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Non-small cell lung cancer (NSCLC) with oncogenic driver mutations was previously deemed "forbidden territory" for immunotherapy.1 With the continuous generation of evidence, immunotherapy is expected to bring hope for such NSCLC with oncogenic driver mutations after acquired tyrosine kinase inhibitor (TKI) resistance. However, given the intricate interplay between driven mutations, targeted therapy, and immune microenvironment, the efficacy of immunotherapy in advanced NSCLC patients with diverse oncogenic driver mutations remains a topic of ongoing debate. In this context, Chinese Expert Consensus on Immunotherapy for Advanced NSCLC with Oncogenic Driver Mutations (2022 edition) was first launched in 2022 by the Society of Cancer Precision Medicine of Chinese Anti-Cancer Association and the Lung Cancer Expert Group of Chinese Medical Journals, aiming to provide standardized treatment guidance for clinical practice.2 As ongoing research delves into the application of immunotherapy to treat NSCLC harboring oncogenic driver mutations, the therapeutic paradigm for these patients continues to evolve. The expert group developed the Chinese Expert Consensus on Immunotherapy for Advanced non-small cell lung cancer with Oncogenic Driver Gene Mutations (2023 edition). This updated consensus integrates the latest evidence and clinical experiences to accurately reflect the research progress of immunotherapy in this field and its implication for clinical practice. The expert panel conducted in-depth discussion on current evidence and clinical experience to formulate the consensus, which comprehended tumor microenvironment and clinical evidence of immunotherapy for NSCLC with mutations of eight driver genes, including EGFR, ALK, BRAF, KRAS, ROS1, RET, MET, and HER-2. Eventually, 10 expert consensuses were developed to provide guidance for immunotherapy in these patients in terms of pathological testing, population selection, treatment regimen selection, safety management, and other aspects. The level of consensuses recommendation was determined by the consistency of expert panel voting Table 1, detailed information in the Supplementary File, https://links.lww.com/CM9/B932. Table 1 - Recommendations for immunotherapy of advanced NSCLC with oncogenic driver mutations. Recommendation items Recommendation level EGFR mutations Consensus opinion 1: ICIs are not recommended for treatment-naïve advanced NSCLC patients with EGFR-sensitive mutations. Consistent NSCLC with EGFR-sensitive mutations is usually associated with a low immunogenicity and non-inflammatory TME. Early-phase clinical trials have demonstrated that ICIs with or without chemotherapy are less effective than conventional standard target therapy in treatment-naïve advanced NSCLC patients with EGFR-sensitive mutations. In addition, ICIs plus EGFR-TKIs show limited efficacy but induced significant safety risks. Consensus opinion 2: Re-biopsy is recommended for advanced NSCLC patients after resistance to the EGFR-TKIs, and both drug-resistance driver genes and TME-related biomarkers should be included. Consistent Based on the impact of EGFR-TKIs on tumor and TME, re-biopsy should be performed under appropriate conditions. In this case, clinical experts and pathologists should jointly develop detection plan according to the patients' and specimens' conditions to provide the subsequent precision treatment options for patients. Tumor tissues were preferred for testing gene mutations and biomarkers, while other specimens like blood, serous effusion, and cerebrospinal fluid might replace the tissue specimens when they were unavailable for testing. High-throughput screening assays are preferred to obtain comprehensive information regarding drug-resistance, including tumor and TME-related biomarkers. Consensus opinion 3: ICIs-based treatments options are recommended for advanced NSCLC patients with extensive progression after resistance to the EGFR-TKIs and in the absence of effective targeted or conventional therapy. Consistent Patients' physical status should be considered together with disease progression patterns and risk factors for to select the optimal ICI-based treatment. 