With continuous advancements in immunotherapy research, significant progress has been made in improving survival outcomes for patients with non-small cell lung cancer (NSCLC). Recently, based on the results of the KEYNOTE-671 study, the National Medical Products Administration (NMPA) approved the PD-1 inhibitor pembrolizumab for perioperative treatment in patients with resectable stage II, IIIA, and IIIB NSCLC. What is the clinical significance of this newly approved indication for perioperative treatment in NSCLC? What key considerations should clinicians focus on in practice? How will perioperative immunotherapy for NSCLC evolve in the future?

Oncology Frontier invited Professor Lanjun Zhang from Sun Yat-sen University Cancer Center, Professor Chun Chen from Fujian Medical University Union Hospital, and Professor Yuming Zhu from Tongji University-affiliated Shanghai Pulmonary Hospital to discuss the importance and future outlook of standardized perioperative immunotherapy for NSCLC.

Long-term Survival Benefit: The Cornerstone of Perioperative Immunotherapy in NSCLC

As the world’s first and only randomized, double-blind Phase III trial to demonstrate positive outcomes for both event-free survival (EFS) and overall survival (OS) in resectable NSCLC perioperative immunotherapy, the KEYNOTE-671 study presented at the 2023 ESMO Congress revealed groundbreaking data.

After a median follow-up of 36.6 months, pembrolizumab combined with chemotherapy as neoadjuvant therapy followed by pembrolizumab as adjuvant therapy significantly reduced the risk of death by 28% compared to placebo combined with chemotherapy followed by placebo as adjuvant therapy in patients with resectable stage II–IIIB NSCLC (HR 0.72; 95% CI: 0.56–0.93; P = 0.00517). The median OS was not reached in the pembrolizumab group versus 52.4 months in the placebo group. The 4-year OS rates were 67.1% and 51.5%, respectively.

Subgroup analysis further showed consistent benefits across histological subtypes, TNM stages, and PD-L1 expression levels, providing strong support for the clinical application of perioperative immunotherapy.

Professor Lanjun Zhang emphasized that while numerous clinical studies have explored the role of perioperative immunotherapy in lung cancer, the KEYNOTE-671 study stands out due to its combined neoadjuvant and adjuvant treatment design. Notably, the study was designed from the outset with overall survival as its primary endpoint, aligning with the fundamental goal of cancer treatment—prolonging survival. Traditionally, perioperative immunotherapy aimed to downstage tumors, reduce micrometastases, or lower surgical complexity. However, the KEYNOTE-671 study shifts the focus toward achieving long-term survival benefits rather than merely temporary disease remission.

Professor Chun Chen highlighted that the approval of this indication reflects years of dedicated research and clinical exploration in NSCLC perioperative treatment. It represents a significant advancement, offering patients in early and mid-stage NSCLC a promising opportunity for longer and better survival. Helping patients access effective treatments and improve prognosis has always been a priority for thoracic surgeons, and the KEYNOTE-671 study provides a clear answer to this challenge.

Professor Yuming Zhu pointed out that during the era when chemotherapy dominated NSCLC perioperative treatment, the survival benefit for patients was only about 5%, which was far from meeting clinical needs. Immunotherapy, initially explored in late-stage patients, demonstrated tumor shrinkage in some cases, opening the door to potential conversion surgery. However, high-level evidence supporting its use in earlier stages was lacking. The dual-positive EFS and OS results from the KEYNOTE-671 study now give clinicians strong confidence that this treatment model can offer substantial long-term survival benefits for patients with stage II–IIIB NSCLC.

Standardizing Clinical Practice to Safely Deliver Long-term Survival Benefits

Traditional perioperative treatments combining surgery and chemotherapy for lung cancer often resulted in significant drug-related adverse effects, potential complications, and reduced quality of life. The KEYNOTE-671 study addressed these concerns, and data presented at the 2024 ASCO conference confirmed that perioperative use of pembrolizumab did not compromise patients’ health-related quality of life (HRQoL). Moreover, EFS outcomes remained consistent with earlier findings, reinforcing that the long-term survival benefits of perioperative immunotherapy in NSCLC do not come at the expense of health and quality of life. On the contrary, patients experienced fewer discomforts and a higher safety profile.

