Tislelizumab in perioperative NSCLC: a step toward precision and practicality

The RATIONALE-315 trial marks a significant and pivotal advancement in the evolving treatment paradigm for patients with resectable non-small cell lung cancer (NSCLC) (1). According to the interim analysis, the use of perioperative tislelizumab in combination with platinum-based neoadjuvant chemotherapy has resulted in a meaningful improvement in both event-free survival (EFS) and major pathologic response (MPR) compared to chemotherapy alone (1). This combination demonstrated a manageable safety profile and offers strong support for incorporating immune checkpoint inhibitors into the perioperative care framework for early-stage NSCLC. These findings add momentum to the growing global consensus that perioperative immunotherapy can be a cornerstone in curative lung cancer treatment strategies.

MPR and EFS, the dual primary endpoints of RATIONALE-315, are increasingly being accepted as reliable surrogates for long-term outcomes in patients undergoing surgery with curative intent. The tislelizumab group showed a remarkable MPR rate of 56%, significantly higher than the 15% observed in the placebo group. Additionally, EFS was substantially extended [hazard ratio (HR) =0.56, P=0.0003], with consistent benefits across various clinically relevant subgroups, including those defined by histological subtype (squamous vs. non-squamous) and programmed cell death ligand 1 (PD-L1) expression levels. Achieving a pathologic response, including pathologic complete response (pCR) and MPR has been repeatedly linked to improved EFS or overall survival (OS) in prior studies, lending further validation to MPR as a meaningful endpoint (2-4). These associations between early pathological response and long-term outcomes are becoming fundamental in the design and interpretation of perioperative immunotherapy trials.

Compared to other major perioperative immunotherapy studies, including KEYNOTE-671 (3), AEGEAN (5), CheckMate 816 (2), and Neotorch (6), RATIONALE-315 stands out for its flexible neoadjuvant treatment regimen, allowing either three or four cycles of therapy. Moreover, it introduces an extended-interval adjuvant dosing schedule for tislelizumab—administered at 400 mg every six weeks for up to eight cycles. This patient-centered approach may enhance adherence and reduce treatment fatigue, without compromising efficacy. By minimizing the frequency of hospital visits, this regimen could significantly alleviate the logistical burden for patients and healthcare systems, especially in low-resource settings. The dosing strategy also reflects an evolving philosophy in oncology to balance intensive treatment with quality of life and patient preferences.

Although RATIONALE-315 was conducted entirely in China, the trial’s findings resonate with data emerging from international studies evaluating perioperative immunotherapy in NSCLC. Nevertheless, regional differences must be acknowledged. For instance, the prevalence of epidermal growth factor receptor (EGFR) mutations is considerably higher in Asian populations, which has implications for immunotherapy responsiveness (7). EGFR-mutant tumors often exhibit a less inflamed tumor microenvironment and are generally less responsive to immune checkpoint blockade (8). Therefore, the role of immunotherapy in this subgroup remains an area requiring further research and clinical stratification. Subgroup analyses within trials like RATIONALE-315 are invaluable for refining patient selection criteria and tailoring therapeutic approaches in a more personalized manner.

In terms of safety, RATIONALE-315 reported results that were in line with expectations from other programmed cell death protein 1 (PD-1) inhibitor trials. Grade 3 or higher treatment-related adverse events were observed in 72% of patients receiving tislelizumab, compared to 66% in the placebo group. Neutropenia emerged as the most common high-grade adverse event. Importantly, the inclusion of tislelizumab did not hinder the feasibility of definitive surgery. R0 resection rates exceeded 90% in both treatment arms, demonstrating that neoadjuvant immunotherapy, even when combined with chemotherapy, does not compromise surgical outcomes. These safety data are crucial in addressing lingering concerns among surgeons about potential delays or complications arising from neoadjuvant immune-modulating therapy. The pathologic responses and safety of each randomized trial are summarized in Table 1.

