The Introduction of Immune Checkpoint Inhibitors ‘Game Changer’ in NSCLC, Other Cancers

Longterm Follow-Ups Show Continued Success

BERLIN, GERMANY — Presentations at the most recent European Society of Medical Oncology (ESMO) annual conference and other studies underscored the durability of immune checkpoint inhibitors (ICIs), which enable the patient’s immune cells to destroy cancer cells.

Since the first ICIs were approved by the U.S. Food and Drug Administration (FDA), survival rate for lung cancer and other cancers have improved greatly.

“The introduction of ICIs has been a game changer in cancer treatments,” said Roseleen Charania, MD, associate chief medical officer for oncology programs at Evernorth, the health services division of The Cigna Group. “When ICIs are prescribed and administered in an optimal manner, they can provide significant benefits, markedly improving survival rates in comparison to other therapies.”

Evernorth Research Institute reported that, by 2021, 12.1% of oncology patients were receiving ICIs, a 47.5% increase since 2018 that was driven primarily by expanded use in treating breast, colorectal and prostate cancer.

That report looked at how ICIs and other cancer medicines are being used now with data from 47.8 million people, along with examining the data of a smaller group who were treated with infusions of pembrolizumab, the ICI most commonly used for metastatic lung cancer.

Pembrolizumab, marketed as Keytruda, is widely considered the most prescribed ICI, specifically for non-small cell lung cancer (NSCLC). It is considered a foundational, first-line treatment for advanced or metastatic NSCLC, often used either alone or in combination with chemotherapy.

It is recognized as the No. 1 prescribed immunotherapy in advanced NSCLC. Some studies have suggested that it is used as the treatment in more than 80% of cases. It also is approved for a wider range of lung cancer applications compared to other ICIs, including both early-stage (as perioperative treatment) and advanced/metastatic disease.

Led by Heather Wakelee, MD, of Stanford Medicine, the 5-year follow-up of the global, phase 3 KEYNOTE-671 study (NCT03425643), involving perioperative pembrolizumab. The original study showed significant improved event-free survival (EFS; HR, 0.58; 95% CI, 0.46–0.72; P < 0.001) and overall survival (IA2; HR, 0.72; 95% CI, 0.56-0.93; P = 0.0052) vs. neoadjuvant chemotherapy (chemo) in early-stage NSCLC. The results were presented at ESMO and published late last year in ESMO Annals of Oncology.¹

Eligible participants were adults with previously untreated, resectable stage II, IIIA or IIIB (N2) NSCLC per AJCC version 8 were randomized 1:1 to 4 cycles of pembrolizumab 200 mg or placebo Q3W plus chemotherapy, followed by surgery then adjuvant pembrolizumab 200 mg or placebo Q3W for up to 13 cycles (around 9 months) or until progressive disease or unacceptable toxicity. Dual primary endpoints were event-free survival by investigator assessment and overall survival.

With 797 pts randomized to pembrolizumab (n = 397) or placebo (n = 400, the median time from randomization to data cutoff (July 3, 2025) was 60.4 (range, 42.6-85.8) months. The results indicated that the 5-year event-free survival (EFS) rate was 49.9% (95% CI, 44.6%-55.0%) in the pembrolizumab arm and 26.5% (95% CI, 21.7%-31.5%) in the placebo arm. The EFS hazard ratio was 0.58 (95% CI, 0.48-0.69). 5-year overall survival (OS) rates were 64.6% (95% CI, 59.5%-69.2%) and 53.6% (95% CI, 48.3%-58.6%), respectively. In addition, the OS hazard ratio (HR) was 0.74 (95% CI, 0.59-0.92).

“HRs for EFS and OS favored pembro, regardless of baseline disease stage and PD-L1 status,” the authors concluded.

Grade 3 or greater treatment-related adverse effects occurred in 179 of 396 treated pts (45.2%) in the pembrolizumab arm and 151 of 399 treated patients (37.8%) in the placebo arm. Grade 3 or greater immune-mediated adverse effects and infusion reactions occurred in 25 patients (6.3%) and 7 patients (1.8%), respectively.

“After 5 years of follow-up, perioperative pembro plus neoadjuvant chemo continued to prolong EFS and OS vs. neoadjuvant chemo,” the study noted. “Fifty percent of patients in the pembro arm, almost twice as many as in the placebo arm, were alive and event-free at 5 years. These long-term findings support use of perioperative pembro plus neoadjuvant chemo as a standard of care for patients with resectable early-stage NSCLC.”

The five-year benefit demonstrated across overall survival and event-free survival from KEYNOTE-671 supports the continued use of this pembrolizumab-based perioperative regimen as a standard of care for patients with resectable, earlier-stage non-small cell lung cancer,” Wakelee advised. “These consistent results are impactful, as they reflect the importance of intervening for certain patients with earlier stages of non-small cell lung cancer.”

More recently, in a study published earlier this year in the European Journal of Cardiothoracic Surgery, researchers including Wakelee did a subgroup analysis of participants with stage II NSCLC. They found that perioperative pembrolizumab “improved efficacy outcomes with manageable safety versus neoadjuvant chemotherapy alone, consistent with the overall KEYNOTE-671 population. These results support the use of this regimen in patients with stage II disease.”²

“Historically, patients with advanced non-small cell lung cancer faced a poor prognosis, with long-term survival considered unlikely,” added Edward B. Garon, MD, MS, professor of medicine, principal investigator for KEYNOTE-001, David Geffen School of Medicine, the University of California, Los Angeles. “The long-term results from these four trials show that pembrolizumab has helped change what certain patients with advanced NSCLC can hope to achieve.”

 

1. Wakelee H, Spicer J, Gao S, et. Al. LBA67 Perioperative pembrolizumab in early-stage non-small- cell lung cancer (NSCLC): 5-year follow-up from KEYNOTE- 671. ESMO Annals of Oncology. DOI: 10.1016/j.annonc.2025.09.079 
2. Tsuboi M, Wakelee H, Garassino MC, Gao S, et. Al. Subgroup Analysis of Perioperative Pembrolizumab in Clinical Stage II Non-Small-Cell Lung Cancer from the Randomized KEYNOTE-671 Study. Eur J Cardiothorac Surg. 2026 Mar 10;68(3):ezag028. doi: 10.1093/ejcts/ezag028. PMID: 41875364; PMCID: PMC13020334.