Lung cancer is the leading cause of cancer mortality worldwide [1]. Over the past two decades, targeted therapies and immune checkpoint inhibitors have markedly enhanced survival in patients with metastatic non-small cell lung cancer (NSCLC) [2,3]. Similarly, survival improvements in non-metastatic disease have been demonstrated with the use of immune checkpoint inhibitors following chemoradiotherapy for stage III disease, and as perioperative treatment for stage IB-IIIA disease [4-9]. Standard treatments now include chemoradiotherapy followed by immunotherapy, adjuvant (postoperative) immunotherapy, neoadjuvant (pre-operative) chemoimmunotherapy, and combined neoadjuvant chemoimmunotherapy with adjuvant immunotherapy [10-13]. Conversely, targeted therapies played a limited role in non-metastatic disease until recent evidence showed osimertinib and alectinib improve survival in the adjuvant context [14-16]. Recent studies indicate adjuvant osimertinib and alectinib as standard perioperative therapies for epidermal growth factor receptor (EGFR)- and anaplastic lymphoma kinase (ALK)-altered NSCLC respectively. Thus, testing for EGFR and ALK alterations has become essential in the perioperative setting to determine eligibility for adjuvant targeted therapy rather than immunotherapy [13]. Furthermore, recent evidence demonstrates that administering osimertinib following chemoradiotherapy is effective for stage III NSCLC [17]. Therefore, it is essential to identify EGFR and ALK statuses to guide treatment choices for patients with stage IB NSCLC and higher. This review synthesizes findings from recent trials on perioperative and postchemoradiation therapies, emphasizing the necessity of molecular testing for non-metastatic NSCLC.

The A Phase III, Double-blind, Randomized, Placebo-controlled Multi-centre, Study to Assess the Efficacy and Safety of AZD9291 Versus Placebo, in Patients With Epidermal Growth Factor Receptor Mutation Positive Stage IB-IIIA Non-small Cell Lung Carcinoma, Following Complete Tumour Resection With or Without Adjuvant Chemotherapy (ADAURA) study demonstrated that 3 years of adjuvant osimertinib, with or without adjuvant chemotherapy following complete resection, enhanced survival in patients with non-squamous NSCLC who harbor EGFR exon 19 deletions or L858R mutations compared to placebo [14]. In most cases, adjuvant chemotherapy was administered prior to osimertinib. The primary endpoint was investigator-assessed disease-free survival (DFS) in patients with stage II to IIIA disease, while the secondary endpoints included DFS in stage IB to IIIA disease, overall survival, and safety. The hazard ratio (HR) for disease recurrence or death was 0.17 (95% confidence interval [CI], 0.11 to 0.26; p<0.001), with an especially low HR in the stage IIIA subgroup (HR, 0.12; 95% CI, 0.07 to 0.20) (Table 1). The 2-year DFS rate was 89% in the osimertinib group, compared to 52% in the placebo group. This study led to the approval of osimertinib by the United States Food and Drug Administration (FDA) and endorsements by the American Society of Clinical Oncology (ASCO) and the International Association for the Study of Lung Cancer (IASLC) as adjuvant therapy for NSCLC patients whose tumors exhibit EGFR exon 19 deletions or the L858R mutations, as identified by an FDA-approved test [10,13,18]. Subsequent follow-up indicated that this improvement also translated to enhanced overall survival, with an overall HR for death of 0.49 (95% CI, 0.33 to 0.73; p<0.001) [15]. This finding was significant because prior studies involving first-generation EGFR inhibitors demonstrated improved DFS but no substantial benefit in overall survival, suggesting that patients and physicians might defer starting EGFR inhibitors until disease recurrence with expectations of similar survival outcomes to those observed in the adjuvant setting [19-21]. The enhancement in overall survival resulted in the approval by both the European Medicines Agency (EMA) and the Japanese Pharmaceuticals and Medical Devices Agency (PMDA).

