This trial, led by Dr. Jack Roth⁸ at MD Anderson Cancer Center, is one of the pivotal trials from the early 1990s showing the benefit of perioperative CT plus surgery for patients with stage III disease. This prospective, randomized study enrolled 60 patients with untreated, resectable stage IIIA NSCLC and compared the survival probability of perioperative CT with surgery to surgery alone. The 3-year OS was 56% vs 15% in favor of perioperative CT plus surgery, with 35% of patients achieving a clinical major response with 3 cycles of perioperative CT.

This trial introduced the idea of multimodality care for locally advanced lung cancer and inaugurated more than 20 years of trials, leading to a constant evolution in the way we care for these patients. Another important trial in this space was led by Dr. Rafael Rosell⁹ in Spain in the early 1990s and showed a similar benefit to the addition of perioperative CT to surgery for patients with stage III NSCLC.

The reason we are interested in bringing systemic therapy to patients with early-stage NSCLC is that there is still significant room for improvement in outcomes. If we look stage-for-stage between lung cancer and other cancers (eg, breast cancer, melanoma, and colorectal cancer), the survival outcomes are far worse for lung cancer. As we can see in this figure and the corresponding table, the 24-month OS rate for stages IA1 to IA3 ranges from 92% to 97% and the 60-month OS rate ranges from 80% to 90%.¹⁰ However, outcomes drop precipitously as we move through to stage III. Even going from stage IIIA to IIIC, the 24-month OS rate drops from 65% to 30% and the 60-month OS rate drops from 41% to 12%, respectively. Unfortunately, until recently there’s been a lack of good systemic therapies to make a big difference in survival outcomes for patients with early-stage NSCLC. So, it’s an exciting time now to be looking at how to improve outcomes these patients.

The first published study on the use of immune checkpoint inhibition in the treatment of resectable NSCLC by Forde and colleagues¹¹ showed surprising and unexpectedly high pathologic response rates with 2 doses of neoadjuvant nivolumab. This introduced a new era of investigation into immunotherapy for patients with operable lung cancer. It has become a busy space with dozens of trials looking at different strategies to deliver immunotherapy, including single-agent immunotherapy, combination immunotherapy, immunotherapy with classical CT, or immunotherapy with radiotherapy.¹²

Interpreting the results of all these earlier-phase studies is going to be complicated, because the regimens being evaluated are all quite different and each trial has slightly different inclusion criteria. Furthermore, the trial endpoints are variable, including a range of efficacy endpoints such as major pathologic response (MPR), pCR, and survival, as well as other translational endpoints like circulating tumor DNA (ctDNA). It’s an exciting time, but it will be challenging to take all this information into context and decide how to move forward.

One of the main drivers of interest in neoadjuvant therapy for patients with operable lung cancer is the concept that the degree of pathologic response, which can be assessed in a very systematic way, can act as a surrogate marker of survival.

Hellmann and colleagues¹³ retrospectively looked at the association between MPR (defined as ≤10% residual viable tumor cells) and how that correlated with survival. Patients who had deeper pathologic responses had a significant improvement in OS: There was an almost 5-fold increase in the HR for death in patients who had a poor pathologic response with 71% to 100% of residual viable tumor cells after neoadjuvant CT vs those with ≤10% cells (HR: 4.78; 95% CI: 2.06-11.11). 

It stands to reason that if there’s good tumor kill resulting from a systemic therapy in the tumor bed, this may be indicative of micrometastatic tumor killing that would likely translate to an OS benefit. That has yet to be proven in NSCLC, but there is now precedent for the concept from neoadjuvant trials in breast cancer and we will have more data on this soon for NSCLC.

In addition to the scientific interest that we have here, assessing disease pathologic response is a path to more rapidly introducing new therapeutics in this disease setting as the endpoints occur quicker than when we assess OS.

I like to look at neoadjuvant therapy for NSCLC as a process map and think of all the opportunities for improving patient care and learning about the disease. Starting with screening and detection of early-stage NSCLC, there’s an opportunity for risk factor modification, patient education, and primary and secondary prevention.¹² Then there is a huge space around biomarker discovery to supplement radiographic screening strategies.

Once a diagnosis is established, we face a challenge with patients going to upfront surgery because they are not always at their most fit prior to the operation. Our team at McGill University has placed a huge effort, during the last 20 years or so, at studying how to prehabilitate patients so that they are in the best possible condition prior to surgery. Later, I discuss a few ways in which we think neoadjuvant therapy may help with that.

