More is not always better: lessons from the SQUAT trial (WJOG 12119L) in resectable-N2 non-small cell lung cancer
Editorial Commentary

More is not always better: lessons from the SQUAT trial (WJOG 12119L) in resectable-N2 non-small cell lung cancer

Koosha Paydary, Dina Nashed, Mary Jo Fidler

Department of Medicine, Section of Hematology, Medical Oncology and Cell Therapy, Rush University Medical Center, Chicago, IL, USA

Correspondence to: Koosha Paydary, MD. Assistant Professor of Medicine, Department of Medicine, Section of Hematology, Medical Oncology and Cell Therapy, Rush University Medical Center, 1725 West Harrison St., Suite 819, Chicago, IL 60612, USA. Email: koosha_paydary@rush.edu.

Comment on: Hamada A, Soh J, Hata A, et al. Neoadjuvant Concurrent Chemo-Immuno-Radiation Therapy Followed by Surgery and Adjuvant Immunotherapy for Resectable Stage III N2 NSCLC: Primary Results From the SQUAT Trial (WJOG 12119L). J Thorac Oncol 2025;20:1098-107.

Keywords: Non-small cell lung cancer (NSCLC); resectable; neo adjuvant; radiation

Received: 02 April 2026; Accepted: 14 May 2026; Published online: 23 July 2026.

doi: 10.21037/shc-2026-0014

Introduction

The use of neo adjuvant chemoimmunotherapy has revolutionized the treatment landscape of resectable non-small cell lung cancer (NSCLC) in the past few years. Several phase 3 studies have now showed improved event-free survival (EFS) and overall survival (OS) with perioperative or neo adjuvant chemoimmunotherapy, which has resulted in widespread adoption of these approaches for the appropriate patient worldwide (1,2). Despite such improvements, local recurrence and distant metastasis may occur, especially in patients who did not achieve a pathological complete response (pCR). The SQUAT trial (WJOG 12119L) studies whether neo adjuvant treatment intensification with the addition of radiation to chemoimmunotherapy will improve loco regional control and potentially have an effect on the reduction of distant metastases. This is certainly a relevant and critical question, as studies such as AEGEAN have shown improved outcomes in patients with resectable N2 disease (3), while risk of progression may not be similar for all these patients, and further studies to determine patients eligible for treatment intensification with other modalities such as radiation merit further investigation.

In stage II–III disease, the role for radiation has become more niche to “unresectable” situations were concurrent chemotherapy and radiation followed by consolidative durvalumab has been shown to improve loco regional control with improved OS based on the PACIFIC study (4). However, it is unclear whether radiation can have a role to play in resectable NSCLC, where data for administration of neo adjuvant/perioperative chemoimmunotherapy is rapidly evolving. To this end, SQUAT was a multicenter, single arm, phase 2 trial performed at 10 centers across Japan, that evaluated the safety and efficacy of chemoimmuno-radiation, followed by surgical resection and adjuvant immunotherapy in patients with stage III-N2 NSCLC who were deemed to have resectable disease (5).

The SQUAT Trial (WJOG 12119L)

In the prospective single arm SQUAT trial, patients had pathologically confirmed N2 disease prior to enrollment, and also patients with EGFR/ALK alteration were allowed as results from ADAURA and ALINA trials became available after the conduct of this study (6,7). Radiation to 50 Gy/25 fractions was given daily with concurrent weekly carboplatin and paclitaxel with prespecified lung radiation dose limits accordant with best practices. Of note, durvalumab was given on days 1 and 29, which was concurrent with radiation. Surgery could include lobectomy or pneumonectomy and was done 2–6 weeks post completion of radiation, and durvalumab was to be continued for up to one year following surgery. The investigators assigned major pathologic response (MPR) as the primary endpoint with an expected rate of 65%, while secondary endpoints included pCR, progression-free survival (PFS), OS and safety.

