Postoperative adjuvant therapy for driver gene-positive non-small-cell lung cancer patients

Clinical Question How to choose the drugs of adjuvant therapy for non-small-cell lung cancer (NSCLC) patients harboring driver gene mutation? Recommendations Recommendation 1: We suggest osimertinib (80 mg) adjuvant therapy in stage Ib–IIIa EGFR-positive (Ex19del or L858R) NSCLC patients after surgery. According to the results of the ADAURA study, the benefit of osimertinib administration increases with advancing tumor stage. (Strong recommendation, high certainty of evidence) Recommendation 2: We suggest alectinib (600 mg) adjuvant therapy in stage Ib–IIIa ALK-positive NSCLC patients after surgery. (Strong recommendation, high certainty of evidence) Recommendation 3: We suggest atezolizumab (1200 mg) adjuvant therapy in stage II–IIIa KRAS-positive NSCLC patients after surgery, plus 4 cycles of platinum-based chemotherapy. (Weak recommendation, low certainty of evidence) Grading criteria for the quality of evidence and strength of recommendations can be found in Supplementary Table 1, https://links.lww.com/CM9/C612. Recommendation Descriptions There is an increasing number of prospective clinical studies on adjuvant therapy for driver gene-positive NSCLC, with most being phase III multi-center clinical trials. For specific driver gene inhibitors, such as those targeting EGFR, ALK, ROS1, KRAS, and MET, we conducted a search across several databases, including Web of Science, PubMed, Cochrane, Embase, CNKI, and Wanfang data. A total of 563 studies were retrieved, of which 7 met the inclusion criteria—6 were prospective clinical studies, and 1 was a retrospective study. (1)Osimertinib in resected EGFR-mutated NSCLC. In 2020, Wu et al[1] conducted the ADAURA study, a double-blind, global multicenter, randomized controlled clinical trial, to evaluate the efficacy and safety of osimertinib as an adjuvant treatment for patients with EGFR-mutated NSCLC. The study enrolled stage Ib–IIIa postoperative patients with EGFR (Ex19del or L858R) mutations. Participants were randomly assigned in a 1:1 ratio to receive either osimertinib (80 mg, QD) or a placebo. The primary endpoint was disease-free survival (DFS) among patients with stage II to IIIA disease as assessed by investigators, with secondary endpoints, including DFS, overall survival (OS), and safety in patients with stage Ib–IIIa disease. A total of 682 patients were randomized, with 339 in the osimertinib group and 343 in the placebo group. After 24 months of adjuvant therapy, 90% of patients with stage II to IIIa in the osimertinib group (95% confidence interval [CI], 84–93%) and 44% in the placebo group (95% CI, 37–51%) were alive and disease-free (hazard ratio [HR] for disease recurrence or death, 0.17; 99.06% CI, 0.11–0.26; P <0.001). In the overall population, 89% of patients in the osimertinib group (95% CI, 85–92%) and 52% in the placebo group (95% CI, 46–58%) were alive and disease-free at 24 months (HR for disease recurrence or death, 0.20; 99.12% CI, 0.14–0.30; P <0.001). Additionally, 98% of patients in the osimertinib group (95% CI, 95–99%) and 85% in the placebo group (95% CI, 80–89%) were alive and free of central nervous system (CNS) metastasis at 24 months (HR for disease recurrence or death, 0.18; 95% CI, 0.10–0.33). OS data were incomplete, with 29 patients dying at the cut-off date (9 in the osimertinib group and 20 in the placebo group). No new safety concerns emerged during the trial. Collectively, in patients with stage Ib to IIIa EGFR-mutated NSCLC, DFS was significantly longer in those receiving osimertinib adjuvant therapy compared to those receiving a placebo. (2)Postoperative chemotherapy use and outcomes from ADAURA: Osimertinib as adjuvant therapy for resected EGFR-mutated NSCLC. In 2022, Wu et al[2] reported an exploratory analysis of adjuvant chemotherapy