Radiation in the setting of perioperative chemoimmunotherapy in resectable stage III NSCLC: not ready for prime time yet

Introduction

The management of resectable stage III non-small cell lung cancer (NSCLC) has changed substantially in recent years and shifted toward a neoadjuvant, or perioperative (neoadjuvant plus adjuvant) strategy that integrates chemo and immunotherapy with surgery (1). While complete surgical resection remains central to curative intent, surgery alone is insufficient for most patients because of the high risk of distant recurrence (2). Current international guidelines recommend neoadjuvant platinum-based chemotherapy combined with immune checkpoint inhibition for eligible patients with resectable stage II–III NSCLC, followed by surgery, with some strategies continuing adjuvant immunotherapy in the postoperative setting (1,3). The neoadjuvant approach is intended to improve systemic disease control without compromising surgical safety or feasibility (4,5).

The rationale for neoadjuvant chemo-immunotherapy is supported by both biological and clinical considerations. Delivering chemo-immunotherapy before surgery facilitates interaction between the tumor and the immune system, allows earlier treatment of micrometastatic disease and may result in tumour and nodal downstaging, potentially facilitating less extensive resections (6). In addition, the neoadjuvant setting allows direct assessment of pathological response, providing an early (surrogate) measure of treatment efficacy (1,6).

The phase III CheckMate 816 trial established neoadjuvant chemo-immunotherapy as a standard of care. Three cycles of nivolumab combined with platinum-doublet chemotherapy significantly improved event-free survival (EFS) compared with chemotherapy alone [median 31.6 vs. 20.8 months; hazard ratio (HR) 0.63, 97.38% confidence interval (CI): 0.43–0.91] and markedly increased the pathological complete response (pCR) rate (24.0% vs. 2.2%). With longer follow-up, these findings translated into improved 5-year overall survival (OS) (65.4% vs. 55.0%; HR 0.72, 95% CI: 0.523–0.998). Importantly, these benefits were achieved without an increase in surgical complications or a reduction in complete resection rates, supporting the safety of this approach in the preoperative setting (7).

Subsequent phase III trials evaluated perioperative strategies that include postoperative adjuvant immunotherapy following neoadjuvant chemoimmunotherapy. The KEYNOTE-671 trial demonstrated that perioperative platinum-based chemotherapy plus pembrolizumab significantly improved 3-year EFS compared with neoadjuvant chemotherapy alone (54% vs. 35%; HR 0.59, 95% CI: 0.48–0.72), increased pCR rates (18.1% vs. 4.0%), and demonstrated a statistically significant OS benefit, regardless of PD-L1 expression. The 3-year OS was 71% vs. 64% (HR 0.72, 95% CI: 0.56–0.93) (8). Similarly, the AEGEAN trial demonstrated that perioperative chemotherapy plus durvalumab improved EFS (HR 0.68, 95% CI: 0.53–0.88) and increased pCR rates (17.2% vs. 4.3%), compared with neoadjuvant chemotherapy alone (9). The CheckMate 77T trial further confirmed the benefit of a perioperative approach using nivolumab, reporting an 18-month EFS rate of 70.2% vs. 50.0% with neoadjuvant chemotherapy plus placebo (HR 0.58, 97.36% CI: 0.42–0.81), with a pCR rate of 25.3% vs. 4.7% and an MPR rate of 35.4% vs. 12.1% (8).

Across these trials, neoadjuvant chemo-immunotherapy consistently improved pathological response, and EFS (6). Meta-analyses have confirmed these benefits across clinically relevant subgroups, including patients with PD-L1 expression below 1%, supporting broad applicability in resectable stage III disease (6). pCR and major pathological response (MPR) have emerged as important surrogate indicators of disease-based outcomes in the neoadjuvant setting and are strongly associated with improved EFS at the patient level. However, their role as validated trial-level surrogates for OS remains under active investigation (9).

Chemo-immunotherapy approaches may not be appropriate for all NSCLC patients, particularly those with epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements, who derive limited benefit from immunotherapy-based approaches (1). Additional challenges include determining optimal surgical timing after neoadjuvant therapy, defining the value of postoperative immunotherapy in patients achieving a pCR, and managing immune-related toxicities. Successful delivery of neoadjuvant and perioperative strategies depends on coordinated multidisciplinary care within experienced, high-volume centres (1).

The role of radiation in resectable stage III NSCLC remains unclear. Mixed results have been observed in trials of neoadjuvant chemoradiation followed by surgery (10,11). Data predating neoadjuvant chemo-immunotherapy demonstrated no improvement in OS from adjuvant radiation in resected stage III NSCLC (12). Local recurrence remains an ongoing concern, and trials are needed to determine whether radiation adds to the therapeutic efficacy of current neoadjuvant and perioperative treatment approaches (1,13,14).

The SQUAT trial

The SQUAT trial (WJOG 12119L) was a prospective, multicenter, open-label phase II study conducted in Japan to evaluate a neoadjuvant treatment strategy that added radiation to neoadjuvant chemotherapy and immunotherapy, before surgical resection, followed by adjuvant immunotherapy, in patients with resectable stage III N2 NSCLC. The primary results were reported after a median follow-up of 28 months and describe the feasibility, pathological outcomes, survival endpoints, and safety profile of this treatment approach (15).

The investigators conducted this study in the context of increasing adoption of neoadjuvant or perioperative chemo-immunotherapy for resectable stage II–III NSCLC. They hypothesized that integrating radiotherapy into neoadjuvant chemo-immunotherapy could enhance local tumor control and reduce local recurrence rates. The central objective of the trial was to determine whether this combined modality regimen could achieve a predefined MPR rate of 65%, in patients with resectable stage III N2 disease (15).

Eligible patients for the study were aged 20 to 75 years with previously untreated, pathologically confirmed N2-stage NSCLC (American Joint Committee on Cancer 8th edition) (16), including stage IIIA or IIIB. Patients with extranodal extension based in imaging studies were excluded. Additional inclusion criteria included an Eastern Cooperative Oncology Group performance status of 0 or 1 and adequate organ function. The study allowed patients with EGFR mutations or ALK rearrangements, as relevant trial data were not yet available at the time of study design (15).

Between January 2020 and February 2022, 31 patients were enrolled across 10 institutions in Japan (15). Six patients were known to have tumors harbouring an EGFR mutation. All patients received neoadjuvant concurrent chemoradiotherapy consisting of weekly carboplatin (AUC 2) and paclitaxel (40 mg/m²) for five weeks, with concurrent involved-field radiotherapy to a total dose of 50 Gy delivered in 25 fractions. Durvalumab at a fixed dose of 1,500 mg was administered on days 1 and 29 during the neoadjuvant phase. Surgical resection was planned within two to six weeks following completion of radiotherapy, and adjuvant durvalumab was administered every four weeks for up to one year after surgery. The primary endpoint was MPR, defined as ≤10% residual viable tumor in the resected specimen on central pathological review. Secondary endpoints included pCR, progression-free survival (PFS), OS, and safety (15).

Among the 30 patients included in the intention-to-treat population, neoadjuvant therapy was completed by 97% of patients, and 90% underwent definitive surgery. The MPR rate was 63% (90% CI: 47–78%), meeting the prespecified primary endpoint. The pCR rate was 23% (95% CI: 10–42%). At a median follow-up of 28 months, the median PFS was 15 months, and the median OS had not been reached. The 2-year PFS and OS rates were 43% (95% CI: 26–60%) and 76% (95% CI: 56–88%), respectively. Overall, 50% of patients experienced disease recurrence; locoregional recurrence occurred in 20% (6/30), including 7% with isolated local recurrence and 13% with combined local and distant recurrence, while distant-only recurrence was observed in 30% of patients (15).

For the safety analyses, all 31 enrolled patients were included. Grade 3 or 4 treatment-related adverse events occurred in 48% of patients, with neutropenia being the most common severe toxicity. Treatment discontinuation due to adverse events occurred in 10% of patients. One treatment-related death was reported, attributed to concurrent myocardial infarction and immune-mediated pneumonitis following surgery. Radiation pneumonitis occurred in 26% of patients, predominantly at low grade, and grade 3–4 surgery-related complications were reported in 13% of cases (15).

The authors acknowledged several study limitations, including the single-arm design, relatively small sample size, and limited duration of follow-up. They also noted that not all patients initiated or completed adjuvant durvalumab; only 53% (16/30) initiated adjuvant therapy, and just 27% (8/30) completed the planned one year of treatment, and that the number of neoadjuvant immunotherapy cycles (two cycles) was lower than in other neoadjuvant or perioperative trials (15).