The intention to treat set included 30 patients from 10 institutions across Japan, and 25 patient were considered evaluable for efficacy. Most patients had stage IIIA disease, nonsquamous histology (63%), single N2 disease (83% vs. 17% multi station N2), and 33% were PD-L1 negative. Of note, six patients (20%) were EGFR positive, and ALK alteration was unknown in 60% of patients. In the intention-to-treat (ITT) set, 27 patients (90%) underwent surgery, all lobectomies and adjuvant durvalumab was continued in 16 patients and only eight completed one year of durvalumab adjuvantly. Notably, three patients could not undergo surgery within six weeks due to radiation pneumonitis (grade 1 in two patients, grade 2 in one patient).

Regarding efficacy, MPR and pCR were 63% and 23%, respectively. Noteworthy, pathologic responses were deeper in patients with single station N2, PD-L1 positive and EGFR negative status. At a median follow up time of 28 months, 15 (50%) and 10 (33%) patients experienced disease recurrence and death, respectively; in patients who experienced recurrence, nine had distant recurrence and two had recurrence in the radiation field. The median PFS was about 15 months. The 2-year OS was 76%. Moreover, four out of six patients with EGFR positive disease had recurrence that was subsequently treated with an EGFR tyrosine kinase inhibitor (TKI). The exploratory analysis showed that OS/PFS were numerically higher in patients who had MPR or pCR. Regarding safety, 15 patients (48%) had grade 3–4 side effects. One patient who developed immune-mediated pneumonitis and MI after surgery died. In total, 8 patients (26%) developed radiation pneumonitis. Also, 22 patients (71%) experienced surgical complications.

Discussion

Survival outcomes and perioperative complications with chemoimmuno-radiation vs. chemoimmunotherapy

Based on the aforementioned results, the authors concluded that addition of radiation to neo adjuvant chemoimmunotherapy can be a potential strategy to improve local control in stage III-N2 disease. While we cannot make direct comparisons between a single arm phase 2 study and large phase 3 neo adjuvant/perioperative chemoimmunotherapy trials, neither pCR nor survival outcomes were meaningfully improved with the addition of neo adjuvant radiation. Table 1 shows patient characteristics and outcomes of SQUAT and several major neo adjuvant/perioperative chemoimmunotherapy trials. Acknowledging that specific survival data of patients with N2-only disease across phase 3 neo adjuvant/perioperative trials is limited, the PFS and OS of SQUAT trial are not improved compared to the N2 subset of these trials. In an exploratory analysis of patients with N2 disease in CheckMate-77T trial (perioperative chemo-nivolumab), the 1-year EFS was 70% vs. 45% [hazard ratio (HR) =0.46; 95% confidence interval (CI): 0.3–0.7] with a pCR rate of 22% vs. 5.6% (8). Similarly in the phase 2 NADIM II trial (perioperative chemo-nivolumab in stage III only, most of which had N2 disease), the 2-year PFS was 67.2% vs. 40.9% (HR =0.47, 95% CI: 0.25–0.88) (9). In patients with N2 disease of the AEGEAN trial, perioperative durvalumab was associated with an improved 2-year EFS of 66.3% vs. 43.7% (HR =0.63) (10). Collectively, these exploratory analysis suggest that patients with N2 disease already derive substantial benefit from perioperative chemoimmunotherapy. Another explanation for the lack of significant survival improvement in SQUAT compared to chemoimmunotherapy approaches could be elevated risk of higher grade toxicities in patients who are eventually aimed and scheduled to undergo surgery. This could be evident by the low percentage of patients who went on to complete the protocol specified amount of durvalamab infusions. In fact, eight patients developed pneumonitis and a considerable fraction of patients developed perioperative complications resulting in poor outcomes. It is noteworthy that while neoadjuvant chemoimmunotherapy can also increase risk of surgical cancellation due to toxicities by 1–2 percentage points, the overall R0 resection rate is improved (11), which can offset the modest rate of surgical attrition due to treatment toxicities.