Despite the strong results, unanswered questions persist. What is the optimal duration and number of neoadjuvant chemotherapy cycles? How long should adjuvant immunotherapy continue, particularly for patients who already achieve a MPR after neoadjuvant therapy? These are key considerations for both clinical trial design and real-world practice. While OS results have not yet matured in RATIONALE-315, the observed trend (HR =0.62) is encouraging. However, definitive conclusions await longer follow-up and more events. Meanwhile, data from several adjuvant immunotherapy trials present a mixed picture. IMpower010 demonstrated improved disease-free survival (DFS) with adjuvant atezolizumab in stage II–IIIA NSCLC, particularly in PD-L1-positive patients (9). Yet, its OS benefit remains uncertain (10). KEYNOTE-091 (PEARLS) showed modest DFS improvements with adjuvant pembrolizumab (11), and BR.31 failed to achieve its primary endpoint (12). These variable results underscore the complexity and heterogeneity of responses to postoperative immunotherapy.

Such inconsistencies raise the possibility that the principal benefit of perioperative immunotherapy may lie in its neoadjuvant component. Neoadjuvant administration allows earlier exposure of the immune system to tumor antigens while the tumor is still in place, potentially enhancing immune priming and systemic surveillance (13,14). This hypothesis is supported by CheckMate 816, a trial that evaluated neoadjuvant immunotherapy alone and reported benefits in MPR and EFS that are comparable to trials using both pre- and postoperative regimens (2). Therefore, a legitimate question arises: can perioperative strategies be simplified to focus primarily on the neoadjuvant phase? Perhaps adjuvant immunotherapy could be reserved for selected high-risk patients, such as those with residual viable tumor or adverse pathological features.

The broader treatment landscape for resectable NSCLC is clearly being reshaped by immunotherapy. RATIONALE-315 adds further momentum to this transformation, establishing tislelizumab as a promising therapeutic option in the perioperative space. With its flexible dosing schedule and favorable risk-benefit profile, tislelizumab offers clinicians more tools to tailor treatment according to individual patient needs. Beyond NSCLC, tislelizumab has demonstrated clinical activity in other malignancies, including hepatocellular carcinoma (RATIONALE-301), esophageal squamous cell carcinoma (RATIONALE-302), and gastric/gastroesophageal adenocarcinoma (RATIONALE-305/306). These data support its broader antitumor potential and reinforce its value in thoracic oncology (15-18). However, the future lies not only in expanding access to these therapies but also in refining their use. Identifying predictive biomarkers—such as PD-L1 expression, tumor mutational burden, and immune gene signatures—will be essential for selecting patients who are most likely to benefit. Furthermore, the use of circulating tumor DNA to detect minimal residual disease may revolutionize postoperative monitoring and guide decisions about the need for continued systemic therapy (19,20).

The evolving role of surgery in the era of perioperative systemic therapy is equally important. Less invasive procedures, such as segmentectomy, are gaining traction as safe and effective alternatives to lobectomy in early-stage NSCLC (21,22). Particularly in patients with limited pulmonary reserve or small, peripherally located tumors, segmentectomy may provide adequate oncologic control with better preservation of lung function. As such, surgical strategies must be reconsidered within the context of systemic therapy, especially when robust pathological responses are achieved with neoadjuvant treatment. Ongoing studies exploring the synergy between modern surgical techniques and immunotherapy will help define optimal treatment algorithms (23,24).

Interdisciplinary collaboration is more crucial than ever. Surgeons, medical oncologists, radiation oncologists, radiologists, pathologists, and translational researchers must work closely together to unlock the full potential of perioperative immunotherapy. Novel imaging techniques, spatial immune profiling, and adaptive trial designs that incorporate real-time biomarker assessments can further accelerate innovation. Through such coordinated efforts, it may be possible to personalize therapy based on each patient’s unique tumor biology and immune landscape, thereby improving outcomes while minimizing unnecessary treatment. Currently, tislelizumab has been approved in China for multiple indications and is under regulatory review in several other regions, including the EU and the United States. Its expanding global footprint reflects growing confidence in its safety and efficacy across various tumor types.

