Editor's Note: Treating locally advanced lung cancer is a significant clinical challenge, with perioperative treatment being key to improving patient outcomes. At the 2024 International Lung Cancer Conference (CLC 2024), Dr. Wentao Fang from Shanghai Chest Hospital delivered a presentation titled "Neoadjuvant Therapy for Locally Advanced NSCLC." This article provides a brief overview of his report.Neoadjuvant Therapy for Locally Advanced NSCLC
The treatment of locally advanced lung cancer, particularly stage II-III resectable non-small cell lung cancer (NSCLC), remains a clinical challenge, with a 5-year survival rate that is far from optimistic. The primary obstacle to achieving long-term survival is the high rate of recurrence and metastasis. Improving patient outcomes requires advances in surgical techniques, multidisciplinary collaboration, and the development of new drugs and treatment approaches.
Traditional neoadjuvant chemotherapy has shown limited benefits for patients with resectable NSCLC. An analysis of 15 randomized controlled trials (RCTs) revealed a mere 5% improvement in 5-year survival. Similarly, studies on preoperative neoadjuvant chemoradiotherapy have not yielded successful outcomes. However, the past few years have seen breakthroughs in the treatment of resectable NSCLC, thanks to immunotherapy. Several studies have demonstrated that perioperative immunotherapy combined with chemotherapy significantly improves patient outcomes compared to traditional chemotherapy alone. Whether in neoadjuvant (CheckMate 816), adjuvant (IMpower010 and KEYNOTE-091), or “sandwich” neoadjuvant + adjuvant (AEGEAN, Neotorch, KEYNOTE-671, CheckMate 77T, and RATIONALE-315) studies, the results have been promising, with some regimens already approved for clinical use. Across these six phase III trials involving neoadjuvant immunotherapy, the effectiveness of immunotherapy combined with chemotherapy (in terms of pathological complete response [pCR] and major pathological response [MPR]) was significantly superior to chemotherapy alone. Patients receiving neoadjuvant immunotherapy + chemotherapy had higher R0 resection rates and increased proportions of minimally invasive surgery and standard lobectomy. A retrospective study published by Chinese researchers in the International Journal of Surgery also indicated that effective immunotherapy induction could reduce the extent of resection and postoperative complications, potentially preserving organ function.
Exploring Personalized, Precision Perioperative Therapy
Enhancing the efficacy of induction therapy (to reduce recurrence and improve survival) and refining surgical techniques (to make surgery safer and less invasive) are key areas of exploration in the pursuit of personalized precision therapy for NSCLC during the perioperative period. We are particularly focused on the following four critical questions:
Question 1: Should Molecular Testing Be Conducted Before Neoadjuvant Therapy?
The goal of neoadjuvant therapy is to find the most suitable treatment plan for each patient. Our team has conducted the PURPOSE trial, a clinical study on locally advanced NSCLC that is based on tumor biomarkers (such as genetic mutations and PD-L1 expression). The trial includes seven patient cohorts, as well as a real-world control cohort, with more than half of the patients already enrolled. Preliminary results suggest that selecting treatment based on tumor biomarkers significantly improves the objective response rate (ORR) compared to the real-world control group (75% vs. 41.4%). Furthermore, surgery rates, R0 resection rates, and the proportion of minimally invasive/lobectomy surgeries are all higher, with better MPR and pCR outcomes. The effectiveness of real-world induction therapy depends on whether NGS and PD-L1 testing are conducted and whether treatment is selected based on these results (Wang, Front Oncol., 2023).
For example, in patients with EGFR mutations, those with positive driver genes have difficulty benefiting from adjuvant immunotherapy. These patients show poor outcomes with neoadjuvant immunotherapy + chemotherapy, suggesting that targeted therapy ± chemotherapy may be the future direction for EGFR-mutated resectable NSCLC, pending results from the NeoADAURA study. The PURPOSE trial results also indicate that targeted induction therapy holds promise, with different therapeutic responses observed among patients with various driver gene mutations (EGFR 19del vs. 21L858R vs. other rare mutations).
