Perioperative Nivolumab Plus Chemotherapy Represents the Future of Personalized NSCLC Care

Jonathan D. Spicer, MD, PhD, FRCS

The emergence of immunotherapy in the non–small cell lung cancer (NSCLC) treatment paradigm has set in motion a new era of individualized therapy, in which careful attention must be paid to the risk-benefit profiles of chemoimmunotherapy regimens in the adjuvant and neoadjuvant settings and for which patient preferences serve as key deciding factors between available treatment options, according to Mark Awad, MD, PhD. 

In October 2024, the FDA approved nivolumab (Opdivo) in combination with platinum-doublet chemotherapy in the neoadjuvant setting, followed by single-agent nivolumab in the adjuvant setting, for the treatment of adult patients with resectable NSCLC and no known EGFR mutations or ALK rearrangements. This regulatory decision was based on findings from the phase 3 CheckMate 77T trial (NCT04025879).

The addition of this regimen to the NSCLC treatment paradigm is a call for thoracic surgeons to stay informed on the latest treatment strategies and update their practices accordingly, Jonathan Spicer, MD, PhD, emphasized in an interview with OncLive^®.

"Bringing this first wave of checkpoint inhibitor trials to the resectable setting is one big step but there are so many new molecules and new approaches that are being tested," said Spicer, who is an assistant professor of surgery in the Department of Surgery in the Division of General Surgery at McGill University, as well as the Dr. Ray Chiu Distinguished Scientist in Surgical Research at Montreal General Hospital in Quebec, Canada.

"[Going forward], some of the big questions [will regard] more personalized approaches, the potential de-intensification of treatment, and the potential escalation or intensification of treatment," Awad, who serves as chief of the Thoracic Oncology Service at Memorial Sloan Kettering Cancer Center in New York, New York, added.

In the interview, Awad and Spicer discussed the significance of this approval, key efficacy and safety data from the pivotal CheckMate 77T trial, and how this perioperative regimen may influence the future of NSCLC management.

OncLive: What is the significance of this approval?

Awad: We’ve seen a lot of progress in lung cancer in general over the past several years, both for metastatic lung cancer and more recently, for earlier stages of lung cancer, including with advances through trials like CheckMate 77T. [There is] a big problem in thoracic oncology. Historically, in early-stage lung cancer, diagnosed at stages I, II, or III, a large percentage of lung cancers recurred after surgery despite the intent of prior treatments to try to cure patients of their disease. For a few decades, the standard of care was surgery and then giving a few cycles of chemotherapy after surgery.

However, with the emergence of immunotherapy and with immune checkpoint inhibitors initially approved in metastatic lung cancer, now we’re seeing a lot of trials where these immunotherapies are being tested in the perioperative setting. We’ve seen a lot of trials where immunotherapy was administered only after surgery. There then were the trials giving immunotherapy in the neoadjuvant setting, either alone or in combination with chemotherapy.

More recently, we’re seeing perioperative immunotherapy trials presented and published, [in which] immunotherapy with chemotherapy [is administered] before surgery in the neoadjuvant setting, [followed by] surgery. Immunotherapy alone [is then continued] in the post-operative period for 1 year in many cases. We’ve seen trials such as CheckMate 77T, as well as other studies with relatively similar designs. For example, the KEYNOTE-671 [NCT03425643] and AEGEAN [NCT03800134] studies are similarly designed phase 3 trials using perioperative immunotherapy in early-stage resectable lung cancer.

What CheckMate 77T and other [trials] are beginning to show is that using chemotherapy and immunotherapy before surgery, and immunotherapy after surgery, significantly reduces the risk of recurrence. As patients are followed more longitudinally in these trials, we’re seeing a clear separation in terms of how often the cancer tends to come back, depending on whether patients were randomly assigned to the arm of the trial that included immunotherapy, or to the placebo arm of the trial, where patients only received chemotherapy before surgery but did not receive immunotherapy before or after surgery. This is an exciting development in early-stage lung cancer.

Several of these trials will continue to have follow-up. The KEYNOTE-671 trial, which used a different immunotherapy, pembrolizumab [Keytruda], instead of nivolumab, has also reported that patients who received immunotherapy had significant improvements in overall survival [OS], as well as the earlier end point of event-free survival [EFS]. We are seeing that these approaches are helping patients live longer and increasing, we hope, the cure rate for patients with early-stage lung cancer.

Spicer: [This regimen is] an important addition to the options that currently exist for patients. [CheckMate 77T] was strongly positive in favor of perioperative nivolumab. It builds on the current neoadjuvant treatment approach [of neoadjuvant nivolumab plus chemotherapy for patients with resectable disease based on data from] the phase 3 CheckMate 816 trial [NCT02998528]. We still have to define which patients need perioperative therapy vs which are sufficiently treated with a pure neoadjuvant regimen, but [the CheckMate 77T regimen] gives both patients and oncologists the option to escalate treatment if they feel the need to do so after neoadjuvant therapy and surgery.

What were the key efficacy findings from CheckMate 77T?