Discussion

The primary question addressed by the SQUAT trial is whether adding radiotherapy to neoadjuvant chemo-immunotherapy improves local control in resectable stage III N2 NSCLC. Although locoregional recurrence remains a clinically meaningful concern in this population, the role of radiation in the era of perioperative chemo-immunotherapy remains incompletely defined (1,15).

MPR as a surrogate under radiation-immunotherapy combinations

Historically, neoadjuvant chemoradiotherapy was investigated in selected patients with stage III N2 disease to improve locoregional tumour control. Although these strategies demonstrated technical feasibility and, in some studies, enhanced local tumour control, long-term survival advantages were not observed. As systemic recurrence continued to drive long-term outcomes, treatment paradigms shifted toward intensifying systemic therapy rather than escalating local therapy (10).

The SQUAT trial revisits the role of adding radiation to neoadjuvant chemo-immunotherapy. As shown in Table 1, the trial reported a higher MPR rate compared to neoadjuvant or perioperative chemo-immunotherapy studies. However, the pCR rates did not improve, and local recurrence remained clinically significant, with 6 of 30 patients experiencing locoregional recurrence. Additionally, comparison of perioperative trial outcomes showed no clear advantage in progression-free or OS. These results present a biologically interesting yet clinically conflicting outcome: although MPR increased, more definitive indicators of durable disease control, such as pCR and survival endpoints, did not show corresponding improvement (15).

This discordance between MPR and more definitive endpoints raises a central question: does MPR serve as a reliable surrogate for durable disease control when radiation is incorporated into immunotherapy-based regimens? Across neoadjuvant immunotherapy trials, pCR has shown a stronger and more consistent association with EFS than MPR (Table 1). In SQUAT, the absence of improvement in pCR suggests that higher MPR may reflect radiation-induced tumour regression rather than a deeper immunological response predictive of long-term benefit. If pCR more closely correlates with durable outcomes, the lack of difference in pCR may explain the absence of improved survival despite higher MPR rates. A comparable observation was reported by Altorki et al., where low-dose SBRT plus durvalumab produced an MPR rate of 53.3% versus 6.7% with durvalumab alone, yet 3-year disease-free survival was similar between arms. These converging findings suggest that MPR improvements driven by radiation may not translate into the survival gains typically expected from pathological response deepening, though this interpretation requires validation in larger, randomised studies (9,13,15).

Several factors may explain why adding radiation did not clearly improve disease outcomes. First, patients in SQUAT received only two cycles of neoadjuvant chemo-immunotherapy, whereas most neoadjuvant or perioperative trials used four cycles before surgery. Receiving fewer cycles of systemic treatment may have reduced systemic disease control and limited the extent of tumor response before surgery. It is possible that completing a full course of systemic therapy has a greater impact on long-term outcomes than increasing the intensity of local treatment, such as radiation (15).

The inclusion of patients with EGFR-mutated tumors may have influenced the observed efficacy results. EGFR-driven NSCLC is known to be less responsive to immune checkpoint inhibition. Exploratory analyses in SQUAT suggested higher MPR and pCR rates among patients without EGFR mutations. If local recurrence patterns differed by molecular subtype, including EGFR-mutant disease, could have attenuated the ability to detect a true local control advantage. Whether locoregional recurrence in this cohort was associated with mutation status remains unclear and requires further evaluation (15).

Additionally, questions remain about whether the radiation dose and schedule were sufficient to meaningfully alter local tumor biology. It is also possible that, in the presence of effective chemo-immunotherapy, the incremental benefit of radiation to tumor eradication is limited. Similar observations have been reported in other intensification strategies, including concurrent immunotherapy with definitive chemoradiotherapy in unresectable disease as in the PACIFIC-2 trial, which did not show a clear efficacy advantage and raised concerns about pulmonary and immune-mediated toxicity (15,17).