Table 1

Patient characteristics and outcomes of SQUAT and several major neoadjuvant/perioperative chemoimmunotherapy trials in resectable non-small cell lung cancer

Variable SQUAT CheckMate-816 CheckMate-77T AEGEAN NEOTORCH KeyNote-671
Phase of trial II III III III III III
N of patients 30 358 461 802 (740 with modified ITT) 501 (404 with modified ITT) 797
Intervention arm Two cycles of neoadjuvant durvalumab plus weekly carboplatin/paclitaxel and concurrent radiation therapy Three cycles of neoadjuvant nivolumab plus platinum-doublet chemotherapy Four cycles of neoadjuvant nivolumab plus platinum-based doublet chemotherapy followed by adjuvant nivolumab Four cycles of neoadjuvant durvalumab plus platinum-based doublet chemotherapy followed by adjuvant durvalumab Three cycles of neoadjuvant toripalimab plus platinum-based doublet chemotherapy followed by adjuvant toripalimab Four cycles of neoadjuvant pembrolizumab plus cisplatin-based doublet chemotherapy followed by adjuvant pembrolizumab
% [N] of stage III patients 100% [30] 63.1% [113] nivolumab vs. 64.8% [115] chemotherapy only; 63.9%[229] total pts 63.8% [146] nivolumab vs. 64.2% [149]; 64% [295] total pts 71.3% [261] durvalumab vs. 70.3% [263] placebo; 70.8% [524] total pts 99.5% [201] toripalimab vs. 99% [200] placebo; 99.3% [401] total pts 70.3% [279] pembrolizumab vs. 69.8% [279]; 70% [558] total pts
% [N] of patients with N2 disease 100% [30] NR 39.7% [91] nivolumab vs. 38.8% [90] placebo 49.5% [181] durvalumab vs. 49.5% [185] placebo; 45.5% [366] total pts 68.3% [138] toripalimab vs. 71.8% [145] placebo; 70% [283] total pts 42.3% [168] pembrolizumab vs. 46.8% [187] placebo; 44.5% [355] total pts
% [N] of patients with multi-station N2 disease 16.7% [5] NR 13.4% [31] nivolumab vs. 15.9% [37] placebo 9.3% [34] durvalumab vs. 10.7% [40] placebo NR NR
% [N] of patients who underwent surgery after neoadjuvant therapy 90% [27] 83.2% [149] nivolumab vs. 75.4% [135] chemotherapy only 77.7% [178] nivolumab vs. 76.7% [178] placebo 80.6% [295] durvalumab vs. 80.7% [302] placebo 82.2% [166] toripalimab vs. 73.3% [148] placebo 82.1% [325] pembrolizumab vs. 79.4% [317] placebo
% [N] of patients who experienced grade 3–4 toxicity 48% [15] 33.5% [59] nivolumab vs. 36.9% [65] chemotherapy only 32.5% [74] nivolumab vs. 25.2% [58] placebo 42.4% [170] durvalumab vs. 43.2% [172] placebo 63.4% [128] toripalimab vs. 54% [109] placebo 45.2% [179] pembrolizumab vs. 37.8% [151] placebo
% [N] of patients with EGFR/ALK alterations 20% [6] 0% 0% 0% 0% 6.8% [54]
% MPR [N] 63% [19] 36.9% [66] nivolumab vs. 8.9% [16] chemotherapy only 35.4% [81] nivolumab vs. 12.1% [28] placebo 33.3% [122] durvalumab vs. 12.3% [46] placebo 48.5% [98] toripalimab vs. 8.4% [17] placebo 30.2% [120] pembrolizumab vs. 11.0% [44] placebo
% pCR [N] 23% [7] 24% [43] nivolumab vs. 2.2% [4] chemotherapy only 25.3% [58] nivolumab vs. 4.7% [11] placebo 17.2% [63] durvalumab vs. 4.3% [16] placebo 24.8% [50] toripalimab vs. 1.0% [2] placebo 18.1% [72] pembrolizumab vs. 4.0% [16] placebo
% [N] of patients with PD-L1 ≥1% 66.7% [20] 49.7% [178] 55.5% [256] 66.6% [493] 65.6% [265] 63.7% [508]
% [N] of patients who completed course of adjuvant immunotherapy 26.7% [8] NA 37.1% [85] nivolumab vs. 39.7% [92] placebo 24% [88] durvalumab vs. 21.1% [79] placebo 71.3% [144] toripalimab vs. 64.9% [131] placebo 40.4% [160] pembrolizumab vs. 35.3% [141]
Survival outcomes 2-year PFS 43% and OS 76% 5-year OS 65.4% 2.5-year EFS 61% 2-year EFS 63.3% 2-year EFS 64.7% 2-year EFS 62.4%