Awad: This was a randomized trial where half of the patients received chemotherapy plus nivolumab then went to surgery and received nivolumab for 1 year after surgery. The other half of the patients did not receive immunotherapy before or after surgery and were randomly assigned to receive chemotherapy alone. What we’ve seen so far [from the data that have] been presented is that the patients who received neoadjuvant chemotherapy plus immunotherapy had a significant increase in pathologic complete response [pCR] rates and major pathologic response [MPR] rates [vs those in the comparator arm].

We’ve known from prior studies that neoadjuvant chemoimmunotherapy makes a big difference in pCR rate. After patients complete neoadjuvant chemotherapy and immunotherapy, when they get to surgery and the pathologist looks at the specimen under the microscope, they can determine whether there are residual viable cancer cells during the pathology examination. A pCR means that there appear to be no cancer cells remaining at the time of surgical resection. An MPR is also a good response, but that’s the category where the pathologist sees that less than 10% of the area where the cancer had been still has viable tumor cells.

Those are short-term end points. They are important, but we are also concerned with how these patients do in the long run after surgery. What’s their likelihood of recurrence? Do these interventions help patients live longer?

We’ve seen data from CheckMate 77T reporting on EFS, which refers to [the length of time] after patients were treated with this regimen that the cancer came back or showed signs of growth, or [how long after treatment] patients died. As these patients were followed for long periods, we saw that patients who received immunotherapy had much lower rates of recurrence after treatment or surgery. For example, at the 12-month time point, 59% of patients who had received chemotherapy and placebo had recurrence or an event compared with 73% of patients in the nivolumab arm.² When we followed these patients further, at the 18-month landmark time point, 50% of patients who received chemotherapy without immunotherapy had an event vs 70% of patients who received nivolumab. The difference of 50% vs 70% at the 18-month time point means a 20% improvement in the reduction of events [with nivolumab vs placebo].

We will continue to follow these patients longitudinally in the long run to determine whether this [EFS benefit with nivolumab vs placebo] translates to an OS benefit. Do these patients live longer with perioperative immunotherapy? Other trials with longer follow-up have shown that a regimen like this translates to improvements in OS.

When we analyze the different subgroups of patients [in CheckMate 77T], most subgroups benefitted from the incorporation of immunotherapy with chemotherapy. We’ll need additional analyses, but we had a sense that this regimen works well in patients with PD-L1–positive lung cancer. That biomarker, at least in the metastatic setting, correlates with response to immunotherapy. We will continue to parse through the data and evaluate the subgroups.

Patients with more advanced disease, like stage III disease, do better with immunotherapy, [as do] patients with lymph node involvement and patients with a history of tobacco use compared with never smokers. A lot of subgroups favored the use of immunotherapy rather than placebo. However, we’ll want to clarify that going forward. Are there subgroups that do particularly well or that don’t seem to benefit from the incorporation of immunotherapy with chemotherapy?

Spicer: The authors of CheckMate 77T have done a good job of defining the populations within the study that weren’t typically considered to be [eligible for surgery] and showing the important benefits that those patients experienced when they were treated in this perioperative manner. The key subgroups [of patients who benefitted from the addition of nivolumab included] patients with N2 involvement and even more so patients with multi-station N2 involvement. There was a nice presentation by [Tina Cascone, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston] at the 2024 ASCO Annual Meeting evaluating the subgroups of patients with vs without N2 involvement. [The presentation showed] that, at least from an EFS perspective, outcomes were almost no different and surprisingly good whether patients had N2 involvement or not. Traditionally, at least for the past 10 or 20 years, there’s been a move away from offering surgery to patients with N2 disease, especially with the approval of the phase 3 PACIFIC trial [NCT02125461] regimen of consolidation durvalumab after chemoradiation. [However, the CheckMate 77T] data are indicative of the potential benefits of a surgical approach, especially when combined with a drug like nivolumab before and after surgery.

What should be known about the toxicity profiles of perioperative chemoimmunotherapy regimens?

Awad: It is important to consider the safety profile of regimens like this because on a trial like CheckMate 77T, we’re exposing patients to immunotherapy potentially for much longer than they would have received it before; they’re receiving it ahead of surgery and for up to 1 year after surgery. We always want to know: Are we overtreating patients? Are we undertreating patients?

There’s been a lot of discussion around perioperative immunotherapy. CheckMate 816 gave 3 cycles of chemotherapy plus nivolumab before surgery but then no immunotherapy in the adjuvant setting. That treatment approach also resulted in higher pCR rates, MPR rates, and improvements in EFS [vs chemotherapy alone].

The question is: What is the contribution of adjuvant immunotherapy? Is it necessary for all patients? In patients, for example, who achieve a pCR, can we stop at surgery and not necessarily administer more immunotherapy in the post-operative setting? That is an ongoing question that has been up for debate in our community, and it’s important to discuss with patients that it’s a bit of an unknown.

Giving immunotherapy potentially exposes patients to added risks, but this type of approach, combining chemotherapy with immunotherapy, has been approved in the United States and in many other countries worldwide for several years in the metastatic stage IV patient population. [Therefore, we have become] accustomed to looking for specific immune-related adverse effects [AEs]. We’re better at early detection and management of these AEs but we know that adding immunotherapy to any regimen can increase the risk of immune-related AEs.