trials and outcomes based on the ADAURA study. The study enrolled patients with resected stage Ib to IIIa EGFR-mutated NSCLC, who were then randomly assigned in a 1:1 ratio to receive either osimertinib or a placebo for 3 years. Adjuvant chemotherapy prior to randomization was not mandatory and was administered based on the physician’s and patient’s choice. DFS in the general population (Ib–IIIa), with or without adjuvant chemotherapy, was a pre-specified analysis. The exploratory analysis also examined the effects of patient age, disease stage, and geographical location on adjuvant chemotherapy use, as well as the association between DFS and adjuvant chemotherapy use and disease stage. Results showed that out of the 682 patients, 410 (60%) received adjuvant chemotherapy (osimertinib group: n = 203; placebo group: n = 207), with a median duration of 4.0 cycles. Adjuvant chemotherapy was more frequently administered to patients younger than 70 years of age (338 of 509; 66%) compared to those aged 70 years or older (72 of 173; 42%); in patients with stages II to IIIa (352 of 466; 76%) compared to those with stage Ib (57 of 216; 26%); and in patients registered in Asia (268 of 414; 65%) compared to those outside Asia (142 of 268; 53%). In patients who did not receive adjuvant chemotherapy, DFS was superior with osimertinib compared to placebo, regardless of disease stage (DFS HR = 0.23, 95% CI: 0.13–0.40; DFS HR = 0.16, 95% CI: 0.10–0.26, respectively). Overall, these results support osimertinib as an effective adjuvant therapy for patients with stage Ib to IIIa EGFR-mutated NSCLC after resection, with or without prior adjuvant chemotherapy. (3)Adjuvant osimertinib for resected EGFR-mutated stage IB–IIIA NSCLC: Updated results from the phase III randomized ADAURA trial. In 2023, Herbst et al[3] updated the data from the ADAURA study. At the data cut-off date (April 11, 2022), the median follow-up for stage II–IIIa disease was 44.2 months for the osimertinib group and 19.6 months for the placebo group. The DFS HR was 0.23 (95% CI, 0.18–0.30). The 4-year DFS rate was 70% for the osimertinib group and 29% for the placebo group. In the general population, the DFS HR was 0.27 (95% CI, 0.21–0.34), with a 4-year DFS rate of 73% for the osimertinib group and 38% for the placebo group. Patients treated with osimertinib experienced fewer local/regional and distant relapses compared to those receiving a placebo. The CNS DFS HR for stage II–IIIa disease was 0.24 (95% CI, 0.14–0.42). The long-term safety profile of osimertinib remained consistent with earlier analyses. Overall, these updated data suggest that adjuvant osimertinib significantly prolongs DFS compared with placebo, reduces the risk of local and distant recurrence, improves CNS DFS, and maintains a favorable safety profile, supporting its efficacy as an adjuvant treatment in resected EGFR-mutated NSCLC. (4)Overall survival with osimertinib in resected EGFR-mutated NSCLC. In 2023, Tsuboi et al[4] reported the OS results from the ADAURA study. Of the 682 EGFR-mutated NSCLC patients randomized, 339 received osimertinib adjuvant therapy and 343 received a placebo. Among patients with stage II to IIIa disease, the 5-year OS rate was 85% in the osimertinib group compared to 73% in the placebo group (overall mortality HR 0.49; 95.03% CI, 0.33–0.73; P <0.001). In the overall population (stage Ib–IIIa), the 5-year OS rate was 88% in the osimertinib group and 78% in the placebo group (overall mortality HR 0.49; 95.03% CI, 0.34–0.70; P <0.001). After the previously published data cutoff, a new serious adverse event (AE), pneumonia associated with COVID-19, was reported; however, investigators determined that the event was unrelated to the trial protocol, and the patient made a full recovery. The safety profile of adjuvant osimertinib remained consistent with earlier analyses. Collectively, adjuvant