In conclusion, RATIONALE-315 significantly strengthens the evidence base supporting perioperative PD-1 blockade in resectable NSCLC. Tislelizumab’s clinical efficacy, safety, and flexible dosing schedule make it a compelling addition to the armamentarium of thoracic oncology. As the standard of care continues to evolve, it is imperative that multidisciplinary teams remain agile and forward-thinking, embracing novel strategies to optimize curative outcomes. The future of NSCLC treatment lies in an integrated, biomarker-driven approach that combines surgery, immunotherapy, and advanced diagnostics to deliver precision medicine at every stage of care.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Chinese Clinical Oncology. The article has undergone external peer review.

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-25-37/prf

Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-25-37/coif). Y.T. has received research funding from AstraZeneca, Boehringer Ingelheim, Chugai Pharmaceuticals, Daiichi Sankyo, Japan Blood Products Organization, Medtronic, and Otsuka Pharmaceuticals; and honoraria from AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceuticals, Covidien Japan, CSL Behring, Eli Lilly, Japan Blood Products Organization, Johnson and Johnson, MiRTeL, MSD, Nihon Medi-Physics, Novartis, Ono Pharmaceuticals, Roche, Taiho, and Takeda Pharmaceuticals; and has been on the advisory boards of AstraZeneca, Chugai Pharmaceuticals, and Ono Pharmaceuticals, outside of the submitted work. The author has no other conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Yue D, Wang W, Liu H, et al. Perioperative tislelizumab plus neoadjuvant chemotherapy for patients with resectable non-small-cell lung cancer (RATIONALE-315): an interim analysis of a randomised clinical trial. Lancet Respir Med 2025;13:119-29. [Crossref] [PubMed]
2. Forde PM, Spicer J, Lu S, et al. Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer. N Engl J Med 2022;386:1973-85. [Crossref] [PubMed]
3. Wakelee H, Liberman M, Kato T, et al. Perioperative Pembrolizumab for Early-Stage Non-Small-Cell Lung Cancer. N Engl J Med 2023;389:491-503. [Crossref] [PubMed]
4. Tsutani Y, Miyata Y, Suzuki K, et al. Pathologic Response and Survival after Neoadjuvant Chemotherapy with Bevacizumab Followed by Surgery for Clinical Stage II/IIIA Nonsquamous Non-Small-Cell Lung Cancer: Results from a Phase II Feasibility Study (NAVAL). Cancers (Basel) 2024;16:2363. [Crossref] [PubMed]
5. Heymach JV, Harpole D, Mitsudomi T, et al. Perioperative Durvalumab for Resectable Non-Small-Cell Lung Cancer. N Engl J Med 2023;389:1672-84. [Crossref] [PubMed]
6. Lu S, Zhang W, Wu L, et al. Perioperative Toripalimab Plus Chemotherapy for Patients With Resectable Non-Small Cell Lung Cancer: The Neotorch Randomized Clinical Trial. JAMA 2024;331:201-11. [Crossref] [PubMed]
7. Han B, Tjulandin S, Hagiwara K, et al. EGFR mutation prevalence in Asia-Pacific and Russian patients with advanced NSCLC of adenocarcinoma and non-adenocarcinoma histology: The IGNITE study. Lung Cancer 2017;113:37-44. [Crossref] [PubMed]
8. Yang L, He YT, Dong S, et al. Single-cell transcriptome analysis revealed a suppressive tumor immune microenvironment in EGFR mutant lung adenocarcinoma. J Immunother Cancer 2022;10:e003534. [Crossref] [PubMed]
9. Felip E, Altorki N, Zhou C, et al. Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial. Lancet 2021;398:1344-57. Erratum in: Lancet 2021;398:1686. [Crossref] [PubMed]
