Stage III non–small cell lung cancer (NSCLC) remains one of the most challenging clinical scenarios in thoracic oncology. Patients with locally advanced disease, particularly those with T4 tumors or mediastinal nodal involvement (N2–N3), represent a heterogeneous population in whom the optimal integration of systemic therapy, radiation, and surgery remains debated.
Unresectable disease has been treated with concurrent chemoradiotherapy followed by consolidation durvalumab based on the PACIFIC trial, whereas surgery has been reserved for carefully selected patients with potentially resectable tumors. However, the rapid evolution of immunotherapy in earlier stages of NSCLC is beginning to reshape this paradigm.
In our recently published multicenter study evaluating neoadjuvant PD-1/PD-L1 blockade combined with chemotherapy for borderline resectable or unresectable stage III NSCLC, we sought to address a critical evidence gap: whether chemoimmunotherapy can improve resectability and pathological responses in patients with more advanced local disease who were largely excluded from pivotal perioperative trials.
Filling a Gap
Over the past few years, multiple randomized trials, including CheckMate 816, AEGEAN, KEYNOTE-671, and NADIM II, have established chemoimmunotherapy as a standard perioperative or neoadjuvant strategy for resectable stage II–III NSCLC. These studies demonstrated that adding immune checkpoint inhibitors (ICIs) to platinum-based chemotherapy significantly improves pathological complete response (pCR) rates and event-free survival (EFS).
Yet many of these trials enrolled patients with clearly resectable disease and more limited nodal involvement. Patients with bulky N2 disease, certain T4 tumors, or N3 involvement were immanently excluded depending on the local indications. Consequently, clinicians have been left with limited evidence to guide treatment for patients whose disease lies in the “borderline resectable” spectrum, cases in which surgery might be possible but carries a high risk of incomplete resection or early recurrence.
Encouraging Pathological Responses and Surgical Outcomes
In our cohort of 112 patients with stage III NSCLC characterized by T4 tumors and/or N2–N3 nodal involvement, neoadjuvant PD-1/PD-L1 blockade combined with chemotherapy demonstrated encouraging activity. Overall, 75% of patients ultimately proceeded to surgical resection.
Among those who underwent surgery, the pCR rate was 29%, and a major pathological response was observed in 42% of cases. These outcomes are particularly notable given the advanced nature of the disease in this population. Importantly, surgical outcomes were highly favorable, with R0 resections achieved in the vast majority of patients (96.4%).
Moreover, patients who achieved pCR experienced substantially longer EFS compared with those who did not, underscoring the prognostic value of pathological response after neoadjuvant therapy. Taken together, these findings suggest that chemoimmunotherapy can effectively downstage tumors and enable curative-intent surgery in patients who might otherwise be treated with definitive chemoradiotherapy alone.
Reconsidering the Role of Surgery in N2 Disease
The role of surgery in mediastinal nodal disease has long been controversial. Randomized trials conducted before the immunotherapy era yielded mixed results when comparing surgery after induction therapy with definitive chemoradiotherapy. As a result, treatment decisions have historically depended heavily on institutional experience and multidisciplinary discussion.
However, the landscape is changing rapidly. Neoadjuvant chemoimmunotherapy has produced unprecedented pathological response rates in several trials. Similarly, NADIM II reported remarkable pathological responses and promising survival outcomes, specifically in patients with stage III disease.
Our findings extend these observations to patients with more advanced nodal disease. Interestingly, we observed comparable pathological outcomes between patients with single-station and multistation N2/N3 disease, suggesting that nodal burden alone may not preclude benefit from neoadjuvant immunotherapy.
Emerging Strategies for N3 Disease
Perhaps the most provocative implication of our study relates to patients with N3 disease, traditionally considered unresectable. In our cohort, patients with N3 nodal involvement who proceeded to surgery experienced substantial nodal downstaging after neoadjuvant therapy.
Although the numbers remain small, these observations raise the possibility that aggressive multimodality approaches, including induction chemoimmunotherapy followed by surgery, may be feasible in carefully selected patients with stage IIIB–IIIC disease. Several ongoing phase II studies are currently exploring this strategy, reflecting a broader shift toward testing the limits of resectability in the immunotherapy era.
Biomarkers and Treatment Selection
Our study also highlights the importance of integrating biomarkers into treatment decision-making. Higher PD-L1 expression was associated with a greater likelihood of pCR, and combining PD-L1 with tumor mutational burden further enriched for responders. In contrast, tumors harboring KRAS/STK11 or KRAS/KEAP1 co-mutations were associated with resistance to neoadjuvant chemoimmunotherapy.
These findings are consistent with prior work showing that these genomic alterations define a subset of tumors with immunologically “cold” microenvironments and relative resistance to immune checkpoint blockade. As biomarker-driven strategies continue to evolve, integrating genomic and immune features may help identify patients most likely to benefit from aggressive multimodality treatment.
Looking Ahead
While our results are encouraging, prospective validation remains essential. Randomized trials focusing specifically on patients with bulky N2 or N3 disease will be necessary to determine whether surgery after neoadjuvant immunotherapy improves long-term outcomes compared with definitive chemoradiotherapy, and several prospective studies are already ongoing.
Nevertheless, the broader message is that the boundaries of resectability in NSCLC are changing. As systemic therapies become more effective, the integration of surgery into multimodality treatment strategies (e.g., ICI+ADC, ICI+RASi, among others) may expand the pool of patients who can be treated with curative intent, even among those with historically high-risk, locally advanced disease.
References
- Antonia, S. J. et al. Durvalumab after chemoradiotherapy in stage III non–small-cell lung cancer. New England Journal of Medicine 377, 1919–1929 (2017).
- Heymach, J. V. et al. Perioperative Durvalumab for Resectable Non–Small-Cell Lung Cancer. New England Journal of Medicine 389, 1672–1684 (2023).
- Forde, P. M. et al. Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer. New England Journal of Medicine 386, 1973–1985 (2022).
- Wakelee, H. et al. Perioperative Pembrolizumab for Early-Stage Non–Small-Cell Lung Cancer. New England Journal of Medicine 389, (2023).
- Ricciuti, B. et al. Neoadjuvant PD-1 and PD-L1 Blockade With Chemotherapy for Borderline Resectable and Unresectable Stage III Non-Small Cell Lung Cancer. JAMA Oncology. 11, 735-741 (2025)
