Neoadjuvant Immunotherapy is Helping Redefine Resectability in NSCLC

Clinical trials investigating the use of neoadjuvant treatment regimens consisting of chemotherapy/immuno-oncology (IO) combinations, such nivolumab (Opdivo) plus platinum-based chemotherapy in the phase 2 NADIM II trial (NCT03838159), have produced promising response rates, according to Neel P. Chudgar, MD, who noted that this strategy could help more patients non–small cell lung cancer (NSCLC) proceed to resection.

In the open-label, randomized, multicenter NADIM II study, the addition of neoadjuvant nivolumab (Opdivo) to platinum-based chemotherapy was evaluated in patients with potentially resectable, stage IIIA to IIIB NSCLC, resulting in a 24-month overall survival rate of 85.3% (95% CI, 75.7%-96.1%) vs 64.8% (95% CI, 47.4%-86.4%) with chemotherapy (95% CI, 0.14%-0.93%; HR, 0.37; P = 0.003).¹

“Determining resectability does require a surgeon to be present, but it's also [important to have] support of the other providers, such as medical and radiation oncologists, so that we know what the best multimodal treatment strategy is for [patients with] locally advanced [NSCLC]. It's not going to be one treatment that helps treat these folks; it's going to be a combination of them,” Chudgar, an assistant professor of Cardiothoracic and Vascular Surgery at Albert Einstein College of Medicine in New York, New York, explained.

In an interview with OncLive^®, Chudgar discussed a presentation he gave at the 21st Annual Winter Lung Cancer Conference^® on the how to define resectability in patients with NSCLC and expanded on remaining questions that exist for this patient population.²

Additionally, Chudgar is a thoracic surgeon, associate director of Clinical and Translational Research, Thoracic Surgery, and an attending physician at Montefiore Medical Center, also located in New York, New York.

OncLive: What is the rationale of your presentation, ‘What is the Definition of Resectability?’ and what are some of the controversies that are currently at play in this space?

Chudgar: This was a challenging presentation to put together because there is so much controversy in this area. When I first started thinking about the definition of [resectability], I tried to think of the different pieces that come together, and I looked at patient factors, [including] medical operability, which I don't think is as contested, so this wasn't a big part of my presentation. However, there were 2 other factors that I wanted to pay more attention to: technical factors, as to whether the tumor can be technically removed and safely taken out, and oncologic factors.

Although we be able to [resect a tumor], is that going to be something that's safe and or feasible to do for the patient's oncologic outcome? Those were the parts that I tried to focus on more, but it is an area where data are sparse. Even in what data have been attempted to be put together, there has not [been] a lot of consensus to say that for [a particular] stage of disease, or for [a particular] patient, we can or cannot definitively resect them.

What are some of the reason’s surgery may be considered for patients with clinical T4 disease?

[My institution has] studied this through the National Cancer database, and we aimed to present some of the data that were published in the European Journal of Cardiothoracic Surgery.³

There were a few things to consider. One of them was when we looked at patients with clinical T4 tumors, [there was a percentage] of those patients [whose tumors] were not clinical T4. Although we don't have data to [point to] the reason why that was the case, we may assume part of it is invasion preoperatively is not invasion at the time of surgery. In some ways, we may tend to shy away from [operating on] clinical T4 invasive tumors, when in fact, they are not invasive. That’s one reason that we can operate.

Additionally, we found through our study that patients can be resected safely. As far as outcomes that were available through the National Cancer database, things like 30- and 90-day mortality or remission rates show that resection is safe.

Furthermore, minimally invasive resection is safe for patients. Data from this study showed us that we can consider surgery, we can consider it minimally invasively, and it can be done safely with survival that's also reasonable.

What risks and limitations should be considered when determining whether patients with stage IIIB disease are eligible for resection?

This is one of the hardest places in determining resectability because this is a very heterogeneous class of patients when it comes to those with stage IIIB disease. Those [patients who] are tougher, [such as] those with positive mediastinal nodes [N2], can be broken those down into single station N2 vs multi-station N2, [as well as] patients with bulky N2 disease or invasive N2 disease. This is where there are not discrete data to say we can or cannot resect patients.

[Resectability for] patients with single-station N2 disease [is likely less contested]. If they meet routine criteria as far as medical operability, those patients can most likely be resected. There are more challenges in the bulky, multi-station N2 [population].

There are data from recent neoadjuvant trials, such as chemotherapy/IO trials like the NADIM II trial [in patients with resectable stage IIIA disease] for instance, where a large percentage of patients did have multi-station N2 disease. Patients were able to make it to surgery and get resected.

When we looked at the outcomes of those patients [enrolled on, there was a 2-year overall survival [rate of 85.3% in patients treated with neoadjuvant nivolumab plus chemotherapy], which is quite good for a cohort of patients with multi-station N2, [stage IIIA disease].

How might neoadjuvant immunotherapy affect resectability?

This [question] is going to be one of the key pieces that makes the evolution of the definition of resectability continue to come up as a question. As we find response rates that are very promising in this era of neoadjuvant IO in addition to chemotherapy, we will probably find that more patients will be in a category of resectable [disease], where they may have been unresectable [in the past].

[At the meeting], I presented the case of a patient where when you looked at the scan, you knew there were questions from a technical perspective of resectability. It was a patient who had bulky N2 disease. From an oncologic perspective, we had questions of resectability.

Although this was a single case, he was a patient who had an excellent response to his chemotherapy/IO [combination treatment] to the point where when we looked at his restaging scans, he was in a position where we could safely consider resection, which he did undergo. We found that we were able to technically resect him, and he had a complete pathologic response. Immunotherapy is going to push the bounds of who we're able to offer surgery to in the future.

What is the importance of multidisciplinary collaboration when determining if a patient is eligible for resection?

When we discuss these patients, [it is important] to remember that [their disease is] complex. In determining what is going to be the best treatment options for them, it's key to have a medical oncologist, a thoracic surgeon, and a radiation oncologist looking together to see what we can do and what's going to be in the best interest of the patient.

References

1. Provencio M, Serna R, Nedal E, et al. Progression-free survival and overall survival in NADIM II study. J Thorac Oncol. 2022;17(9):S2-S3. doi:10.1016/j.jtho.2022.07.014
2. Chudgar NP. What is the definition of resectability? Presented at: 21st Annual Winter Lung Cancer Conference; February 2-4, 2023; Hollywood, FL.
3. Rodriguez-Quintero JH, Elbahrawy MM, Montal AM, et al. Minimally invasive surgery for clinical T4 non-small-cell lung cancer: national trends and outcomes. Eur J Cardiothorac Surg. 2024;65(3):ezae009. doi:10.1093/ejcts/ezae009