EFS, event-free survival; ITT, intention-to-treat; MPR, major pathologic response; N, number; NA, not applicable; NR, not reported; OS, overall survival; pCR, pathologic complete response; PFS, progression-free survival.

The PACIFIC-2 study failed to show benefit from addition of immunotherapy to concurrent chemo-radiation in unresectable NSCLC (12). In PACIFIC-2 also, about 55% of patients in each arm (chemoradiation plus durvalumab vs. chemoradiation plus placebo) had N2 disease. In PACIFIC-2, PFS curves for both arms largely overlapped in the first 6 months of treatment, and combined rates of pneumonitis were quite similar in both arms (28.8% vs. 28.7% for durvalumab and placebo, respectively), while bleeding events and infections were more common in the durvalumab arm. A similar lack of benefit was seen in the small cell lung cancer space with addition of concurrent atezolizumab to chemoradiation in the Alliance LU-005 study (13). This was in contrast to the ADRIATIC trial that showed durvalumab after chemoradiation can improve outcomes (14). Taken together, these studies indicate that timing of immunotherapy with regard to radiation matters, as concurrent treatment does not translate to improved outcomes, and it does expose patients to increased toxicity and may be stimulating cytotoxic T cells in a radiated field (15). Regarding neo adjuvant chemoradiation, real-world evidence suggests increased pulmonary complications such as acute respiratory distress syndrome (ARDS) following surgery in patients with locally advanced NSCLC (16). As timely surgery is critical in patients with N2 disease, increased rate of side effects can be a culprit in delaying surgery or rendering a patient ineligible for surgery altogether. These observations underscore the importance of timely surgery in patients with N2 disease to mitigate risk of recurrence and improve survival, signaling that “more is not better” due to elevated risk of safety issues and surgical delay, even in patients with N2 disease.

Rate of distant metastasis

Another observation from SQUAT is the high number of patients who experienced distant metastasis. It is not clear if improved MPR in the absence of PCR, can result in improved survival, as nine patients developed distant metastasis. The authors have raised the possibility that perhaps administration of only two doses of neoadjuvant durvalumab with chemoradiation could have resulted in lack of adequate systemic disease control. Across various perioperative trials, it is thought that the improved OS is likely due to elimination of micro metastatic disease, which can attain disease control prior to surgery. The chemotherapy dosing and schedule that was used in combination with radiation in this study is also based on the “radio sensitization” paradigm, in order to improve radiation efficacy. The chemoimmunotherapy used in phase 3 perioperative studies includes high-dose platinum doublet chemotherapy that is given for at least 3 cycles prior to surgery. These studies collectively demonstrated improved EFS with neo adjuvant “high-dose” chemoimmunotherapy given for at least 3 cycles prior to surgery. Therefore, it is possible that substituting higher dose and more frequent chemoimmunotherapy with radiosensitizing dose and only 2 cycles of durvalumab (versus 4 cycles in AEGEAN trial), did not result in adequate disease control prior to surgery. Another important observation is that only about half the patients were started on adjuvant durvalumab after surgery, the reasons for which remain unclear. While the extent of benefit from adjuvant immunotherapy among large phase 3 trials remains to be answered, several reports have indicated improved outcomes in patients who did not achieve a pCR. In SQUAT, it would be prudent to recognize the reasons for not pursing adjuvant durvalumab (i.e., decreased performance status, possible side effects from prior multimodality treatment, etc.), and whether patients without adjuvant immunotherapy experienced more frequent local recurrences or distant metastasis.