osimertinib provides a significant OS benefit for patients with stage Ib to IIIa EGFR-mutated NSCLC following complete resection. (5)Three-year safety, tolerability, and health-related quality of life outcomes of adjuvant osimertinib in patients with resected stage IB to IIIA EGFR-mutated NSCLC: Updated analysis from the phase 3 ADAURA trial. In 2023, John et al[5] reported results from the ADAURA study, designed to evaluate the safety, tolerability, and quality of life (QoL) associated with osimertinib as adjuvant therapy in patients with EGFR-mutated NSCLC at a 3-year follow-up. The study randomized patients with resected EGFR-mutated NSCLC to receive either 80 mg of osimertinib or a placebo once daily for 3 years in a 1:1 ratio. Safety assessments were conducted at baseline, at weeks 2, 4, and 12, and every 12 weeks thereafter until the completion or discontinuation of treatment, with an additional assessment 28 days post-discontinuation. Health-related quality of life (HRQoL) was measured using the SF-36 survey at baseline, week 12, week 24, and every 24 weeks until relapse, treatment completion, or discontinuation. The data cutoff was April 11, 2022. Safety and HRQoL analysis included 337 and 339 patients in the osimertinib group, and 343 patients in the placebo group. The median total exposure time was longer in the osimertinib group compared to the placebo group: 35.8 (range 0–38) months versus 25.1 (range 0–39) months. Most AEs were reported within the first 12 months of treatment (97% in the osimertinib group versus 86% in the placebo group). AEs leading to dose reduction, interruption, or discontinuation occurred in 12%, 27%, and 13% of patients in the osimertinib group, respectively, compared to 1%, 13%, and 3% in the placebo group. Stomatitis and diarrhea were the most common adverse reactions leading to dose reduction or interruption of osimertinib, while interstitial lung disease was the most common cause of osimertinib discontinuation (as per protocol). There was no significant difference between osimertinib and placebo in the time to deterioration of the physical and psychological components of the SF-36 survey. Overall, combined with the observed efficacy benefits, these data further support the use of osimertinib as adjuvant therapy in patients with stage Ib to IIIa EGFR-mutated NSCLC. (6)Alectinib in resected ALK-positive NSCLC. In 2024, Wu et al[6] conducted the ALINA study, a global, multicenter, double-blind, randomized controlled trial, to evaluate the efficacy and safety of alectinib as postoperative adjuvant therapy in patients with ALK-positive NSCLC. In the clinical study, patients with completely resected ALK-positive stage Ib (tumors ≥4 cm), stage II, or IIIa NSCLC, were randomly assigned in a 1:1 ratio to receive either alectinib (600 mg, BID) for 24 months or 4 cycles of platinum-based chemotherapy. The primary endpoint was DFS, which was first stratified in patients with stage II or IIIa disease and then tested in the intention-to-treat (ITT) population. Secondary endpoints included CNS DFS, OS, and safety. A total of 257 patients were randomly assigned to receive alectinib (130 patients) or chemotherapy (127 patients). Among patients with stage II or IIIa disease, the 2-year survival and DFS rates were 93.8% in the alectinib group and 63.0% in the chemotherapy group (HR for disease recurrence or death: 0.24; 95% CI, 0.13–0.45; P <0.001). In the ITT population, the rates were 93.6% and 63.7%, respectively (HR: 0.24; 95% CI, 0.13–0.43; P <0.001). Alectinib also showed significant clinical benefit in CNS DFS compared to chemotherapy (HR for CNS disease recurrence or death: 0.22; 95% CI, 0.08–0.58). The OS data are still immature, and no unexpected safety events have been observed. Collectively, compared with platinum-based chemotherapy, adjuvant alectinib therapy for stage Ib–IIIa