The ALINA study demonstrated that 2 years of adjuvant alectinib following complete resection significantly enhances patient survival with ALK fusion-positive NSCLC, compared to adjuvant chemotherapy [16]. The primary endpoint, DFS, applied to patients with stage II to IIIA disease as assessed by the investigator. The HR for disease recurrence or death was 0.24 (95% CI, 0.13 to 0.45; p<0.001). The 2-year DFS rate was 94% in the alectinib group versus 63% in the chemotherapy group. The HR for disease recurrence or death in patients with stage IB (≥4 cm) to IIIA disease was similarly 0.24 (95% CI, 0.13 to 0.43; p<0.001). This was consistent across stages, and in the stage IIIA group, the HR was 0.25 (95% CI, 0.12 to 0.53). The overall survival data remain immature. The outcomes facilitated FDA, EMA, and PMDA approvals, and endorsements by the IASLC and the National Comprehensive Cancer Network (NCCN) guidelines for alectinib as adjuvant therapy [13,22].

The recommended duration for adjuvant osimertinib following complete resection is 3 years, as per the ADAURA trial [14]. Similarly, adjuvant alectinib is advised for 2 years postresection, according to the ALINA trial protocol [16]. However, the optimal duration for targeted adjuvant therapy following complete resection remains uncertain. An updated DFS analysis from the ADAURA trial has indicated that extending osimertinib treatment beyond 3 years could benefit some patients [23]. Further clinical trials are required to explore these aspects, with the phase II, single-arm A Study of 5 Years of Adjuvant Osimertinib in Completely Resected Epidermal Growth Factor Receptor Mutation (EGFRm) Non-small Cell Lung Carcinoma (NSCLC) (TARGET) study evaluating the safety and efficacy of 5 years of adjuvant osimertinib in patients with completely resected EGFR-mutated stage II to IIIB NSCLC [24]. Additionally, the Icotinib Following Chemotherapy Versus Chemotherapy as Adjuvant Therapy in Stage IIA-IIIA NSCLC With EGFR Mutation (ICTAN) trial, comparing 6 and 12 months of adjuvant icotinib, could also provide valuable data. The detection of circulating tumor DNA, including postoperative molecular residual disease, may aid in determining treatment duration, with several ongoing clinical trials [25,26].

Following the success of adjuvant targeted therapy, neoadjuvant treatment has gained increased interest. A randomized phase 2 trial comparing neoadjuvant erlotinib and chemotherapy demonstrated a numerical improvement in progression-free survival (PFS) [27]. However, it failed to meet the primary endpoint of objective response rate, and there was no improvement in overall survival. To date, the efficacy of neoadjuvant targeted therapy remains unproven [28,29]. A Study of Osimertinib With or Without Chemotherapy Versus Chemotherapy Alone as Neoadjuvant Therapy for Patients With EGFRm Positive Resectable Non-Small Cell Lung Cancer (NeoADAURA) represents the sole ongoing phase 3 targeted therapy trial, comparing neoadjuvant osimertinib plus chemotherapy, or osimertinib alone, with chemotherapy alone in patients possessing EGFR mutation-positive, resectable II-IIIB (N2) NSCLC [30]. Additionally, phase 2 studies investigating capmatinib for MET proto-oncogene, receptor tyrosine kinase (MET)-altered NSCLC and selpercatinib for ret proto-oncogene (RET)-fusion positive NSCLC are still underway [28]. Because neoadjuvant treatment can result in disease progression that potentially precludes curative resection, the current recommendation is to administer neoadjuvant targeted therapy only within a clinical trial setting.

Ongoing studies are expected to provide insights into the use of perioperative targeted therapy for non-metastatic NSCLC. Several adjuvant therapies targeting EGFR-mutated NSCLC are currently under investigation in clinical trials (Table 2) [31,32]. For instance, the Icotinib as Adjuvant Treatment for Stage II-IIIA Lung Adenocarcinoma Patients with EGFR Mutation (ICWIP Study) trial's study protocol is akin to that of the ADAURA trial but substitutes icotinib for osimertinib as the treatment arm [33]. The replication of results from the ADAURA trial is an area of significant interest. In addition to the TARGET and ICTAN trials, the Erlotinib Hydrochloride in Treating Patients With Stage IB-IIIA Non-small Cell Lung Cancer That Has Been Completely Removed by Surgery (ALCHEMIST)-EGFR trial is exploring whether 2 years of adjuvant erlotinib can improve overall survival [34,35]. The ADAURA2 trial investigates whether patients with stage IA2 and IA3 benefit from adjuvant osimertinib [36]. The NeoADAURA is currently the sole ongoing phase 3 neoadjuvant targeted therapy trial [30]. Few phase 3 trials address non-EGFR -mutated NSCLC (Table 2), including two trials using ALK inhibitors and another examining serpercatinib for RET-fusion positive NSCLC [37].

