Revisiting the role of neoadjuvant radiotherapy in stage III non-small cell lung cancer: insights from the SQUAT trial

Lung cancer remains the leading cause of cancer-related mortality worldwide, exceeding deaths from both breast and prostate cancers (1). Despite advances in surgical resection, disease recurrence continues to be a major contributor to mortality (2), underscoring the ongoing need for more effective strategies to achieve durable local and systemic disease control. In this context, neoadjuvant multimodal therapies, including immunotherapy, chemotherapy, and radiotherapy, have emerged as critical components of treatment paradigms for patients with resectable non-small cell lung cancer (NSCLC) (3). Consequently, substantial research efforts have focused on evaluating and refining multimodal treatment strategies to improve oncologic outcomes (4-6).

The SQUAT trial is a multicenter, single-arm, phase II study in which Hamada et al. evaluated whether the addition of neoadjuvant radiotherapy to standard neoadjuvant chemo-immunotherapy in patients with resectable stage III NSCLC would improve local disease control (7). Notably, the study’s prospective multicenter design enhances the generalizability of its findings and supports the feasibility of implementing this approach across institutions. Eligible patients were 20–75 years of age, had no prior treatment, and were diagnosed with clinical T1–T3/T4 N2M0, stage IIIA NSCLC. Patients with tumors harboring epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase translocations were also included. A total of 31 patients with stage III NSCLC were enrolled over a period of 2 years, including one patient who was deemed ineligible after registration and excluded from efficacy analyses with 16 of the 30 patients (53%) initiating adjuvant durvalumab therapy, only eight (27%) completed one year of treatment. Major pathologic response (MPR) served as the primary endpoint, with pathologic complete response (pCR), progression-free survival (PFS), overall survival (OS), and safety assessed as secondary outcomes. In addition to its clinical endpoints, the trial provides valuable biologic insights into locoregional control in a high-risk stage III N2 population and demonstrates the feasibility of integrating concurrent radiotherapy into neoadjuvant chemoimmunotherapy.

The SQUAT trial demonstrated a notably high MPR rate (63% in intention-to-treat population), suggesting that the addition of radiotherapy may enhance local tumor eradication in this high-risk population. Importantly, locoregional recurrence was uncommon, supporting the biological rationale that radiotherapy may improve local control in patients with stage III disease. From a surgical standpoint, it is also important to emphasize that the ultimate goal in real-world practice extends beyond pathologic response to achieving complete (R0) resection. In this regard, the reported R0 resection rate of 87% in the SQUAT trial is notable and represents a meaningful clinical outcome. However, despite the improved MPR rate, this pathologic benefit did not translate into higher pCR rates or improved survival outcomes, highlighting the complexity of using pathologic response as a surrogate endpoint for long-term benefit.

The SQUAT trial also reopens an important and unresolved question in thoracic oncology: the extent to which pathologic response serves as a reliable surrogate for long-term outcomes in the era of multimodal therapy. While major pathologic response has been widely adopted as an intermediate endpoint in neoadjuvant trials, its predictive value for survival appears inconsistent, particularly when treatment intensification preferentially improves local control without meaningfully altering distant failure patterns. In SQUAT, improved MPR was accompanied by relatively modest progression free survival and a predominance of distant recurrence, emphasizing that pathologic response alone may be insufficient to capture the complexity of treatment benefit in stage III disease.

From a biological perspective, the addition of radiotherapy to neoadjuvant chemoimmunotherapy is compelling, given its potential to enhance antigen release, augment immune priming, and improve locoregional control. However, these theoretical advantages must be balanced against practical tradeoffs, including treatment-related toxicity, potential delays to resection, and concern for reduced ability to deliver effective systemic therapy postoperatively. In the SQUAT trial, treatment-related adverse events were not negligible, with 36% of patients experiencing serious adverse events and 10% requiring treatment discontinuation, underscoring the clinical impact of intensified therapy. In the SQUAT cohort, fewer patients initiated or completed adjuvant immunotherapy, raising the possibility that intensified local therapy may inadvertently compromise systemic disease management, a concern that may be particularly relevant in a population already at elevated risk for distant metastasis.

Several limitations of this study warrant consideration. Firstly, only two cycles of neoadjuvant chemo-immunotherapy were administered to the patients to limit toxicity, fewer than in most trials, which may have contributed to suboptimal systemic disease control and higher rates of distant recurrence. Secondly, patient selection may also represent a limitation, as the strict eligibility criteria and inclusion of a highly selected population with resectable stage III N2 disease may limit generalizability and potentially overestimate pathologic response without reflecting real-world outcomes. In addition, the inclusion of patients with oncogenic driver mutations, as well as those with unknown EGFR or ALK status, introduces further heterogeneity that may confound interpretation of treatment efficacy, particularly given the variable responsiveness of these subgroups to immunotherapy. Moreover, the limited initiation and completion of adjuvant therapy, together with the relatively high rate of serious adverse events, may have adversely impacted systemic disease control and overall outcomes.

Future studies should focus on optimizing the balance between local and systemic treatment intensity. Randomized trials comparing neoadjuvant chemo-immunotherapy with and without radiotherapy are needed to define which patients, derive meaningful benefit from treatment escalation. Improved patient selection may help tailor multimodal strategies. Furthermore, strategies to enhance systemic control will be critical to reducing distant failure.

Ultimately, the SQUAT trial highlights both the promise and limitations of treatment escalation strategies in resectable stage III NSCLC. Rather than a universal role for neoadjuvant radiotherapy, these data suggest the need for more precise patient selection and trial designs that integrate biomarkers, nodal burden, and patterns of failure. As neoadjuvant and perioperative approaches continue to evolve, future studies should prioritize endpoints that reflect durable disease control while preserving the ability to deliver effective systemic therapy across the entire treatment course.

In conclusion, Hamada et al. report a well-conducted study presenting preliminary data on the addition of neoadjuvant radiotherapy to neoadjuvant chemoimmunotherapy. Although higher MPR rates were observed, it remains premature to conclude whether the incorporation of radiotherapy into neoadjuvant regimens will translate into durable long-term oncologic outcomes. In real-world practice, the main goal is to maximize survival, which depends not only on pathologic response but also on achieving resectability and complete (R0) resection. The SQUAT trial highlights that pCR and MPR alone may be insufficient as standalone markers of success, underscoring the importance of delivering both adequate neoadjuvant and adjuvant therapy, along with careful patient selection, to optimize long-term outcomes.

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-2026-1-0005/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://shc.amegroups.com/article/view/10.21037/shc-2026-1-0005/coif). The authors have no conflicts of interest to declare.

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