Editor's Note: Melanoma is one of the more common malignant tumors clinically. In recent years, although immunotherapy has brought new hope to melanoma patients, the issue of resistance has become increasingly prominent. At the 2024 Annual Progress Seminar of Chinese Clinical Oncology (BOC) and Beast of ASCO® 2024 China (BOC/BOA 2024), Professor Yu Chen from Fujian Cancer Hospital shared the latest research achievements in the field of melanoma treatment. In an exclusive interview with Oncology Frontier, Professor Chen further discussed the mechanisms of immunotherapy resistance and explored the potential of various individualized treatment plans to overcome resistance.Interpreting Subgroup Analysis Results from the EBIN Study
Oncology Frontier: The EBIN study (LBA9503) showed no significant difference in progression-free survival (PFS) between dual-target plus dual-immunotherapy sequential treatment and direct immunotherapy in the overall patient population, but a trend of benefit was observed in certain subgroups. How should these subgroup analysis results be interpreted, and what guidance do they provide for clinical practice?
Professor Yu Chen: In Europe and the United States, both immunotherapy and targeted therapy have been approved as first-line treatments for skin melanoma. For patients with BRAF mutations, optimizing the use of dual-target and dual-immunotherapy is a current research focus. Existing studies seem to favor dual-immunotherapy (ipilimumab plus nivolumab) as the initial treatment, followed by targeted therapy upon disease progression. However, the benefits of sequential immunotherapy after targeted induction therapy remain unclear. The EBIN study provides preliminary reference answers to this question.
In this study, newly diagnosed metastatic melanoma patients with BRAF mutations were divided into two cohorts: cohort 1 received dual-immunotherapy, while cohort 2 received dual-target induction therapy for 12 weeks followed by dual-immunotherapy. The primary endpoint was PFS. In the intent-to-treat (ITT) population, there was no significant difference in PFS. In the first six months of treatment, targeted therapy outperformed immunotherapy in terms of PFS and overall survival (OS). Over time, the survival curves for targeted therapy and immunotherapy intersected, with immunotherapy showing a trend toward better survival benefits. The study’s predefined subgroup analysis revealed that patients with high lactate dehydrogenase (LDH > 2ULN) and liver metastases could benefit from this sequential approach (HR values were 0.46 and 0.49, respectively). This suggests that for patients with liver metastases or high LDH levels (relatively less responsive to immunotherapy), starting with targeted induction therapy to control the disease followed by sequential immunotherapy might be a good treatment option, reducing the risk of disease progression or death. In clinical practice, treatment plans should still be individualized based on the specific circumstances of each patient.
Potential Advantages of IBI363 in Melanoma Treatment
Oncology Frontier: At ASCO 2024, you presented the phase I study results of IBI363 for advanced melanoma. What are the potential advantages of IBI363 compared to traditional monoclonal antibodies, and what is your view on the application prospects of bispecific antibodies in melanoma?
Professor Yu Chen: IBI363 is a first-in-class PD-1/IL-2α-biased bispecific antibody fusion protein. It can block the PD-1 checkpoint while delivering alpha-biased IL-2 signals through cis-activating to restore exhausted tumor-specific T cells. Chinese melanoma patients predominantly have acral and mucosal subtypes, which have low response rates to PD-1 monoclonal antibody monotherapy. Additionally, clinical treatment options are relatively limited after PD-1 resistance. In this study, we observed an overall objective response rate (ORR) of 28.1% in Chinese melanoma patients; among PD-1 resistant patients, the ORR was 21.2%, and the disease control rate (DCR) was 67.3%. In the 1 mg/kg Q2W dose group (n=25), the ORR was as high as 32.0%. The overall safety profile was acceptable. Therefore, we are very optimistic about the further development of this research and hope to explore its clinical application potential in acral and mucosal melanoma subtypes more deeply.
Current Research Progress on PD-1 Resistant Melanoma
Oncology Frontier: Treatment of PD-1 resistant melanoma is a current research hotspot and challenge. Could you share the latest research progress in this area?
Professor Yu Chen: Immunotherapy has been widely used in various treatment stages of melanoma, including adjuvant therapy, first-line treatment for advanced disease, and later-line treatments, significantly improving patient survival. However, the issue of resistance to immune checkpoint inhibitors has become a key clinical challenge. The mechanisms of immunotherapy resistance are relatively complex and mainly involve three aspects: failure to generate effective antitumor T cells, inability of tumor-specific T cells to exert effective antitumor functions, and failure to form effector memory T cells. Currently, various treatment strategies are being explored and validated to address these different resistance mechanisms.
Internationally, tumor-infiltrating lymphocyte (TIL) therapy has made the most rapid progress. Lifileucel, as a late-line treatment option for melanoma, has achieved an ORR of 31.4% and was approved by the US FDA in February this year. In China, oncolytic virus therapy is progressing rapidly, with a phase III registration study of recombinant human GM-CSF oncolytic type II herpes simplex virus (OH2) currently enrolling patients. At this year’s ASCO conference, several exploratory studies on treatment options for immune-resistant populations were also presented. In the IGNYTE study, the combination of oncolytic virus RP1 (herpes simplex virus type I expressing human GM-CSF and GALV-GP-R-) with PD-1 monoclonal antibody achieved an ORR of 32.7%. In the KEYMAKER 02A study, the combination of PD-1, CTLA-4, TIGIT, and VEGFR-TKI achieved an ORR of approximately 18% to 28%. The phase I dose-escalation and expansion cohort study of the new CXCR1/2 inhibitor SX-682 conducted by MD Anderson showed an ORR of 21% in the 200 mg dose group. In a phase I study, the bispecific antibody FS222 targeting PD-L1/CD137 achieved an ORR of 47.4% (9/15 PR, 4 cases of SD) and a DCR of 68.4% in patients with cutaneous melanoma who failed immunotherapy. Overall, current explorations for treating immune-resistant populations have shown initial effectiveness, with ORRs around 30%, mainly targeting cutaneous melanoma subtypes. However, further validation through large-scale clinical studies is still needed.
Professor Yu Chen
- Member of the Party Committee of Fujian Cancer Hospital
- Ph.D., Chief Physician, Doctoral Supervisor
- Secretary of the General Branch of the Department of Internal Medicine, Deputy Director of the Department of Internal Medicine
- Deputy Director and Head of the Phase I Ward, Clinical Trial Center for Drugs, Fujian Cancer Hospital
- Director of the Melanoma, Urologic, and Soft Tissue Tumor Medical Oncology Subspecialty
- Head of the Melanoma MDT Group, Fujian Cancer Hospital
- Executive Director of the Hepatobiliary and Pancreatic Tumor Diagnosis and Treatment Center
- Recipient of the Fujian Province May Fourth Youth Medal
- Executive Committee Member of the Melanoma Expert Committee, Chinese Society of Clinical Oncology (CSCO)
- