Stage III non-small cell lung cancer (NSCLC) patients exhibit significant heterogeneity, allowing for the application of various treatments in diverse sequences. With recent advancements, it‘s now possible to integrate immunotherapy or targeted therapy with surgical interventions for stage III NSCLC patients. Consequently, it’s crucial to endeavor, through multidisciplinary collaboration, to identify and implement the most tailored treatment strategy for each individual.

During the past decade, there have been substantial advances in lung cancer treatments. Targeted therapies, immunotherapies, stereotactic body irradiation, and refinements in video-assisted thoracic surgery have significantly enhanced the outcomes. Even patients with advanced or metastatic lung cancer often maintain high quality of life and exhibit prolonged survival. However, despite these advancements, many patients still confront challenges such as post-surgery or post-radiation recurrence, resistance to chemotherapy, and brain metastasis. Thus, lung cancer remains the primary cause of cancer-related mortality [1].

For patients with stage 1 and 2 NSCLC, surgery is performed whenever possible, and adjuvant chemotherapy may be prescribed if needed. For patients with stage 4 NSCLC, the primary approach is anticancer therapy; palliative radiation treatment or salvage surgery may be considered if necessary. However, the factors involved for patients with stage 3 NSCLC are more complex; careful consideration of various treatment options is required [1,2]. Stage 3 has been divided into sub-stages 3A, 3B, and 3C with distinct 5-year survival rates (36%, 26%, and 13%, respectively) [3]. Multidisciplinary care is needed to select the most suitable treatment for each individual. The conventional approach for patients with stage 3 NSCLC considered unsuitable for surgery has been concurrent chemoradiation followed by a waiting period to observe the treatment outcomes. However, considering the recent introduction of adjuvant immunotherapies and targeted therapies after surgery or radiation, lung cancer treatment outcomes have further improved [4]. This improvement has encouraged clinicians to carefully consider the selection of an optimal treatment. Several studies by the multidisciplinary teams of various hospitals have revealed extensive variations in the staging and treatment of patients with stage 3A NSCLC. While some variations may be inevitable when dealing with challenging patients, more principled treatment is needed [5].

In this review, we discuss the current treatment guidelines and practices for patients with stage 3 NSCLC, as well as treatment strategies that have recently been actively investigated, with a focus on pre- and post-surgery immunotherapies and the corresponding treatment outcomes [2,3,6-12].

In the American Joint Committee on Cancer 8th edition of lung cancer staging, a greater emphasis is placed on the detailed T stage classification, compared with the previous edition. In the 7th edition, tumors ≥7 cm were classified as T3; in the 8th edition, they are classified as T4. Similarly, cases exhibiting invasion of the diaphragm were classified as T3 in the 7th edition; in the 8th edition, they are classified as T4 [13]. In contrast, cases involving lesions within 2 cm of the main bronchial carina were classified as T3 in the 7th edition; in the 8th edition, that distance has been removed, and all cases involving invasion of the main bronchus are now classified as T2 [13,14]. These changes are likely attributable to advances in surgery and radiation treatment. Some cancers previously classified as T2N2M0 or T3N2M0/stage 3A are now classified as T3N2M0 or T4N2M0/stage 3B. Thus, it is essential to review research conducted in the era of the 7th edition to appropriately apply the staging criteria of the 8th edition in clinical practice [5].

Stage 3 NSCLC presents a wide variety of cases, each with numerous potential treatment strategies. Stage 3 includes cancers ranging from T4N0M0 (with rather large tumors but no lymph node metastases) to T4N3M0 (with large tumors and multilevel lymph node metastases) that render surgical interventions impossible and radiotherapy difficult. NSCLC can be broadly classified as resectable, potentially resectable, or unresectable [1,2,15,16]. In a modified Delphi study involving 30 physicians from diverse specialties who responded to a 76-item questionnaire, a significant majority of participants (up to 93%) reached a consensus on the following treatment approaches [16]. The panel recommended surgery followed by (neo)adjuvant chemotherapy for single-station disease patients [16]. For those with multi-station N2 disease, the panel suggested surgery with concurrent chemoradiotherapy (CCRT), followed by adjuvant immunotherapy [16].

One study showed that a tri-modal approach significantly improved survival and the relapse free survival in patients with locally advanced NSCLC, emphasizing the importance of multidisciplinary decision [17]. Perioperative platinum-based chemotherapy increased such survival by 5.4% compared with surgical monotherapy, while the complications of grade 3 or higher developed in >60% of patients. However recent study revealed major pathological responses to neoadjuvant chemotherapy in about 22% of patients with non-squamous NSCLC [16,18,19].