As of October 2024, the FDA has approved six different regimens as perioperative immune checkpoint inhibitors (Table 1). The first to be approved was atezolizumab, administered for 1 year following surgery and adjuvant chemotherapy [5]. In the Study to Assess Safety and Efficacy of Atezolizumab (MPDL3280A) Compared to Best Supportive Care Following Chemotherapy in Patients With Lung Cancer (IMpower010) study, the primary endpoint was investigator-assessed DFS, tested first hierarchically in a subgroup of patients at stage II-IIIA whose tumors had programmed death-ligand 1 (PD-L1) expression on 1% or more of tumor cells, then in all stage II-IIIA patients, and finally across the intention-to-treat stage IB-IIIA population. The study met all three primary endpoints, with HRs for disease recurrence or death at 0.66 (95% CI, 0.50 to 0.88; p=0.004), 0.79 (95% CI, 0.64 to 0.96; p=0.020), and 0.81 (95% CI, 0.67 to 0.99; p=0.040), respectively. However, at the first prespecified interim analysis for overall survival, following a median 45-month follow-up, the HR for death was 0.995 [38]. Both the FDA and PMDA approved the use of atezolizumab for stage II to IIIA NSCLC with PD-L1 expression of 1% or higher, while the EMA restricts its approval to EGFR - and ALK -negative NSCLC where tumors show PD-L1 expression of 50% or higher. In addition, another phase 3 adjuvant trial, 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), involved administering pembrolizumab or placebo every 3 weeks for 18 cycles following surgery and adjuvant chemotherapy [39]. The HR for DFS in patients with stage IB (4 cm or larger) to IIIA was 0.76 (95% CI, 0.63 to 0.91; p=0.001). The HR for overall survival at the interim analysis was 0.87 (95% CI, 0.67 to 1.15; p=0.17), leading to approval by the FDA and EMA, though not by PMDA. No definitive conclusions could be drawn on whether patients with EGFR or ALK -altered NSCLC benefit from adjuvant pembrolizumab, due to the limited number of patients with known alterations being included.

The initial approval of neoadjuvant treatment involved nivolumab, administered in combination with chemotherapy across three cycles [6]. Patients with documented EGFR mutations or ALK fusions were excluded from the CheckMate 816 study. The study's two primary endpoints were event-free survival in patients with stage IB to IIIA NSCLC, as reviewed by a blinded independent central committee, and pathologic complete response. The HR for event-free survival—encompassing disease progression, recurrence, or death—was 0.63 (97% CI, 0.43 to 0.91; p=0.005). The HR for mortality was 0.57 (99% CI, 0.30 to 1.07; p=0.008) during the initial prespecified interim analysis, which failed to meet the prespecified statistical significance threshold of 0.0033.