Then moving on to neoadjuvant therapy: The use of immune checkpoint inhibitors prior to surgery has strong scientific rationale. If a patient has a vigorous immune system that has not suffered from the impact of an advancing cancer, neoadjuvant immunotherapy may be an opportunity to expand tumor-specific T-cells in the peripheral blood, which may serve to offer more durable responses and cancer control. The idea of a tumor immunization effect in the neoadjuvant period is strongly supported by preclinical data and now emerging clinical data in the setting of melanoma. Hopefully, we’ll be able to demonstrate the same immunization effect more convincingly in patients with lung cancer as well.

Once a patient undergoes surgery and we have a resected cancer specimen, there are tremendous scientific opportunities here with the collection of tissue and blood samples. Access to specimens will support and expand our understanding of the biology of lung cancer and its response to treatment pressures like immunotherapy or various combinations thereof. This will create further opportunities for identifying biomarkers that indicate response and the likelihood of progression in the postoperative survivorship period.

Now let’s discuss the concept of prehabilitation in further detail.

This table highlights the results of a randomized, controlled trial comparing prehabilitation vs rehabilitation in the postoperative period for patients with lung cancer.¹⁴ Prehabilitation takes time, so this was a multimodal program where patients underwent multiple assessments, including nutritional, physiological, and psychological, and as a result of these assessments, tailored interventions were made for these patients.

One of the most striking outcomes with prehabilitation was in the postoperative day of discharge. Almost 3 times as many patients were discharged within 1 or 2 days of their operation in the prehabilitation group vs the rehabilitation group (42% vs 16%, respectively; P = .0069). There were also notable improvements in patient-reported outcomes, including an improvement in the mental SF-36 summary 4 weeks after surgery with prehabilitation vs rehabilitation (15.2% vs 14.5%, respectively; P = .052). In addition, patients were in better physical and overall condition 1 or 2 months after surgery. These data quite convincingly showed that prehabilitation was beneficial for patients undergoing lung cancer surgery.

The promising prehabilitation results also raised the question: What is the value of taking an extra 4-6 weeks to get a patient fit for surgery in the context of unchecked cancer progression? Could we combine prehabilitation with neoadjuvant therapy to maintain the patient’s physiologic function while bringing them to surgery in a safe way?

To answer this question, our group conducted a retrospective analysis of patients with NSCLC who received neoadjuvant therapy followed by curative-intent surgery at McGill University Health Center between 2015-2020 (N = 93) and identified 12 of them who were screened to undergo a prehabilitation program.¹⁵ The 9 patients who completed full neoadjuvant prehabilitation therapy were discharged after surgery at an earlier point in time than those who did not; these patients also improved their 6-minute walk test despite receiving neoadjuvant therapy. As you can see from our small experience, the combination of neoadjuvant therapy with neoadjuvant prehabilitation prior to surgery for our patients with early-stage lung cancer can be effective.

I strongly believe it is important to take a multimodal approach in the care of our patients with early lung cancer, one that includes a cancer-directed therapy that is effective and tailored to that patient’s tumor along with incorporation of a prehabilitation program that makes the best use of that neoadjuvant therapy time such that the operation is conducted in the safest possible way and so that the maximum number of patients make it to the operation. This seems even more feasible with the advent of immunotherapy, which seems to have a more tolerable adverse event (AE) profile than CT and a powerful pathologic effect on the tumor, which we’ll talk more about below.

Globally, the adoption of neoadjuvant therapy has been slow. With the exception of patients with single-station stage III NSCLC, most centers around the world go for upfront surgery. That said, many of the biggest cancer centers have been long-time adopters of neoadjuvant CT allowing for retrospective analyses of this modality, such as the following study from the Memorial Sloan Kettering Cancer Center.

This retrospective study looked at stage-matched cohorts of patients (N = 330) who received either neoadjuvant CT or adjuvant CT for cT2-4N0-1M0 NSCLC with R0 resection.¹⁶ We know from more comprehensive meta-analyses that there is no major difference between a neoadjuvant approach vs an adjuvant approach in terms of disease-free survival and OS. The difference is seen in the AE rate, and this study reflects that. Here, there were more than twice as many grade ≥3 AEs with adjuvant therapy compared with neoadjuvant therapy, which is a very important finding. 

For me, it’s all about the global experience of each individual patient—not just what happens at surgery, but what happens before and after. If we can deliver systemic treatment that has proven benefit and do it in a way that reduces the AE rate or the serious AE rate, the patients will ultimately benefit. 

Now we discuss some of the results of various studies with neoadjuvant immunotherapy.

In 2018, Forde and colleagues¹¹ reported the results of a pivotal trial that included 21 patients with untreated, resectable, stage I-IIIA NSCLC. Patients in this trial received 2 doses of preoperative nivolumab, and 45% (95% CI: 23-68) experienced an MPR, with responses occurring whether the tumors were PD-L1 positive or negative.

This study changed the NSCLC treatment landscape forever.

The LCMC3 study is an open-label, multicenter phase II trial that enrolled 181 patients.¹⁷ Patients in this trial had untreated, resectable stage IB-IIIB NSCLC and received 2 doses of preoperative atezolizumab. The results of this trial were presented at the WCLC 2020 conference.¹⁸

As often happens with larger studies, the MPR was less impressive than the smaller study of neoadjuvant nivolumab but still more than we might expect with classical CT. In the efficacy population (n = 144), the MPR response rate was 21% in the resected population and the pCR rate was 7%.

In a phase II trial combining atezolizumab with carboplatin/paclitaxel in the treatment of stage IB-IIIA NSCLC, with 70% of the 30 enrolled patients having stage IIIA disease, 97% of patients impressively made it to surgery.¹⁹ There was an 87% R0 resection rate, and 57% of patients achieved an MPR. In the graph on the right side of the slide, 10 of 26 patients who underwent successful R0 resection had a 100% pathologic response, which is ideal.

Data like these, where almost one half the patients experienced a pCR from systemic therapy alone, have not been seen before.

NADIM is an open-label, multicenter, single-arm phase II trial that enrolled 46 treatment-naive patients with stage IIIA NSCLC.²⁰ Patients received 3 cycles of carboplatin/paclitaxel plus nivolumab before surgery and then adjuvant nivolumab for 1 year. 

The results of the NADIM trial were also impressive, with 83% of patients having an MPR and 63% having a pCR. Of interest, of the 5 patients who did not undergo surgery (the gray bars), some patients had survival >18 months after enrollment. This leads one to wonder if perhaps some of those patients had a pCR and did not need surgery. 

This study raised a lot of questions with never-before-seen efficacy from systemic therapy alone and dictated some changes in the next trial that we are going to discuss—CheckMate 816.

CheckMate 816 is a randomized, open-label phase III trial specifically examining neoadjuvant nivolumab plus CT vs CT alone in patients with newly diagnosed, resectable stage IB-IIIA NSCLC without sensitizing EGFR or ALK mutations (N = 358).^21-23 Patients were to have surgery within 6 weeks of the completion of CT and had the option to complete adjuvant CT with or without radiation. When the trial was first introduced, there was an exploratory arm to evaluate the combination of nivolumab plus ipilimumab, which was dropped based on the results of the NADIM trial.

The primary endpoints of CheckMate 816 were pCR and event-free survival, both by blinded independent pathology review. Key secondary endpoints were OS, MPR, and time to death or distant metastases, and some key exploratory endpoints were devised around the feasibility of surgery and perioperative AEs. 

The combination of neoadjuvant nivolumab plus CT resulted in an improved pCR rate vs CT alone (24% vs 2.2%, respectively) with an odds ratio of 13.9 (95% CI: 3.49-55.75, P <.0001).^21,22 If we look at just the resected population, the pCR rate is closer to one third (30.5%), so these are promising results. The MPR rate in the intention-to-treat population was 36.9% with nivolumab plus CT vs 8.9% with CT alone, with an odds ratio of 5.70 (95% CI: 3.16-10.26).

We will see if this translates to event-free survival positivity in the coming years, but these are very promising findings. (Editor’s note: A press release in November 2021 indicated that the CheckMate 816 trial met its primary endpoint of event-free survival. These data will be presented at a future conference.)

If we look at pathologic regression in the primary tumor by stage, you can see that regardless of disease stage, the depth of response is dramatically higher in the chemoimmunotherapy cohort than in the CT only group.²² The median residual viable tumor percentage for patients with stage IB/II disease was 28% for nivolumab plus CT vs 79% with CT alone, and for patients with stage IIIA, was 8% vs 70%, respectively. Again, I consider these to be very promising data.

In the CheckMate 816 trial, 90 patients had available prior specimens to evaluate ctDNA, 87 of whom had detectable ctDNA at cycle 1, Day 1.²¹ There was a strong association between the clearance of ctDNA and the occurrence of pCR. In patients treated with nivolumab plus CT with ctDNA clearance, the pCR rate was 46% vs 13% for patients treated with CT only with ctDNA clearance. Without ctDNA clearance, the pCR rate was 0% and 3% with nivolumab plus CT and CT alone, respectively.

It will be interesting to see if, by combining metrics like ctDNA, radiologic interpretations, and other clinical and pathologic parameters, we will be better able to predict the occurrence of pCR. Perhaps we will be able to tailor our operations or decide whether local therapy is even necessary. However, for the time being, many patients still have residual disease and surgery will be an important part of their care.

Regarding surgical outcomes, it’s interesting to see that 94% of patients were able to complete neoadjuvant chemoimmunotherapy and only 85% completed CT alone, which wasn’t expected.²² When you think of adding an additional active anticancer agent to a regimen, it’s not typical for it to be more tolerable, but here that seemed to be the case. 

Relatively similar numbers of patients were able to go on to surgery, but fewer patients in the chemoimmunotherapy arm (16%) were unable to undergo surgery arm as compared with the CT alone arm (21%).

As a surgeon, I was struck by the finding that the operations were a little more than 30 minutes shorter in the patients who received chemoimmunotherapy (184 minutes vs 217 minutes with CT alone), which is contrary to reports from various surgeons that patients treated with checkpoint inhibitors prior to surgery tend to have more difficult operations. It would be unusual for the operations to be more difficult and be 30 minutes shorter.

When we looked at these data by stage, the differences held up when comparing stage IB/II to stage IIIA disease.²² More patients who received neoadjuvant nivolumab plus CT received surgery than those who received CT alone, and the surgery times were again shorter. The biggest difference was seen with stage IIIA disease, where 83% of patients in the nivolumab plus CT arm received surgery, with a median duration of 186 minutes, compared with 72% in the CT only arm receiving surgery with a median duration of 218 minutes.

At ASCO 2021, Lim and colleagues²⁴ reported results from the VIOLET trial, a randomized trial comparing open surgery vs minimally invasive surgery. They did a thorough job comparing the 2 techniques for stage-matched patients, looking a year out from the operation. There was a significantly lower rate of AEs in patients who underwent minimally invasive surgery vs open surgery. In addition, the quality of life was improved with minimally invasive surgery, and the health-related cost of the minimally invasive approach was less than surgeries performed by an open approach. Based on these data, we know that if we can reduce the number of patients requiring thoracotomy, this could potentially be beneficial to patients.

In the CheckMate 816 trial, neoadjuvant nivolumab plus CT appears to do just that, most strikingly in patients with stage IIIA disease where 30% of patients in the nivolumab plus CT arm were approached by a minimally invasive technique vs 19% in the CT only arm.²² Of those who were approached by a minimally invasive technique, 11% patients required conversion to an open operation in the chemoimmunotherapy arm vs 20% in the CT only arm. Conversions can be problematic; sometimes these conversions are emergent conversions for bleeding or because the patient requires complex intervention, like a bronchoplasty or vascular reconstruction. So, for me, these were convincing data that the type of treatment was making these operations more approachable.

Perhaps the most striking surgical result in CheckMate 816 is that the type of surgery performed was quite different between the 2 cohorts. We know that patients who undergo pneumonectomy have almost double the major AE rate and almost triple the mortality rate at 90 days as compared with those who undergo a lobectomy.^25,26 In CheckMate 816, 17% of patients with stage IIIA disease—who are usually our most complicated surgical patients—who were treated with neoadjuvant nivolumab plus CT needed a pneumonectomy vs 30% of those with stage IIIA disease who received CT only.²² I think that this is something that will most likely affect event-free survival.

When we looked at the completeness of resection, it was more or less equivalent between the 2 cohorts regardless of baseline disease stage, with a few more complete resections in the patients treated with nivolumab plus CT vs those treated with CT alone (83% vs 78%), and obviously this is what we want.²² The median number of lymph nodes dissected was also similar between the 2 groups.

Looking at the global CheckMate 816 population, there was no major difference in length of hospital stay between the 2 cohorts. However, the length of stay after lung surgery is something that’s highly influenced by geographic regions and cultural expectations. Thus, when we look at the length of stay by region, taking note that approximately one half the patient population was recruited in Asia, the length of hospital stay for patients who received nivolumab plus CT seems to, on average, be 2 days less than in patients who received nivolumab plus CT. Length of stay is a decent metric for AEs as patients who have many AEs will stay longer in the hospital. So, I think these are interesting data, especially when examined by region.

This figure represents the Common Terminology Criteria for Adverse Events reporting of surgery-related complications for the CheckMate 816 trial. The most striking finding is that patients in the CT-only arm had double the number of AEs relating to pain (8% vs 16%) vs patients who received nivolumab plus CT. This fits with the higher number of patients who required either conversion to open surgery or open surgery at the outset since open operations are more painful. Furthermore, compared with patients receiving chemoimmunotherapy, patients treated with CT alone had higher incidences of shortness of breath (1% vs 4%), nausea (1% vs 3%), and chest pain (1% vs 3%), which are all things that may be more likely in the context of open surgery.