Biomarker selection

In selecting patients for neo adjuvant chemoimmunotherapy approach, it is imperative to rule out—at least—EGFR/ALK alterations prior to start of treatment. This is in fact due to lack of benefit from immunotherapy in this subset of patients, resulting in FDA approval of osimertinib post chemoradiation instead of durvalumab per LAURA trial (17). Several large phase 3 studies such as KEYNOTE-789 and CHECKMATE-722 have also shown lack of benefit from immunotherapy in this population (18,19), and most perioperative trials mandated EGFR/ALK wild type status prior to treatment initiation. The SQUAT trial, however, did not biomarkerly select patients for neo adjuvant durvalumab with radiation. Not surprisingly, four out of six patients with EGFR positive disease had disease recurrence, and pathologic responses were higher in EGFR negative patients, further underscoring the importance of biomarker testing in all patients who are considered for neo adjuvant immunotherapy-based approaches.

Conclusions

In conclusion, the authors attempted to answer a fair question which was to delineate the role for treatment intensification with addition of neo adjuvant radiation to improve loco regional control in N2 resectable disease. However, the design of the study—including two doses of neoadjuvant durvalumab only and no biomarker selection—may have dampened the beneficial impact of increased MPR to translate into meaningful survival improvements. While the answer to this question remains open, the insights from this trial indicate that concurrent radiation is likely not the answer to the question of “how to improve loco regional control” in resectable N2 disease. It is noteworthy that while neo adjuvant immunotherapy-based approaches are now largely adopted across the world, careful patient selection through multidisciplinary discussions is key. The SQUAT trial is an applaudable study that was conducted across 10 academic centers, and solely in Japan, while institutional differences in surgical expertise and practices can impact outcomes. SQUAT further provides insights on how radiation can impact outcomes in the era of perioperative therapy, and while treatment intensification merits future studies, we should not sacrifice the benefit of early systemic disease control over attempts to reinforce loco regional control in patients with locally advanced disease who are considered to have resectable cancers. Future studies can be conducted to evaluate role for sequential radiation with chemoimmunotherapy prior to surgery, in carefully biomarker selected patients.

Acknowledgments

None.

Footnote

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

Peer Review File: Available at https://shc.amegroups.com/article/view/10.21037/shc-2026-0014/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://shc.amegroups.com/article/view/10.21037/shc-2026-0014/coif). K.P. received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from MJH Health Sciences and Targeted Oncology; support for attending the International Association for the Study of Lung Cancer (IASLC) 2025, as part of IASLC academy award winner; served on advisory boards of Partner therapeutics, Bayer, Regeneron, Catalyst Pharmaceuticals, American Journal of Managed Care; served as subject matter expert of American Cancer Society; served as mentor during ASCO MSR program of American Society of Clinical Oncology. M.J.F. received consulting fees from AstraZeneca, Gilead, Lilly, Janssen, Nuvation, Regeneron (companies that have drugs used in the perioperative space). The other author has no conflicts of interest to declare.

Ethical Statement: The authors are 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/.

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doi: 10.21037/shc-2026-0014
Cite this article as: Paydary K, Nashed D, Fidler MJ. More is not always better: lessons from the SQUAT trial (WJOG 12119L) in resectable-N2 non-small cell lung cancer. Shanghai Chest 2026;10:16.

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