3.1 Patients can benefit from ICIs plus chemotherapy plus anti-angiogenesis therapy. Strong 3.2 ICIs plus platinum-based chemotherapy showed favorable efficacy in multiple studies and were better tolerated than ICIs plus platinum-based chemotherapy and anti-angiogenesis therapy. Strong 3.3 Patients with disease progression or intolerance to chemotherapy could benefit from ICIs plus anti-angiogenesis therapy. Strong ALK fusions Consensus opinion 4: ICIs are not recommended for treatment-naïve advanced NSCLC patients with ALK fusions. Consistent NSCLC with ALK fusions is generally associated with a low immunogenicity and a non-inflammatory TME. Several early-phase studies have shown the limited efficacy of ICIs plus ALK-TKIs in the treatment of patients with ALK fusion-positive NSCLC, of which crizotinib or ceritinib in combination with ICIs could raise safety risks. Consensus opinion 5: ICIs are not recommended for advanced NSCLC patients with resistance to ALK-TKIs Weak ALK-TKIs have shown a complex regulatory effect on the TME of NSCLC and reduce tumor immunogenicity. However, there is little evidence-based support of ICIs treatment in NSCLC patients with resistance to ALK-TKIs. The current research data only suggest that immunotherapy is ineffective in treating NSCLC patients with resistance to ALK-TKIs. KRAS mutations Consensus opinion 6: ICIs-based treatments are recommended for advanced KRAS-mutated NSCLC patients. Consistent NSCLC with KRAS mutations is frequently associated with a high immunogenicity and an inflammatory microenvironment. NSCLC patients with KRAS mutations can benefit from ICIs with or without chemotherapy ± bevacizumab compared to chemotherapy alone, regardless of the treatment lines. Besides, NSCLC patients with drug-resistant STK11 or KEAP1 co-mutations may also benefit from immunotherapy. Nevertheless, KRASG12C inhibitors are not yet available in China. Anyway, ICIs-based treatment is recommended for KRAS-mutated NSCLC patients. BRAF mutations Consensus opinion 7: ICIs-based treatments are recommended as the first-line treatment for advanced NSCLC patients with BRAF non-V600 mutations. It is recommended for NSCLC patients with BRAF V600 mutations when the targeted therapy is inaccessible or extensive progression occurs after resistance to targeted therapy. Strong BRAF mutations, particularly non-V600E mutations, are frequently associated with a high tumor immunogenicity and an inflammatory microenvironment. Several retrospective studies have shown that patients with BRAF mutations may benefit from the ICIs therapy. HER-2 mutations Consensus opinion 8: ICIs-based treatments are recommended for advanced NSCLC patients with HER-2 mutations. Weak NSCLC with HER-2 mutations is highly immunogenic with a complex and heterogeneous TME. Various retrospective, small-sample studies have suggested that HER-2 mutated NSCLC might benefit from ICIs-based therapy; however, more studies are needed to validate the point. MET exon 14 skipping mutations Consensus opinion 9: ICIs-based treatments are recommended for advanced NSCLC patients with MET exon 14 skipping after resistance to targeted therapy. Weak NSCLC with MET exon 14 skipping mutations shows a low immunogenicity with a complex and heterogeneous TME. Some NSCLC patients show an inflammatory microenvironment. Multiple small-sample, retrospective studies have suggested that MET exon 14 skipping-positive NSCLCs might benefit from ICIs-based therapeutic strategies, although future studies are needed to validate these findings and provide more evidence-based medicine. Safety management Consensus opinion 10: The concomitant use of EGFR-TKIs or ALK-TKIs with ICIs is not recommended due to high safety risk. However, the safety issues observed in these early-phase studies of MET-TKIs plus KRASG12C inhibitors plus ICIs need further validation. The sequential use of the targeted therapy followed by ICIs should focus on the "washout" period to avoid potentially additive adverse events. The washout period should be set based on the half-life of the precursor drug, organ recovery, and disease progression to balance safety and efficacy. In conclusion, immunotherapy in advanced NSCLC patients with high-risk conditions should be cautious and require multidisciplinary evaluation and close monitoring. Consistent Recommendation level: Consistent: 100% of experts reached consensus; Strong: 75–99% of experts reached consensus; Weak: 50–74% of experts reached consensus; No recommendation: <50% of experts reached an agreement. ALK: Anaplastic lymphoma kinase; BRAF: V-raf murine sarcoma viral oncogene homolog B1; EGFR: Epidermal growth factor receptor; HER-2: Human epidermal growth factor receptor-2; ICIs: Immune checkpoint inhibitors; KRAS: Kirsten rat sarcoma virus; MET: Mesenchymal-epithelial transition; NSCLC: Non-small cell lung cancer; TME: Tumor microenvironment; TKIs: Tyrosine kinase inhibitors. However, many questions remain to