Radiation-immunotherapy combinations in the neoadjuvant setting

It is important to understand the SQUAT trial within the broader context of studies combining radiotherapy and immunotherapy in the neoadjuvant setting. Several early-phase trials have investigated this combination using varying radiation doses, fractionation schemes, and sequencing strategies in relation to systemic therapy. These approaches range from low-dose immunomodulatory stereotactic body radiotherapy (SBRT) used as an immune primer (Altorki et al., NCT02904954), to concurrent chemoradiotherapy combined with dual checkpoint inhibition (INCREASE trial, NL8435), to sequential radiation-first strategies designed to sensitize the tumor microenvironment before chemo-immunotherapy (NEORADJUVANT trial, NCT06800339) (13,18,19).

Despite their design differences, a notable pattern has emerged across these trials. The INCREASE trial as well as the trial by Altorki demonstrated the ability of radiation to enhance pathological response, particularly MPR. Longer term outcomes have not been reported from the INCREASE trial. Altorki et al. reported an MPR rate of 53.3% with low-dose SBRT plus durvalumab, compared to 6.7% with durvalumab alone, providing evidence for a biological interaction between radiation and immunotherapy. However, improvements in MPR were not accompanied by corresponding gains in survival; 3-year disease-free survival was similar between arms despite the marked difference in pathological response. A comparable observation was noted in the SQUAT trial, where higher MPR did not translate into improved survival endpoints. These findings raise the possibility that MPR may not reliably predict durable disease control when radiation is incorporated into immunotherapy-based regimens, though this interpretation requires validation in larger randomized studies (13,15,18,19).

Additionally, the incorporation of radiation—whether concurrent, sequential, or as a low-dose primer—may introduce additional toxicity, including radiation pneumonitis and immune-mediated adverse events. The clinical significance of these risks depends on the magnitude of any associated efficacy benefit, which remains to be established. Collectively, these trials suggest that while combining radiation with immunotherapy has a biological rationale and can enhance local tumor regression, evidence demonstrating that this translates into clinically meaningful improvements in survival is currently lacking. Whether this reflects limitations in trial design, patient selection, radiation dosing, or a true biological ceiling of the approach remains an open question (13,15,18,19).

Patient selection and future directions

It is also possible that any benefit of adding radiation may be confined to a subset of patients. Careful analyses of existing trial data are needed to identify factors predictive of local recurrence. It would be informative to evaluate whether patients who do not achieve pCR or MPR are at higher risk of locoregional failure, and whether specific molecular or clinical characteristics define a population more likely to benefit from radiation intensification. Such analyses could help guide patient selection in future trials evaluating the role of adjuvant or neoadjuvant radiation in this setting (9,15).

The findings from SQUAT and the broader immunoradiotherapy literature reflect an ongoing challenge in stage III NSCLC: distant recurrence remains the predominant pattern of treatment failure. Even when local pathological response is improved, systemic micrometastatic disease may continue to influence long-term outcomes. This does not necessarily imply that local therapy escalation is without value, but rather that its potential benefit may be difficult to demonstrate without concurrent optimization of systemic disease control (15).

Safety considerations

The safety profile further emphasizes the need for caution. Quadruple-modality therapy increased treatment complexity and cumulative toxicity. Although surgical resection remained feasible, the additional toxicity burden must be carefully balanced against uncertain survival benefit in a curative-intent population. Treatment-related adverse events reported in SQUAT and in representative neoadjuvant chemo-immunotherapy trials are summarized in Table 2 (6,15).

Conclusions

Neoadjuvant chemo-immunotherapy remains the standard of care for resectable stage II–III NSCLC. At present, there is no evidence to support the routine addition of radiotherapy or the use of neoadjuvant quadruple-modality therapy outside of clinical trials. Although the SQUAT trial showed increased major pathological response, complete pathological response and long-term outcomes were similar to those seen with current standard approaches, and treatment complexity and toxicity warrant caution. Accordingly, current treatment paradigms remain unchanged; however, these findings highlight areas for future research, including patient selection, treatment sequencing, and strategies to better link local response with durable systemic disease control (1,15).

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-2026-1-0013/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-2026-1-0013/coif). P.M.E. has received honoraria for lectures from AstraZeneca, Eli Lilly, Merck, Pfizer and Sanofi; honoraria for advisory board meetings from Astrazeneca, Johnson & Johnson, Novartis, Merck, Pharmacosmos, Roche, and Sanofi; and serves as the Chair of the Ontario Clinical Oncology trials Group (OCOG) Data Safety and Monitoring Committee. 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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