Pembrolizumab has been approved as the first neoadjuvant and adjuvant treatment, administered with cisplatin-based chemotherapy for four cycles, followed by surgery and adjuvant pembrolizumab for up to 13 cycles [7]. In the KEYNOTE-671 trial, the two primary endpoints were investigator-assessed event-free and overall survival in patients with Stage II to IIIB (N2) NSCLC. The HR for disease progression, recurrence, or death was 0.58 (95% CI, 0.46 to 0.72; p<0.001); the HR for death alone was 0.72 (95% CI, 0.56 to 0.93; p=0.005) [40]. These treatment regimens have received approval from the FDA, EMA, and PMDA. Conversely, neoadjuvant and adjuvant administration of durvalumab has been approved by the FDA and EMA, but not by the PMDA. In the Study of Neoadjuvant/ Adjuvant Durvalumab for the Treatment of Patients With Resectable Non-small Cell Lung Cancer (AEGEAN) study, patients with EGFR or ALK alterations were excluded following a protocol amendment, and durvalumab was administered with cisplatin-based chemotherapy for four cycles before surgery, followed by adjuvant durvalumab for 12 cycles [8]. The two primary endpoints were event-free survival and pathologic complete response. Event-free survival was significantly longer with durvalumab compared to placebo, presenting a HR of 0.68 (95% CI, 0.58 to 0.88; p=0.004) at the first interim analysis. Data for overall response were not reported. Furthermore, only the FDA has authorized the neoadjuvant and adjuvant administration of nivolumab as of October 2024. In the CheckMate 77T study, patients with alterations in EGFR and ALK were excluded, and nivolumab was administered alongside cisplatin-doublet chemotherapy for four cycles, followed by surgery, and then adjuvant nivolumab for 1 year [9]. The primary outcome, event-free survival, was evaluated by a blinded independent review. The HR for disease progression, recurrence, abandonment of surgery, or death was reported as 0.58 (95% CI, 0.42 to 0.81; p<0.001).

The ADAURA and ALINA studies demonstrated that osimertinib and alectinib use postsurgery enhances survival rates. Similarly, the perioperative immune checkpoint inhibitor studies indicated improved survival, applicable to adjuvant, neoadjuvant, or both contexts. Direct comparisons between studies are not feasible; however, four updated guidelines offer comparable perspectives. ASCO releases rapid recommendation updates nearly annually, the NCCN publishes several versions within a year, and the Japan Lung Cancer Society (JLCS) annually updates its guidelines, which are published in Japanese [10,11,22,41,42]. The IASLC has recently published a recommendation specifically addressing neoadjuvant and adjuvant treatments for resectable NSCLC [13]. A schematic diagram summarizing the guidelines and recommendations from ASCO, NCCN, JLCS, and IASLC is presented as Figure 1.

For patients with stage IA NSCLC, no further testing is required postsurgery. For patients with stage IB NSCLC, a 3-year regimen of adjuvant osimertinib is recommended following the resection of EGFR -mutated NSCLC, without the administration of platinum-based adjuvant chemotherapy. For stage I NSCLC without EGFR mutations, no treatment is advised or approved after surgery in the United States or Europe. In Japan, the JLCS guideline suggests tegafur and uracil for stage I NSCLC larger than 2 cm [43,44]. For stage II patients, 3 years of adjuvant osimertinib is advised following platinum-based adjuvant chemotherapy after resection of EGFR -mutated NSCLC. If the NSCLC is ALK fusion-positive, alectinib is the recommended treatment postsurgery. In cases of NSCLC lacking EGFR or ALK alterations, resection followed by platinum-based adjuvant chemotherapy is advised. The ASCO and NCCN guidelines recommend immunotherapy for up to 1 year if PD-L1 expression is 1% or higher, and advise against further treatment if PD-L1 expression is less than 1% [10,22]. In Europe, adjuvant immunotherapy is approved only for NSCLC cases exhibiting PD-L1 expression of 50% or higher. In Japan, adjuvant atezolizumab is approved for NSCLC with PD-L1 expression of 1% or higher; however, no recommendation is provided for or against the 1% to 49% subgroup [42]. For NSCLC cases negative for EGFR and ALK alterations, the IASLC recommends neoadjuvant chemoimmunotherapy followed by surgery, irrespective of PD-L1 expression [13]. When surgery is conducted first, adjuvant immunotherapy is advised if PD-L1 is 50% or higher, while immunotherapy should be considered if PD-L1 is between 1% and 49%.