One study of 8,110 patients treated in 52 South Korean institutions from 2014 to 2016 assessed the treatment preferences and outcomes of patients with stage 3 lung cancer. Patients with stage 3A NSCLC favored surgery (24.4%); the 2-year survival rate was 45.3%, and surgery was especially beneficial for patients with squamous cell carcinoma. Patients with stage 3B and 3C survived better if they underwent CCRT compared with monotherapies; the survival rates were 27.0% and 24.8%, respectively. Overall, CCRT consistently led to better survival in patients with later stages of cancer [20].

For patients with stage 3 NSCLC who are eligible for surgery, neoadjuvant chemotherapy or chemoradiation is typically advised, particularly when they exhibit N2 involvement or superior sulcus tumors. If pre-surgery chemotherapy is not prescribed, postoperative adjuvant chemotherapy is recommended. For tumors considered unresectable, the suggested treatment is CCRT. If the disease does not progress after CCRT, durvalumab should be considered [21].

Recently, targeted therapies such as estimated glomerular filtration rate (EGFR)-tyrosine kinase inhibitors and immunotherapies have led to promising outcomes in metastatic lung cancer, and when prescribed as adjuvants after surgery or CCRT. The ADAURA (ClinicalTrials.gov identifier: NCT02511106) study showed significant improvements in the 5-year survival rates of patients with stage 1B, 2, and 3A who had EGFR exon 19 deletions or L858R mutations and received osimertinib for 3 years after surgery, compared with such patients who received placebo [4]. Similarly, the A Phase III, Randomised, Double-blind, Placebo-controlled, Multi-centre, International Study of MEDI4736 as Sequential Therapy in Patients with Locally Advanced, Unresectable Non-Small Cell Lung Cancer (Stage III) Who Have Not Progressed Following Definitive, Platinum-based, Concurrent Chemoradiation Therapy (PACIFIC) study revealed substantial improvements in the survival rates of patients with stage 3 NSCLC who had tumor cell programmed death-ligand 1 (PD-L1) expression levels ≥1% and received 1 year of durvalumab consolidation therapy after CCRT, compared with controls [6,22,23]. More recently, immunotherapies used as neoadjuvants, adjuvants, or both, improved the survival of patients with stage 3 lung cancer who had undergone surgical resection. Perioperative immune checkpoint inhibitors (ICIs) rendered patients with potentially resectable tumors eligible for surgery and reduced postoperative recurrence in high-risk cases [7]. However, ICI therapy may trigger hyper-progression or severe adverse events that render some patients ineligible for surgery. Moreover, the radiological distinction between tumor progression and immune system-related responses, such as inflammation and tumor cell death after ICI treatment, can be challenging [24]. Several studies have identified cases in which tumor sizes increased after ICI treatment, but examination of resected tissues revealed a major pathological response (i.e., <10% cancer cells) or complete pathological response (i.e., no cancer cells). Further in-depth research is required [6,9,10,12]. We have organized the treatment guideline for stage 3 NSCLC patients according to the approval and reimbursement status in South Korea as of January 2024 (Figure 1).

Deciding between adjuvant and neoadjuvant treatment is not a straightforward issue. However, if the tumor size is large or the tumor is adjacent to surrounding blood vessels and bronchi, making it potentially resectable, opting for neoadjuvant treatment might be more beneficial.

