Editor’s Note: The 2024 CACA Integrated Lung Cancer Conference, hosted by the Chinese Anti-Cancer Association and the Chinese Anti-Cancer Association’s Integrated Lung Cancer Committee (under preparation), was held in Zhuhai on October 25–26, 2024. With the theme “Uniting Efforts, Leading the Future,” the conference gathered leading domestic experts and scholars in the field of pulmonary tumors for in-depth and broad academic exchanges on hot and challenging topics related to lung cancer. During the conference, Oncology Frontier invited Dr. Gen Lin from the Cancer Center of Beijing Chest Hospital, Capital Medical University, for an exclusive interview. Professor Lin shared insights into the current clinical practice of immunotherapy for non-small cell lung cancer (NSCLC) and progress in strategies to address secondary resistance in immunotherapy.

Oncology Frontier: In recent years, immunotherapy, represented by immune checkpoint inhibitors (ICIs), has developed rapidly. The exploration of both monotherapy and various combination treatment models has delivered groundbreaking results, reshaping the treatment landscape for advanced NSCLC. Could you first introduce the current clinical practice of immunotherapy in advanced NSCLC?

Dr. Gen Lin: Indeed, immunotherapy has reshaped the treatment paradigm for advanced NSCLC in several key aspects. For patients with driver gene-negative lung adenocarcinoma or squamous cell carcinoma, chemo-immunotherapy has become the first-line standard treatment. Patients with high PD-L1 expression (PD-L1 ≥ 50%) can achieve excellent outcomes with PD-1/L1 inhibitors as monotherapy. Moreover, dual-immunotherapy regimens have also shown outstanding performance in clinical practice. For second-line treatment, immunotherapy is an excellent option for patients who have not previously received it. This demonstrates that immunotherapy has become a cornerstone of treatment for such patients.

For patients with driver gene-positive NSCLC, there is still an opportunity for immunotherapy, especially after resistance to targeted therapies. For instance, patients resistant to third-generation EGFR inhibitors can opt for chemo-immunotherapy with or without anti-angiogenic agents. Thus, high-level evidence-based medicine has established a robust foundation for clinical practice in this patient group.

Oncology Frontier: Immunotherapy has become the standard first-line treatment for driver gene-negative advanced NSCLC. However, resistance remains an inevitable challenge. Could you share the current clinical strategies to address resistance to immunotherapy and any recent advancements in this area?

Dr. Gen Lin: Secondary resistance to immunotherapy is a persistent clinical challenge, and there is currently no standard treatment strategy. The lack of a unified definition of secondary resistance to immunotherapy complicates the issue. Three major international consensus guidelines provide differing definitions. In 2020, the Society for Immunotherapy of Cancer (SITC) defined primary and acquired resistance to ICIs in advanced cancers. In 2021, the European Society for Medical Oncology (ESMO) updated its clinical definitions of acquired resistance in NSCLC immunotherapy. In 2022, Chinese clinical experts formulated the Consensus on the Clinical Definition of Secondary Resistance to NSCLC Immunotherapy to address this issue.

The lack of standardization underscores the importance of establishing consistent criteria for identifying secondary resistance to immunotherapy in various clinical scenarios. A key question is how long after discontinuing immunotherapy due to various reasons can disease progression be classified as secondary resistance. According to SITC guidelines, discontinuation for more than three months qualifies as secondary resistance, while ESMO and the Chinese consensus require a minimum of six months. From an evidence-based perspective, patients discontinuing immunotherapy for over six months might experience disease progression due to pharmacokinetic-related loss of drug efficacy, allowing for potential rechallenge with immunotherapy. Progression following rechallenge would then qualify as secondary resistance. Conversely, disease progression within six months of discontinuation is unlikely to respond to further immunotherapy, making the six-month threshold a critical parameter.

Another challenge is defining secondary resistance in combination regimens, now the standard first-line treatment. SITC guidelines state that patients achieving a progression-free survival (PFS) of over six months with combination therapy are classified as benefiting, and disease progression qualifies as secondary resistance. However, this does not account for whether the benefit derived from the immunotherapy component. The Chinese consensus differs fundamentally in this regard. Patients achieving a PFS of over 18 months with first-line chemo-immunotherapy, or a PFS of over 12 months with second-line chemo-immunotherapy, are considered to have benefited primarily from immunotherapy. These thresholds minimize misclassification of patients with primary resistance, significantly improving the accuracy of identifying secondary resistance.

Translating research on secondary resistance into clinical practice requires three essential components: mechanistic understanding, biomarker identification, and therapeutic development. Mechanistic studies have made notable progress, focusing primarily on tumor antigen loss or alterations and defects in antigen presentation pathways. Additionally, increased expression of co-inhibitory molecules such as TIM-3, LAG-3, and VISTA on T cells hampers their ability to recognize and attack tumors, contributing to resistance. This raises an important question: how does secondary resistance to immunotherapy differ from that in targeted therapy? Targeted therapies act on key molecular pathways within tumor cells, with resistance often resulting from reactivation of downstream signaling. Immunotherapy, on the other hand, relies on the PD-1/PD-L1 pathway to activate immune cells, enhancing anti-tumor responses. Resistance mechanisms in immunotherapy thus primarily involve T cells, including their failure to recognize or kill tumors, or their exhaustion. Future research must delve deeper into these mechanisms, focusing on T cells as well as macrophages and NK cells.

Oncology Frontier: Precision immunotherapy strategies tailored to the patient’s immunogenomic profile are essential for achieving personalized treatment. What are the key considerations for implementing standardized personalized immunotherapy in clinical practice?

Dr. Gen Lin: Standardized precision immunotherapy strategies must be rooted in evidence-based medicine. For advanced NSCLC patients, first-line monotherapy choices typically depend on PD-L1 expression, followed by tumor mutational burden (TMB). Patients with PD-L1 ≥ 1% may benefit from monotherapy, while those with high TMB have shown greater responses to immunotherapy. Microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) status also serves as reliable biomarkers for monotherapy benefit. However, these biomarkers are not yet effective for evaluating benefits from combination therapies. At present, chemo-immunotherapy is a standard treatment option for all patients based on evidence, though it falls short of the precision required for personalized immunotherapy.

Dr. Gen Lin

• MD, PhD, Chief Physician, Doctoral Supervisor

• Director, Cancer Center, Beijing Chest Hospital, Capital Medical University

• Recognized as an Outstanding Mid-Career Expert in Fujian’s Healthcare System

• Vice Chair, Chinese Anti-Cancer Association Malignant Mesothelioma Committee

• Chair, Lung Cancer Committee, CSWOG

• Vice Chair, CSCO Patient Education Committee

• Standing Committee Member, CSCO Immunotherapy Expert Committee

• Standing Committee Member, CSCO Neuro-Oncology Expert Committee