The treatment strategy for resectable stage III NSCLC is highly complex, incorporating options such as adjuvant targeted therapy, adjuvant immunotherapy, and neoadjuvant chemoimmunotherapy followed by surgery, with or without further adjuvant therapy, all of which are supported by clinical guidelines. When comparing adjuvant trials, osimertinib has demonstrated a significantly reduced HR for both disease-free and overall survival when compared to adjuvant atezolizumab or pembrolizumab. Consequently, all three guidelines favor adjuvant osimertinib or alectinib following surgery over adjuvant atezolizumab. Regarding neoadjuvant therapy, the ASCO guidelines recommend neoadjuvant chemoimmunotherapy, neoadjuvant chemotherapy, or neoadjuvant concurrent chemoradiation followed by surgery, instead of upfront surgery with subsequent adjuvant therapy, while the NCCN and JLCS guidelines are less explicit [11,22,42]. Given that overall survival rates for adjuvant atezolizumab and placebo are similar, yet appear to be potentially superior with neoadjuvant therapy when compared to controls, the ASCO recommendation seems justified. Nonetheless, it remains uncertain whether patients with EGFR - or ALK -altered NSCLC derive greater benefit from neoadjuvant therapy as compared to adjuvant osimertinib or alectinib. Available data indicate that overall survival is notably higher with surgery followed by adjuvant osimertinib or alectinib rather than neoadjuvant therapy followed by surgery. The IASLC endorses adjuvant osimertinib or alectinib over neoadjuvant therapy for stage 2 or 3 EGFR - or ALK -altered NSCLC [13].

Several studies have demonstrated an improvement in survival with treatment following definitive chemoradiotherapy for stage III disease. Durvalumab was the earliest to exhibit a survival benefit over placebo when administered after definitive chemoradiotherapy in patients with stage III disease, as revealed in the Global Study to Assess the Effects of MEDI4736 Following Concurrent Chemoradiation in Patients With Stage III Unresectable Non-Small Cell Lung Cancer (PACIFIC) trial [4]. Patients who underwent chemotherapy and concurrent radiotherapy for locally advanced, unresectable stage III NSCLC were randomized to receive either durvalumab or placebo for up to 12 months. The HR for disease progression or death was 0.52 (95% CI, 0.42 to 0.65; p<0.001). Following an extended follow-up period of 25 months, the HR for death was 0.68 (95% CI, 0.47 to 0.997; p=0.0025) [45]. More recently, long-term 5-year survival data have been reported [46]. These updated results showed an OS stratified HR of 0.72 (95% CI, 0.59 to 0.89; median, 47.5 months vs. 29.1 months) and PFS stratified HR of 0.55 (95% CI, 0.45 to 0.68; median, 16.9 months vs. 5.6 months), aligning well with the initial findings. The estimated 5-year overall survival rates for durvalumab and placebo were 42.9% and 33.4%, respectively, while the estimated 5-year PFS rates were 33.1% and 19.0%. Additionally, an exploratory post hoc subgroup analysis indicated an HR for death of 0.61 (95% CI, 0.44 to 0.85) in NSCLC patients with PD-L1 expression of 1% or higher and 1.15 (95% CI, 0.75 to 1.75) with less than 1%. No conclusions were drawn for patients with EGFR - or ALK - altered NSCLC, as only 29 out of 476 patients (6.1%) treated with durvalumab exhibited known alterations. Durvalumab is currently approved by the FDA, EMA, and PMDA for use following definitive chemoradiotherapy in the treatment of locally advanced, unresectable stage III NSCLC.

Recent publication of the LAURA trial results reveal a phase 3 study that compared osimertinib with placebo in patients with unresectable stage III EGFR -mutated NSCLC, which had not progressed during or after chemoradiotherapy [17]. Patients were required to have completed at least two cycles of platinum-based chemotherapy, either concurrent with or followed by radiation therapy of 54 to 66 Gy. The primary endpoint was PFS, evaluated by a blinded independent central review. HR for disease progression or death was 0.16 (95% CI, 0.10 to 0.24; p<0.001). Interim overall survival data, with a maturity of 20%, revealed an HR for death of 0.81 (95% CI, 0.42 to 1.56; p=0.53), indicating that longer follow-up is necessary. Subsequently, the FDA-approved osimertinib in September 2024 for the treatment of adult patients with locally advanced, unresectable stage III NSCLC harboring EGFR exon 19 deletions or L858R mutations who had not progressed during or following platinum-based chemoradiation therapy. EMA and PMDA have yet to approve osimertinib for this indication.

