Interpretation of expert consensus on treatment for stage III non‐small cell lung cancer

Abstract

Stage III non-small cell lung cancer (NSCLC) encompasses a group of diseases with high heterogeneity. Currently, it is considered that both staging and optimal treatment of stage III NSCLC require the joint work of a multidisciplinary team (MDT) of expert physicians within the tumor committee. With the advent of precision therapy, targeted therapy and immunotherapy provide more novel options for patients with stage III NSCLC. However, the management of stage III NSCLC remains complex and controversial, with a myriad of potentially feasible options. At present, the management of stage III NSCLC does not satisfy medical needs, and consistent progress and breakthroughs are urgently needed in standardized diagnosis and treatment strategies. Moreover, the unique demographics of Chinese NSCLC pose further challenges when applying clinical trial data into clinical practice. This includes differences in smoking rates, prevalence of oncogenic driver mutations, and access to health care resources [1, 2]. In view of the above situation, after in-depth communications and discussions, experts on lung cancer clinical research, transformational research, and basic research achieved consensuses about the multidisciplinary comprehensive treatment and biomarkers for resectable and unresectable stage III NSCLC at the 19th lung cancer summit and issued Expert Consensus on Treatment for Stage III Non-Small Cell Lung Cancer on June 15, 2022 [3]. The consensus provides recommendations in the following six respects: (1) Redefining the definition of “resectability”; (2) adjuvant targeted therapy for stage III NSCLC patients; (3) adjuvant immunotherapy for wild type stage III NSCLC; (4) selection of neoadjuvant or adjuvant therapy for stage III NSCLC patients; (5) treatment options for unresectable stage III NSCLC patients; and (6) translational research on molecular residual disease (MRD). Meanwhile, the level of evidence and strength of recommendations for this consensus are described in an easy-to-understand way and in line with international standards. The consensus emphasizes the importance of MDT consultation and recommends that stage III NSCLC should be classified into one of two categories, “resectable” and “unresectable,” by MDT before the initiation of treatment. Potential resectability is defined as resectable after neoadjuvant therapy. The number of patients for whom resection is possible has been increased by improved surgical techniques and the advancement of neoadjuvant therapy. Data have suggested that stage III NSCLC patients could benefit from neoadjuvant therapy. Therefore, it is recommended that patients participate in clinical trials. As the postoperative adjuvant therapy for NSCLC has evolved from chemotherapy to precision therapy, the consensus recommends routine detection of epidermal growth factor receptor (EGFR) and programmed death-ligand 1 (PD-L1) for stage III NSCLC patients prior to treatment, allowing the possibility for precision therapy, which has not yet been recommended clearly by American Society of Clinical Oncology (ASCO)4 and European Society for Medical Oncology (ESMO)5 Guideline. ESMO5, ASCO4 and the National Comprehensive Cancer Network (NCCN)6 guidelines have given a positive answer to whether adjuvant chemotherapy is necessary after complete resection of stage III NSCLC with EGFR mutation. However, with the publication of the results of ICAN/CTONG1804, a real-world noninterventional trial and ADAURA trial, it is found that adjuvant chemotherapy is not necessary for stage III NSCLC patients with the EGFR mutation after complete resection. Unlike other guidelines that only recommend osimertinib, the consensus affirms the role of first- and third-generation EGFR tyrosine kinase inhibitors (TKIs) in postoperative adjuvant therapy and recommends that first- and third-generation EGFR-TKIs are suitable for postoperative adjuvant therapy, whereas osimertinib is preferable. Based on results of Multigene Index to Evaluate the Relative benefit of Various Adjuvant therapies (MINERVA) scoring model established by Wu Y-L et al., which showed that patients with both EGFR and retinoblastoma (RB1) mutations may benefit from adjuvant chemotherapy rather than gefitinib, the consensus uniquely proposes that adjuvant chemotherapy should be prioritized in stage III lung cancer patients with mutated RB1 and EGFR genes. The consensus recommends adjuvant immunotherapy for driver mutation-negative patients with stage III NSCLC in line with NCCN guidelines, which is different in ASCO and ESMO guidelines [4-6]. The consensus recommends that adjuvant immunotherapy should be administered after the completion of postoperative chemotherapy and should be restricted to PD-L1-positive patients, preferably for patients with PD-L1 > 50%. Stage III NSCLC patients who refuse adjuvant chemotherapy but have PD-L1 > 50% can consider receiving adjuvant immunotherapy. ADAURA and numerous other studies have demonstrated that adjuvant EGFR-TKI targeted therapy could improve disease-free survival (DFS) of resectable EGFR-mutated NSCLC patients. Meanwhile, CTONG1103 and NEOS have also shown that neoadjuvant targeted therapy could be beneficial. Therefore, the consensus proposes that patients with resectable EGFR-mutant NSCLC tend to receive adjuvant targeted therapy, whereas potentially resectable patients may consider neoadjuvant targeted therapy. For stage III NSCLC patients with negative driver genes, neoadjuvant immunotherapy has yet to be recommended by the guidelines. Based on the results of the CheckMate-816 trial, the consensus recommends that stage III NSCLC patients without driver genes tend to receive neoadjuvant immunotherapy and proposes that perioperative immunochemotherapy is the future for stage III NSCLC patients without driver genes. The previous guidelines only recommended immune checkpoint inhibitor (ICI) consolidation therapy after concurrent chemoradiotherapy for patients with stage III NSCLC. With the publication of GEMSTONE-301 trial, the consensus recommends ICI consolidation therapy not only after concurrent chemoradiotherapy but also after sequential chemoradiotherapy. The consensus recommends strongly sugemalimab consolidation immunotherapy after concurrent or sequential chemoradiotherapy in patients with stage III NSCLC. Circulating tumor Deoxyribo Nucleic Acid (ctDNA)-MRD is first introduced in a consensus on treatment for stage III NSCLC. It recommends ctDNA used as a biomarker of MRD for prognostic prediction. Adjuvant therapy is recommended for MRD-positive patients by ctDNA analysis after definitive treatment. There are still some limitations in the consensus: (1) many issues were not discussed, such as diagnosis, follow-up, how to choose concurrent chemoradiotherapy, sequential chemoradiotherapy and radiotherapy for unresectable stage III NSCLC, how to choose adjuvant chemotherapy, etc. and (2) some recommendations first proposed by consensus need to be further verified in the future. In conclusion, the release of the consensus is of great significance to clinical practice, doctors, and patients: (1) promoting the standardization of precision diagnosis and treatment in patients with stage III NSCLC in China; (2) providing more practical guidance for clinicians; and (3) establishing the optimal diagnosis and treatment plan for patients, and ultimately leading to longer survival and better quality of life. Conception and design: All authors. Collection and assembly of data: Weichi Luo, Qing Zhou. Data analysis and interpretation: Weichi Luo, Qing Zhou. Manuscript writing: All authors. Final approval of manuscript: All authors. Accountable for all aspects of the work: All authors. None. Qing Zhou: Lecture and presentation fees from AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, MSD, Pfizer, Roche, and Sanofi outside the submitted work. Not applicable. Not applicable. Not applicable.