Perioperative Pembrolizumab Offers Survival Benefits in NSCLC

Jonathan Spicer, MD

Given as a perioperative treatment regimen, pembrolizumab (Keytruda) yielded a statistically significant and clinically meaningful improvement in overall survival (OS) compared with neoadjuvant placebo plus chemotherapy followed by adjuvant placebo among patients with resectable stage II, IIIA or IIIB (T3-4N2) non-small cell lung cancer (NSCLC), according to findings from the phase 3 KEYNOTE-671 trial (NCT03425643).^1,2

The study’s dual primary end point of event-free survival (EFS) was also met among patients treated with pembrolizumab plus chemotherapy as the 24-month EFS rate was 62.4% with this combination vs 40.6% for those given placebo plus chemotherapy (HR, 0.58; 95% CI, 0.46-0.72; P <.00001). At 24 months, the OS rate was 80.9% among patients in the pembrolizumab arm vs 77.6% in the placebo arm (HR, 0.73; 95% CI, 0.54-0.99; P =.02124).²

Most recently, findings showed that with a follow-up of 36.6 months, the trial demonstrated an EFS HR of 0.59 and a significant and clinically meaningful OS HR of 0.72 in favor of the perioperative pembrolizumab arm. Moreover, patients who achieve pathologic complete response (pCR) benefit from this therapy, as well as some patients without pCR as they may obtain benefit from continuing this treatment.

As a result, the FDA approved pembrolizumab in combination with platinum-containing chemotherapy as neoadjuvant treatment and with continuation of pembrolizumab monotherapy as postsurgical adjuvant treatment for patients with resectable NSCLC based on data from KEYNOTE-671 in October 2023.¹

In an interview with Targeted Oncology^TM, Jonathan Spicer, MD, assistant professor of surgery, McGill University, further discussed the background and findings of the KEYNOTE-671 trial.

Holographic concept of lung cancer: © catalin - stock.adobe.com

Targeted Oncology: Can you provide an overview of the KEYNOTE-671 trial?

Spicer: KEYNOTE-671is a randomized, phase 3, placebo-controlled trial where patients with stage II, IIIA or IIIB non-small cell lung cancer that was deemed resectable were randomized to perioperative pembrolizumab with neoadjuvant chemotherapy vs neoadjuvant chemotherapy with preoperative placebo. In the second interim analysis, we presented the overall survival results, as well as updated EFS and toxicity data.

What type of patient was included in the study?

This was a study dedicated to patients with resectable stage II, IIIA, IIIB non-small cell lung cancer. This includes patients with tumors greater than 4 cm and no nodes, all the way to patients with tumors deemed T4 and T2 disease, which would be the IIIBs. That was the range of patients that were included. They also had to be eligible to receive cisplatin-based chemotherapy.

Please discuss the findings from the study.

The main finding of the study is that the overall survival end point, which was a coprimary end point, along with EFS, is positive. That is the first immunotherapy-based study in the resectable non-small cell lung cancer space to ever show that. It is also the first study using a neoadjuvant strategy since the early 1990s to show that neoadjuvant therapy in resectable non-small cell lung cancer can offer an overall survival benefit, so these are landmark findings for our discipline.

The combination is now FDA-approved. Can you further discuss this indication?

The FDA approval mimics most of the trial requirements in the sense that the stages for which it would apply are aligned. As I said, [it is for patients with] stage II, IIIA, IIIB [disease], which includes patients with tumors greater than 4 cm on a CT scan, with or without ipsilateral lymph nodes that are deemed resectable surgically. The only difference between the label and the study is that the FDA label allows for any platinum doublet as opposed to requiring cisplatin, which was 1 of the requirements of this study.

What is important to know about this FDA approval?

There are 2 points. One is when we add immunotherapy to neoadjuvant chemotherapy and surgery, we obtain improvements that are notable with a hazard ratio of 0.72 for overall survival. That is what we are trying to achieve in patients being treated with surgery where the intent is to cure them. That is a big deal because that has never been shown before in resectable lung cancer.

The other aspect that is critical is that this can be achieved using a neoadjuvant study or strategy. There are basically 3 types of trials that have been conducted using immunotherapy in this space. There is the pure neoadjuvant strategy where patients get immunotherapy with chemo followed by surgery. There is the adjuvant setting where patients get surgery, followed by chemo, and then immunotherapy. Then there is this perioperative strategy, which is the 1 employed in KEYNOTE-671. Hundreds, if not thousands, of patients have enrolled into numerous phase 3 studies using all these different designs. Of all of them, this is the first to show an overall survival benefit. That is another important milestone.

What we are not so certain of is who are the patients who need that postoperative treatment vs those who do not. The study is not designed to answer that question, nor can we ever definitively address that without doing the proper study. This is sort of a platform of treatment that has overall survival benefit, and I think will be deployed into the real world for clinicians to apply and to study to understand those sorts of unknowns a little bit better as we go along.

What should a community oncologist know about the KEYNOTE-671 study and moving this regimen into clinical practice?

It really takes a multidisciplinary team of experts working together and communicating. It takes a closely knit network of surgeons, thoracic surgeons, medical oncologists, pathologists, and you need input from the radiation oncologist because some of the stage groupings will overlap with other treatments. That determination of resectability or the potential benefit of surgery is at the core of the discussion. Community oncologists just need to reach out and make sure they have a team around them to identify these patients and not to shy away from neoadjuvant treatments, even though they can be logistically a little bit more complicated to arrange if you are not in the habit of doing it. There is clearly a lot of benefit for these patients, so I would argue that for patients that meet these trial criteria, or the indications by the label, this is the regimen that offers overall survival benefit, so it is the one that I recommend people adopt for the time being.

What unmet needs still exist in this space?

There are still tons of unanswered questions. We do not want to over treat patients and we do not want to under treat them. We need to do a lot more translational work from this study, and others, to better understand how to tailor the treatment plan to the patient's needs, to offer them benefit, and then avoid toxicity when we do not think that there is a benefit to be derived. Some of the analyses I hope to, with the rest of the KEYNOTE-671 team, produce are the outcomes by pathological complete response, the outcomes by type of surgery that patients had, and the impact of this whole regimen on the quality of life of patients throughout the therapeutic course.

REFERENCES:

1. Merck announces pivotal KEYNOTE-671 trial meets dual primary endpoint of overall survival (OS) in resectable stage II, IIIA or IIIB non-small cell lung cancer (NSCLC). News release. Merck. October 10, 2023. Accessed March 26, 2024. https://tinyurl.com/2swrjb4a

2. Wakelee HA, Liberman M, Kato T, et al. KEYNOTE-671: randomized, double-blind, phase 3 study of pembrolizumab or placebo plus platinum-based chemotherapy followed by resection and pembrolizumab or placebo for early stage NSCLC. J Clin Oncol. 2023;41 (suppl 17):LBA100. doi:10.1200/JCO.2023.41.17_suppl.LBA100