be solved regarding immunotherapy in NSCLC patients with oncogenic driver mutations. Although its favorable anti-tumor efficacy has been observed in multiple treatments of EGFR-TKI resistant NSCLC, it is vital to subdivide patients to match with the best treatment options and achieve precise treatment. Immunotherapy for rare and uncommon mutations has received increasing attention, but the current studies are small-sample sized, retrospective studies, and high-level evidence is needed. In addition, the mechanism of hyper-progressive disease, the susceptible population, and coping strategies of NSCLC with oncogenic driver mutations receiving immunotherapy deserve to be explored in depth. It is hoped that more evidence will be available in future to answer these questions, and expert group will continue to update and enrich this consensus to better reflect the updating of clinical treatment concepts and the rapid development of clinical practice in immunotherapy for NSCLC with oncogenic driver mutations. Consultant experts Ying Cheng, Jilin Cancer Hospital; Weimin Li, West China Hospital of Sichuan University. Expert team leader Baohui Han, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine. Writing author Hua Zhong, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine. Expert members (in alphabetical order by last name) Lejie Cao (Anhui Provincial Hospital); Yuan Chen (Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology); Tianqing Chu (Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine); Jiuwei Cui (The First Affiliated Hospital of Jilin University); Liren Ding (The Second Affiliated Hospital of Zhejiang University School of Medicine); Qisen Guo (Shandong Cancer Hospital); Baohui Han (Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine); Yuchen Han (Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine); Jie Hu (Zhongshan Hospital, Fudan University); Cheng Huang (Fujian Cancer Hospital); Meijuan Huang (West China Hospital of Sichuan University); Kai Li (Tianjin Medicine University Cancer Institute and Hospital); Manxiang Li (The First Affiliated Hospital of Xian Jiaotong University); Mengxia Li (Army Medical Center of PLA); Wei Li (The First Affiliated Hospital of Bengbu Medical College); Weifeng Li (The General Hospital of Southern War Zone); Xingya Li (The First Affiliated Hospital of Zhengzhou University); Wangjun Liao (Nanfang hospital of Southern Medical University); Dongmei Lin (Beijing University Cancer Hospital); Anwen Liu (The Second Affiliated Hospital of Nanchang University); Jiwei Liu (The First Affiliated Hospital of Dalian Medical University); Lihua Liu (The Fourth Hospital of Hebei Medical University); Ying Liu (Jilin Cancer Hospital); Jun Lu (Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine); Xuezhen Ma (Qingdao Central Hospital); Jianzhen Shan (The First Affiliated Hospital of Zhejiang University School of Medicine); Meiqi Shi (Jiangsu Cancer Hospital); Yongqian Shu (Jiangsu Provincial Hospital); Xia Song (Shanxi Cancer Hospital); Yong Song (The General Hospital of Eastern War Zone); Chunxia Su (Shanghai Pulmonary Hospital, Tongji University); Panwen Tian (West China Hospital of Sichuan University); Jialei Wang (Fudan University Shanghai Cancer Center); Kai Wang (The Fourth Affiliated Hospital of Zhejiang University School of Medicine); Weibo Wang (Shandong Provincial Hospital); Yan Wang (Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College); Ziping Wang (Beijing University Cancer Hospital); Jianming Ying (Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College); Qitao Yu (The Affiliated Cancer Hospital of Guangxi Medical University); Zhuang Yu (The Affiliated Hospital of Qingdao University); Xinmin Yu (Cancer Hospital Affiliated of University of Chinese Academy of Sciences); Jian Zhang (Xijing Hospital); Xueyan Zhang (Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine); Mingfang Zhao (The First Affiliated Hospital of China Medical University); Yanqiu Zhao (The Affiliated Cancer Hospital of Zhengzhou University); Diansheng Zhong (Tianjin Medical University General Hospital); Hua Zhong (Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine); Runbo Zhong (Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine); Chengzhi Zhou (The First Affiliated Hospital of Guangzhou Medical University); Qinghua Zhou (West China Hospital of Sichuan University); Li Zhuang (Yunnan Cancer Hospital). Academic secretariat Runbo Zhong, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine. Conflicts of interest None.
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