Most patients don’t have serious complications or AEs but a small percentage of patients can have more serious AEs. Stimulation of the immune system can cause inflammation in healthy organs or tissues. Some patients can get colitis, hepatitis, or pneumonitis; any organ could get inflamed. We especially don’t want patients to develop AEs in the pre-operative setting, which may preclude them from getting to surgery because surgery plays an important role in hopefully curing patients of early-stage lung cancer.

However, most patients on these trials who have been randomly assigned to the immunotherapy arms have still been able to get to surgery at similar rates [as those randomly assigned to the control arms] or sometimes are even more likely to get to surgery because their cancer has been more likely to respond in the pre-operative setting. In general, these types of regimens are manageable from a safety standpoint, but it’s important to counsel patients on potential AEs and check in with them frequently, both in the pre-operative setting and in the adjuvant setting. Giving immunotherapy more chronically for several months or 1 year after surgery can also cause AEs that can be bothersome. These may not be serious, life-threatening AEs or AEs leading to hospitalization, but they can interfere with quality of life and cause more chronic, low-grade AEs, such as joint aches and pains, muscle aches and pains, or other similar types of AEs that bother patients.

What were the safety findings from CheckMate 77T?

Spicer: [The safety profile of the CheckMate 77T regimen is] typical of all the trials of PD-1 or PD-L1 inhibitors in the resectable setting and is also consistent with what’s been previously reported in the metastatic setting. No big surprises there. In CheckMate 816, there was almost no measurable increase in AEs between the chemotherapy-only group and the chemotherapy/nivolumab group, whereas in CheckMate 77T, [as well as in] the other perioperative trials, there were more AEs in the patients receiving perioperative immunotherapy [than those in the placebo arm].

[Whether to receive this regimen is] for the patients to decide. [This regimen would] seem acceptable if there is a gain in survival as a result of those AEs, but that’s what we don’t have full clarity on. Adding a whole year of immunotherapy exposes patients to risks that they wouldn’t be exposed to if they didn’t receive immunotherapy. Which patients to adjudicate [this regimen] to and how to make decisions that don’t increase the toxicity, both the medical toxicity and financial toxicity of additional treatment, is going to be the subject of investigation for the next few years.

How could the FDA approval of nivolumab plus chemotherapy open the door for other investigations of perioperative immunotherapy regimens in NSCLC?

Awad: [The eligibility criteria for CheckMate 77T did] not include a [large], individualized selection of biomarkers. [CheckMate 77T] and similar trials excluded patients who had known EGFR mutations or ALK rearrangements, but essentially all other patients [with resectable NSCLC] were allowed on the trial and treated with 1 [investigational] regimen, in this case chemotherapy plus nivolumab. However, there are many subtypes of lung cancer and they don’t all respond to immunotherapy. Can we continue to personalize treatment for patients and further subdivide patients in the neoadjuvant setting to tailor regimens more precisely depending on additional biomarkers that the tumor may display?

[Additionally], are there some patients we are overtreating who don’t necessarily need chemotherapy and immunotherapy before surgery and 1 whole year of immunotherapy after surgery? Can we safely discontinue immunotherapy, for example, in patients who achieve a pCR, or use tools like circulating tumor DNA monitoring to understand which patients may or may not be able to stop therapy at an earlier time point?

[Furthermore], a large fraction of patients who receive chemotherapy and immunotherapy before and after surgery will experience recurrence of their lung cancer, unfortunately. How do we predict whether that’s going to happen, and how do we tailor, adjust, or add novel agents to the treatment paradigm for early-stage lung cancer to increase the cure rate? These are directions we’ll need to take going forward to help cure more patients.

Spicer: The mantra for a long time has been that we need to work within a multidisciplinary setting. From a surgeon’s perspective, it’s important to be aware of the data and understand your team’s ability to apply these data and monitor your outcomes as you go to make sure they are aligned with what’s previously been published. Teams have to get comfortable with what is [considered] resectable disease in 2024 and 2025, and that might have changed from how they were practicing before these approvals came through. Learning from the other experts in the multidisciplinary team and exchanging insights and reviewing patients together [is important], so all the various options are presented to the patient, and then the patient can choose what suits their goals of care in the most optimal way.

This is an exciting time and just the first step. There are going to be much more [data] coming into this [treatment space]. I’d encourage all clinicians to remain abreast of these developments as they continue to emerge.

References

1. FDA approves neoadjuvant/adjuvant nivolumab for resectable non-small cell lung cancer. FDA. October 3, 2024. Accessed November 13, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-neoadjuvantadjuvant-nivolumab-resectable-non-small-cell-lung-cancer
2. Provencio M, Awad MA, Spicer J, et al. Clinical outcomes with perioperative nivolumab (NIVO) by nodal status among patients (pts) with stage III resectable NSCLC: results from the phase 3 CheckMate 77T study. J Clin Oncol. 2024;42(suppl 17):LBA8007. doi:10.1200/JCO.2024.42.17_suppl.LBA8007