Professor Chun Chen reflected on the historical divide in NSCLC treatment between operable and inoperable disease, with immunotherapy outside of surgery often viewed as a last resort without strong supporting data. However, the evolving field of immunotherapy now spans neoadjuvant, adjuvant, and combined treatment approaches. The HRQoL data from the KEYNOTE-671 study demonstrate that the benefits of immunotherapy are not achieved at the cost of quality of life. Patients can return to society in better health, which is an encouraging outcome. Immunotherapy has evolved from a research hotspot to a comprehensive treatment strategy, solidifying its role in NSCLC care.

The relationship between perioperative immunotherapy and surgery has been widely debated. At the 60th Annual Meeting of the Society of Thoracic Surgeons (STS) in February 2024, the KEYNOTE-671 study reported that compared to neoadjuvant chemotherapy alone, neoadjuvant pembrolizumab combined with chemotherapy did not affect the choice of surgical approach or extend hospital stays. It even improved lymph node downstaging rates (38.9% vs. 28.4%), particularly increasing the rate of downstaging to N0 (34.3% vs. 23.4%).

Further data presented at the 2024 European Society of Thoracic Surgeons (ESTS) Congress confirmed that regardless of lymph node status, baseline disease stage, or surgery type, neoadjuvant pembrolizumab plus chemotherapy significantly improved EFS compared to chemotherapy alone.

Professor Lanjun Zhang noted that in traditional surgical approaches, five-year survival rates decline significantly with advancing tumor stage, and further surgical advancements have reached their limit. The KEYNOTE-671 study revealed that patients’ survival curves plateaued even after two years, demonstrating the safety and efficacy of the “sandwich” treatment model. This approach offers both safety and efficacy, with durable therapeutic effects. Experts are currently collaborating to draft expert consensus and clinical pathways for perioperative immunotherapy to standardize future clinical practice.

Professor Yuming Zhu highlighted that stage II–IIIB NSCLC patients often face lymph node metastases or large tumors, and even after surgical resection, the risk of recurrence or distant metastasis remains. The KEYNOTE-671 treatment model presents a promising new option for effectively eliminating distant metastases before surgery, achieving safe tumor downstaging without compromising surgical outcomes. This approach may currently represent the optimal perioperative treatment strategy for stage II–IIIB NSCLC.

A New Era of Personalized Perioperative Treatment for Early- and Mid-Stage NSCLC

Current data from studies like KEYNOTE-671 demonstrate consistent survival benefits of perioperative immunotherapy across various patient subgroups. However, the diversity in clinical practices and the growing need for individualized treatment strategies are driving surgeons to focus more on crafting personalized treatment plans for NSCLC patients.

Professor Lanjun Zhang believes that the future of perioperative immunotherapy for NSCLC will inevitably focus on precision and personalized treatment. On one hand, clinicians aim to better define the scope of immunotherapy through precise diagnostic methods and staging. On the other hand, tailoring the duration of postoperative immunotherapy based on individual patient conditions is another critical aspect worth exploring in the future.

Professor Chun Chen echoed this view, emphasizing that the current “sandwich” treatment model—combining neoadjuvant and adjuvant immunotherapy—was developed through continuous exploration and clinical validation. Moving forward, the focus will remain on determining optimal maintenance periods for immunotherapy before and after surgery. Additionally, leveraging biomarkers to identify patients most likely to benefit and predict prognosis could help achieve safer, less toxic, and more effective treatments, an area that warrants deeper investigation.

Professor Yuming Zhu agreed, noting that perioperative immunotherapy is poised to become the standard treatment model for resectable early- and mid-stage NSCLC. He further suggested that for certain patient populations within the approved indications—such as those with high PD-1 expression—there is potential to explore a “chemotherapy-free” treatment approach. Continued research into immune-related biomarkers may serve as a powerful tool in developing individualized treatment strategies for these specific patients.

Reference

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[2] NSCLC Meta-analysis Collaborative Group. Preoperative chemotherapy for non-small-cell lung cancer: a systematic review and meta-analysis of individual participant data. Lancet. 2014;383(9928):1561-71.

[3] Jonathan David Spicer, et al. 2024 STS.

[4]Ernest Nadal,et al.2024 ESTS.