The 30-day and 90-day surgery–related mortality is not recorded here, as those measures are part of event-free survival reporting, but there were 2 grade 5 surgery-related AEs in the nivolumab plus CT arm—1 pulmonary embolism and 1 aortic rupture. They were deemed unrelated to study drug by the investigator, but I think that once we have event-free survival, we will have to take a closer look at these 30-day and 90-day outcome metrics as they are a little bit more difficult to interpret when you cannot include mortality. Surgeons generally think of 30-day and 90-day mortality as important surgical outcome metrics, and unfortunately, it is too early to report on those for the CheckMate 816 trial.

When taking all this into consideration, I think it’s important to remember that immunotherapy is not the only highly active treatment for NSCLC, and with the current status of biomarker testing globally for patients with resectable disease being limited, there is going to be a significant need for an evolution in how we investigate patients who are eligible for surgery. 

The LEADER trial is investigating the use of various targeted agents in approximately 1000 patients with operable lung cancer.^27,28 In this multicenter, umbrella trial, patients will be screened using local genotype testing or ctDNA analysis, the result of which will be used to select optimal neoadjuvant therapy.

I think this trial gives us a glimpse of our future, where we will offer the best possible targeted therapy with the fewest AEs and the highest degree of pathologic response to our patients before taking them to the operating room. I am a strong advocate for knowing as much about your patient and their disease before you offer them any therapy, including surgery, and so complete biomarker testing from biopsy material prior to surgical resection is of critical importance, in my mind. 

I only briefly mentioned the newly approved adjuvant therapies that exist for patients with resectable lung cancer. First is osimertinib, which is approved by the FDA as adjuvant therapy in adult patients with NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations.²⁹ Osimertinib is a highly active regimen with significant impact on disease-free survival.² Atezolizumab has also recently been approved as adjuvant treatment following resection and platinum-based CT for adult patients with stage II to IIIA NSCLC whose tumors have PD-L1 expression on ≥1% of tumor cells.³⁰ These 2 drugs are going to be part of our therapeutic landscape moving forward and are also why it’s important to know as much about your patient’s tumor regarding molecular profiling prior to offering them surgery, because this information has a dramatic impact on what the ideal systemic therapy adjuvant will be.

To illustrate the importance of biomarker testing in our patients with early-stage NSCLC, here is a 62-year-old female patient whom I treated during the COVID-19 pandemic in spring 2020. She had a clinical T3N1 adenocarcinoma with an ALK translocation. At the time, there were significant delays to surgery, but we were able to get approval for her to begin neoadjuvant treatment with alectinib, a tyrosine kinase inhibitor approved for the treatment of patients with ALK-positive metastatic NSCLC.³¹

After 1 month of neoadjuvant alectinib, the patient underwent surgery and, as you see on the right side of the slide, the degree of radiologic response was quite significant. I was somewhat concerned that the superior vena cava was going to be involved based on the initial scan. However, at surgery, I was able to do a standard right upper lobectomy and node dissection, and the tumor peeled off the superior vena cava nicely. The patient was able to go home on postoperative Day 2. At pathologic review, she had only 15% residual viable tumor cells.

Going forward, I think it will be very interesting to see how these targeted therapies fit together with emerging immune checkpoint inhibitor–based therapies in the setting of resectable NSCLC.

I think the next step is to start to understand and predict which patients have a pCR and to address some of these populations we know have an unmet need. 

There is a prospective, randomized, open-label phase II trial of neoadjuvant pembrolizumab on the horizon that is not yet recruiting.³² This is a trial comparing 9 weeks of neoadjuvant pembrolizumab vs pembrolizumab plus CT in patients with stage IA3-IIA NSCLC (planned N = 44). After surgical resection and mediastinal lymph node dissection, patients will receive adjuvant pembrolizumab plus CT for 36 weeks.

These are not patients who typically get systemic therapy, but we do know that they have quite high recurrence rates. One of the unique features of this study is that because we expect a fair degree of radiographic response for these lesions, depending on which treatment they receive and what their biomarker makeup is, some patients may be approachable by segmentectomy.

So the question is: Can we further tailor the operation to be less invasive and less impactful and to remove less lung parenchyma, all of which is important for patients to enjoy a better quality of life? We’re looking at the ctDNA resolution metrics and advanced radiographic imaging—which includes not only CT and PET but also MRI—to understand and perhaps be better able to predict a pCR. With this information, perhaps one day, we can design trials of surgery after optimal neoadjuvant therapy vs surveillance vs resection. This is some of the work that we have ongoing.