10. Felip E, Altorki N, Zhou C, et al. Overall survival with adjuvant atezolizumab after chemotherapy in resected stage II-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase III trial. Ann Oncol 2023;34:907-19. [Crossref] [PubMed]
11. O'Brien M, Paz-Ares L, Marreaud S, et al. Pembrolizumab versus placebo as adjuvant therapy for completely resected stage IB-IIIA non-small-cell lung cancer (PEARLS/KEYNOTE-091): an interim analysis of a randomised, triple-blind, phase 3 trial. Lancet Oncol 2022;23:1274-86. [Crossref] [PubMed]
12. Goss G, Darling GE, Westeel V, et al. CCTG BR.31: A global, double-blind placebo-controlled, randomized phase III study of adjuvant durvalumab in completely resected non-small cell lung cancer (NSCLC). Ann Oncol 2024;35:S1238.
13. Blank CU, Rozeman EA, Fanchi LF, et al. Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma. Nat Med 2018;24:1655-61. [Crossref] [PubMed]
14. Versluis JM, Long GV, Blank CU. Learning from clinical trials of neoadjuvant checkpoint blockade. Nat Med 2020;26:475-84. [Crossref] [PubMed]
15. Qin S, Kudo M, Meyer T, et al. Tislelizumab vs Sorafenib as First-Line Treatment for Unresectable Hepatocellular Carcinoma: A Phase 3 Randomized Clinical Trial. JAMA Oncol 2023;9:1651-9. [Crossref] [PubMed]
16. Shen L, Kato K, Kim SB, et al. Tislelizumab Versus Chemotherapy as Second-Line Treatment for Advanced or Metastatic Esophageal Squamous Cell Carcinoma (RATIONALE-302): A Randomized Phase III Study. J Clin Oncol 2022;40:3065-76. [Crossref] [PubMed]
17. Qiu MZ, Oh DY, Kato K, et al. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first line treatment for advanced gastric or gastro-oesophageal junction adenocarcinoma: RATIONALE-305 randomised, double blind, phase 3 trial. BMJ 2024;385:e078876. [Crossref] [PubMed]
18. Xu J, Kato K, Raymond E, et al. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma (RATIONALE-306): a global, randomised, placebo-controlled, phase 3 study. Lancet Oncol 2023;24:483-95. [Crossref] [PubMed]
19. Abbosh C, Frankell AM, Harrison T, et al. Tracking early lung cancer metastatic dissemination in TRACERx using ctDNA. Nature 2023;616:553-562. [Crossref] [PubMed]
20. Ohara S, Suda K, Sudhaman S, et al. Clinical Significance of Perioperative Minimal Residual Disease Detected by Circulating Tumor DNA in Patients With Lung Cancer With a Long Follow-up Data: An Exploratory Study. JTO Clin Res Rep 2025;6:100762. [Crossref] [PubMed]
21. Saji H, Okada M, Tsuboi M, et al. Segmentectomy versus lobectomy in small-sized peripheral non-small-cell lung cancer (JCOG0802/WJOG4607L): a multicentre, open-label, phase 3, randomised, controlled, non-inferiority trial. Lancet 2022;399:1607-17. [Crossref] [PubMed]
22. Aokage K, Suzuki K, Saji H, et al. Segmentectomy for ground-glass-dominant lung cancer with a tumour diameter of 3 cm or less including ground-glass opacity (JCOG1211): a multicentre, single-arm, confirmatory, phase 3 trial. Lancet Respir Med 2023;11:540-9. [Crossref] [PubMed]
23. Ujiie H, Ebana H, Suzuki J, et al. Developing novel non-assistant help operation in dual-portal robotic-assisted thoracic surgery (neoDRATS). JTCVS Tech 2024;27:146-50. [Crossref] [PubMed]
24. Trabalza Marinucci B, Mancini M, Siciliani A, et al. Surgical Techniques for Non-Small-Cell Lung Cancer After Neoadjuvant Chemo-Immunotherapy: State of Art and Review of the Literature. Cancers (Basel) 2025;17:638. [Crossref] [PubMed]