoadjuvant osimertinib that interestingly didn’t show any complete pathologic response, but some major pathologic response, and a good amount of at least a pathologic response. It highlights that different mechanism of action in terms of immunotherapy and TKIs [tyrosine kinase inhibitors] in the neoadjuvant and adjuvant settings.

Benjamin Levy, MD: A lot of questions to answer. For the sake of time, a great discussion, we’ll see how this discussion evolves over the next 12 to 24 months. It may be very different if we came back next year.

Transcript edited for clarity.