ALK-positive NSCLC provides significantly longer DFS. (7)IMpower010: Exploratory analysis of DFS by KRAS status in patients with stage II–IIIA NSCLC treated with adjuvant atezolizumab vs. best supportive care (BSC). A retrospective analysis of the IMpower010 phase III clinical trial, conducted by Reck et al[7] and presented at the 2023 ASCO Meeting, was designed to evaluate the efficacy of postoperative adjuvant atezolizumab immunotherapy in patients with stage II–IIIa NSCLC who have PD-L1 expression ≥1% or ≥50% and KRAS mutations. The study involved patients with completely resected KRAS-mutated NSCLC who had received cisplatin-based chemotherapy (1–4 cycles, 21 days per cycle), followed by randomization to either atezolizumab (1200 mg, Q3W, up to 16 cycles) or BSC. This post hoc analysis specifically assessed DFS in subgroups of patients based on their KRAS mutation status. Whole-exome sequencing (WES) was used to retrospectively evaluate KRAS mutation status in the resected tumor tissues, including all KRAS mutation types, such as KRASG12C. However, due to the limited number of patients, a separate analysis for the KRASG12C subgroup was not conducted. Of the 1005 ITT patients (all stage Ib–IIIa NSCLC), 603 were part of the WES Biomarker Evaluable Population (WES-BEP), which included 536 patients with stage II–IIIa NSCLC. Among these, the prevalence of KRAS mutations and KRASG12C mutations in stage II–IIIa WES-BEP was 22% (n = 118) and 10% (n = 52), respectively. KRAS mutations were predominantly found in white, non-squamous, and smoking populations. In the stage II–IIIa WES-BEP, atezolizumab demonstrated an improvement in DFS compared to BSC, regardless of KRAS mutation status. Similarly, in the KRAS-mutant stage II–IIIa WES-BEP, atezolizumab improved DFS compared to BSC, irrespective of PD-L1 status. In the IMpower010 trial, the prevalence of KRAS mutations and KRASG12C in resected NSCLC was similar to that observed in metastatic NSCLC. Although the exploratory analysis was limited by a small patient population, the DFS benefits appeared consistent across KRAS status, supporting the use of atezolizumab therapy in these subgroups. Expert committee Baohui Han (Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine), Charles A. Powell (Icahn School of Medicine at Mount Sinai), Chunlin Zhuang (School of Pharmacy, Second Military Medical University), Desheng Lyu (The Second Hospital of Dalian Medical University), Haipeng Liu (Shanghai Pulmonary Hospital, Tongji University School of Medicine), Jianchun Duan (Chinese Academy of Medical Sciences and Peking Union Medical College), Jie Hu (Zhongshan Hospital, Fudan University), Jinxin Bei (Sun Yat-sen University Cancer Center), Jun Lu (Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine), Lijuan Zou (The Second Hospital of Dalian Medical University), Liufu Deng (Shanghai Jiao Tong University School of Medicine), Nan Bi (Chinese Academy of Medical Sciences and Peking Union Medical College), Ni Li (Chinese Academy of Medical Sciences and Peking Union Medical College), Peng Zhang (Shanghai Pulmonary Hospital, Tongji University School of Medicine), Qi Wang (The Second Hospital of Dalian Medical University), Rong Yin (Jiangsu Cancer Hospital), Shiyong Sun (School of Medicine and Winship Cancer Institute, Emory University), Tangfeng Lyu (Jinling Hospital, Medical School of Nanjing University), Tao Jiang (Shanghai Pulmonary Hospital, Tongji University School of Medicine), Wenzhao Zhong (Guangdong Provincial People’s Hospital), Xiaowu Deng (Sun Yat-sen University Cancer Center), Yang Jin (Union Hospital, Huazhong University of Science and Technology), Ying Shen (Shanghai Jiao Tong University School of Medicine), Yong He (Daping Hospital), Yongqian Shu (Jiangsu Province Hospital) Writing Group Jun Lu (Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine) Conflicts of interest None.