Recently, perioperative treatments using ICIs have been extensively researched; many positive results have been reported (Table 2). A 2018 New England Journal of Medicine paper evaluating neoadjuvant nivolumab treatment was the first such study; 21 patients with stage 1, 2, and 3 cancers, including seven patients with stage 3A cancers (33%), were enrolled [7]. The pathological response was high (42.8%). Notably, although increases in tumor size were evident on computed tomography, some cases revealed no cancer cells on pathological examination; thus, it was difficult to assess the effects of ICI treatment using computed tomography alone [8,12]. In the later Neo-Adjuvant Immunotherapy (NADIMII) study, neoadjuvant nivolumab in combination with cytotoxic chemotherapy led to a significant increase in the proportion of patients undergoing definitive surgery (93%, compared with 69% for patients receiving cytotoxic therapy alone) [24]. In the CheckMate 816 Phase 3 study, patients with stage 1B (tumors ≥4 cm) to stage 3A NSCLC who received nivolumab plus platinum-doublet chemotherapy exhibited significant improvements in event-free survival, overall survival, and pathological complete response [12]. The Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010) study revealed that atezolizumab prescribed after adjuvant chemotherapy improved disease-free survival among patients with resected stage 2-3A NSCLC, especially among patients with ≥1% PD-L1-positive tumor cells; 11% of patients experienced grade 3 and 4 adverse events related to atezolizumab, and 1% of such patients experienced grade 5 events [10]. The Study of Pembrolizumab (MK-3475) vs Placebo for Participants With Non-small Cell Lung Cancer After Resection With or Without Standard Adjuvant Therapy (MK-3475-091/KEYNOTE-091) (PEARLS) study revealed that the median disease-free survival was 53.6 months among patients receiving pembrolizumab, compared with 42.0 months in the placebo group (hazard ratio [HR], 0.76; p=0.0014). In the population with a PD-L1 tumor proportion score of 50% or higher, neither the pembrolizumab group nor the placebo group achieved a median disease-free survival. Adverse events of grade 3 or higher were observed in 34% of the pembrolizumab group and 26% of the placebo group [25]. The KEYNOTE-671 study evaluated pembrolizumab as both a neoadjuvant treatment and an adjuvant treatment. At 24 months, the event-free survival rates were 62.4% in the pembrolizumab group and 40.6% in the placebo group (HR, 0.58; p<0.001); the overall survival rates were 80.9% and 77.6%, respectively. The pembrolizumab group exhibited considerably more major pathological and complete responses. Grade 3 or higher adverse events were more common in the pembrolizumab group (44.9%) than in the placebo group (37.3%) [26].

There are so many ongoing clinical trials including phase I, II, and III in stage 3 NSCLC patients. We summarized the phase II and III clinical trials that have produced or are expected to produce significant results and will soon available for clinical application.

Stage 3 NSCLC is a multifaceted condition; it is difficult to always ensure the best possible outcomes [2-4,9,22,26]. Such patients are subjected to multimodal interventions associated with therapeutic risks and adverse events; it is challenging to enhance long-term survival. For stage 3 NSCLCs that can be surgically excised, no consensus optimal multimodal strategy has emerged; patient preferences, collaborative decision-making, and multidisciplinary team proficiency are key factors that influence the preferred treatment [2,3,13,17,27]. When stage 3 NSCLC is non-operable, CCRT is the recommended therapy. Durvalumab has become a standard post-treatment for patients with stage 3 non-operable NSCLC and ≥1% PD-L1-positive tumor cells who have undergone two rounds of platinum-infused CCRT. This approach may further improve the outcomes of patients with stage 3 NSCLC [23].

Considering the recent introductions of immunotherapies and targeted therapies in neoadjuvant and adjuvant settings, more patients with NSCLC stage 3 now consider surgery, and the postoperative prognosis has improved [1,4,7,10-12,25,28-30]. However, some patients may experience severe ICI-associated adverse events; there is a need to conduct additional research regarding ICI indications and relevant biomarkers.

In the contemporary landscape of advanced systemic therapies, a precise definition of resectable stage 3 NSCLC is urgently required to ensure consistent planning by multidisciplinary teams and to facilitate robust comparisons across trials exploring multimodal treatment strategies for various subsets of patients with stage 3 NSCLC [13,21]. Stage 3 tumors previously considered unresectable may become resectable after appropriate induction therapy. Surgical interventions may enhance survival by facilitating locoregional control. During the navigation of evolving treatment paradigms, tumor-specific attributes become increasingly relevant to personalized treatment decisions for patients with stage 3 NSCLC [1-4,9,22,26].

NSCLC stage 3 presents with marked heterogeneity, leading to diverse therapeutic strategies and outcomes in contemporary oncology. Consequently, NSCLC demands an integrated approach involving multiple disciplines for optimal management (Figures 1, 2). Notably, when surgical intervention is achievable, the prognosis for patients tends to be more favorable. Recent advancements include the incorporation of immunotherapeutic agents into the treatment regimen for stage 3 NSCLC, marking a significant stride in the field. Current research landscapes also feature a myriad of ongoing clinical trials exploring further potential benefits and applications. Nonetheless, ICIs are not devoid of adverse events, and certain patients may remain unsuitable for surgical procedures. Thus, there’s an imperative to further delineate the clinical markers and biomarkers that can guide patient selection for ICI therapies.