The publication of the LAURA study has prompted an update to the ASCO guidelines [12]. For unresectable stage III NSCLC, platinum doublet chemotherapy and concurrent radiotherapy are recommended. In jurisdictions where osimertinib is approved postchemoradiation, EGFR mutation status is critical, as osimertinib is indicated for EGFR -mutated NSCLC, whereas durvalumab is the treatment of choice for EGFR -negative NSCLC. In countries where osimertinib is not approved following chemoradiation, durvalumab remains the recommended therapy irrespective of EGFR status. However, clinicians and patients might consider abstaining from durvalumab in the PD-L1 negative subgroup, as demonstrated by a HR for death exceeding one in the PACIFIC trial [45].

Because perioperative treatment must be customized based on EGFR , ALK , and PD-L1 status, molecular testing is essential prior to making any treatment decisions (Table 3). For example, in stage IB EGFR -mutated NSCLC, adjuvant osimertinib is recommended postsurgery; hence, the EGFR test result must be available by the time the patient recovers from surgery. For stage II disease, osimertinib is advised after surgery and adjuvant chemotherapy, whereas alectinib is suggested as adjuvant therapy immediately postsurgery without additional chemotherapy. Consequently, EGFR and ALK test results should be obtained after the patient finishes adjuvant chemotherapy and surgery, respectively. If neoadjuvant therapy is under consideration for stage II disease, the status of EGFR and ALK must be established at diagnosis to formulate a treatment plan. In resectable stage III disease, multiple treatment options exist, making EGFR and ALK status crucial for decision making. Thus, patients with resectable stage III disease need to know the results of their EGFR and ALK tests at the time of diagnosis. Finally, for patients with unresectable stage III disease undergoing definitive chemoradiotherapy, osimertinib should be administered in countries where it is approved. Consequently, in such countries, a EGFR test result is necessary upon completion of chemoradiotherapy.

Whether tumors should be tested for other genes, i.e., ROS proto-oncogene 1, receptor tyrosine kinase (ROS1), BRAF V600E, MET , RET, KRAS proto-oncogene, GTPase (KRAS G12C), erb-b2 receptor tyrosine kinase 2 (ERBB2), and neurotrophic tyrosine kinase receptor (NTRK) remains uncertain. Prospective randomized trials involving EGFR -mutated, metastatic NSCLC have demonstrated that molecular targeted therapy is the most effective and safe treatment for this population, with immunotherapy not being superior to chemotherapy [47,48]. However, it may be inappropriate to generalize these findings to NSCLC with all other gene alterations. The IASLC consensus recommendations advocate for the utilization of biomarker testing beyond EGFR and ALK [13]. In countries where multi-gene testing is accessible, next-generation sequencing is preferred over single-gene testing for EGFR and ALK [49]. The decision to administer neoadjuvant or adjuvant chemoimmunotherapy to patients with NSCLC harboring non-EGFR/ALK driver alterations should be considered individually.

Several key areas for investigation remain open: (1) Does adjuvant targeted therapy improve cure rates? (2) Is adjuvant targeted therapy effective for NSCLC with driver oncogenes other than EGFR or ALK? (3) Should perioperative immunotherapy be withheld from patients with driver oncogene positive NSCLC? (4) Does neoadjuvant targeted therapy improve survival compared to surgery alone or surgery followed by adjuvant targeted therapy? (5) Does the addition of targeted therapy to adjuvant immunotherapy improve survival in patients with specific driver oncogene positive NSCLC, such as BRAF V600E, MET exon skipping, and KRAS G12C? (6) What is the optimal duration of adjuvant targeted therapy? (7) Does the detection of molecular residual disease help guide adjuvant treatment? Ongoing phase 3 trials are currently addressing questions (2), (4), and (6). Future trials and real-world data are necessary to resolve the remaining queries.

Osimertinib became the first targeted therapy approved for non-metastatic NSCLC, receiving FDA approval in 2020. Subsequently, in 2024, adjuvant alectinib after surgery and osimertinib following definitive chemoradiotherapy were approved for stage II-IIIA and stage III disease, respectively. These approvals highlight that targeted therapies enhance survival rates in patients with non-metastatic NSCLC. Molecular testing is now essential when making treatment decisions for these patients.