Question 2: Should PD-L1 Expression Be Considered in Immunotherapy Induction?
In six phase III trials involving neoadjuvant immunotherapy (CheckMate 816, AEGEAN, Neotorch, KEYNOTE-671, CheckMate 77T, and RATIONALE-315), PD-L1 expression levels generally showed a positive correlation with pCR and partial response (PR) rates, with higher PD-L1 expression leading to better event-free survival (EFS). The PURPOSE trial found that immunotherapy combined with chemotherapy as a neoadjuvant treatment is not suitable for all patients, with unsatisfactory outcomes for those with negative PD-L1 expression.
Question 3: Should Postoperative Treatment Continue in a “Sandwich” Model?
Adjuvant immunotherapy requires biomarker guidance. Current research indicates that whether or not pCR is achieved through neoadjuvant therapy, perioperative immunotherapy + chemotherapy offers better EFS compared to chemotherapy alone. A meta-analysis published in JAMA Network Open in March 2023, which included five clinical studies (four involving neoadjuvant + adjuvant immunotherapy and one involving neoadjuvant immunotherapy alone), found that adding adjuvant immunotherapy to neoadjuvant immunotherapy did not improve EFS (HR=0.90; P=0.59) or OS (HR=1.18; P=0.51), but significantly increased the incidence of adverse events (AEs). A case from the PURPOSE study also suggests that it is difficult to guide postoperative adjuvant therapy based on whether neoadjuvant immunotherapy achieves pCR. To identify patients who may benefit from postoperative maintenance immunotherapy, MRD and ctDNA biomarkers should be used to assess prognosis and treatment efficacy.
Question 4: Exploring Treatment Options for “Unresectable” Stage III Patients
Stage III NSCLC is highly heterogeneous, with ongoing debate about the distinction between resectable and unresectable cases, leading to mixed treatment approaches. To further explore treatment options for these patients, we have initiated a patient-centered, prospective, multicenter, open-label, umbrella phase II clinical trial. The trial will include patients with unresectable stage III NSCLC, grouping them based on factors such as driver genes and immune characteristics, and further subdividing into cold and hot tumors. The trial will explore the efficacy of new drug precision therapy, and it is set to launch soon.
Conclusion: Neoadjuvant Therapy for NSCLC
Treatment for stage II-III lung cancer requires a comprehensive, surgery-based approach that emphasizes individualized precision diagnosis and treatment, rather than applying the same treatment regimen to all patients.
The optimal treatment strategy should include effective induction therapy: using better new drugs for induction treatment; exploring perioperative precision treatment based on tumor biological information.
Surgical challenges after induction therapy: Ensuring R0 resection to achieve oncological outcomes; performing meticulous surgery after effective induction treatment to increase minimally invasive rates, reduce resection extent, and improve surgical outcomes.
Dr. Wentao Fang
- Director of Thoracic Surgery, Shanghai Chest Hospital
- Director of Lung Cancer Surgery, Shanghai Chest Hospital
- Director of Esophageal Disease Center, Shanghai Jiao Tong University
- Doctoral Supervisor, Shanghai Jiao Tong University School of Medicine
- Chairman, Mediastinal Tumor Professional Committee, China Anti-Cancer Association
- Vice Chairman, Esophageal Cancer Professional Committee, China Anti-Cancer Association
- Member, Tumor Staging Committee, China Anti-Cancer Association
- Chairman, Mediastinal Tumor Expert Committee, Chinese Clinical Oncology Association
- Member, Lung Cancer Expert Group, Chinese Society for Thoracic and Cardiovascular Surgery
- Standing Committee Member and Vice Chairman, Minimally Invasive Surgery Expert Committee, Thoracic Surgery Branch, Chinese Medical Doctor Association
- Vice Chairman, Pulmonary Tumor Professional Committee, China Medical Education Association
- Member, Surgery Group, Shanghai Medical Association
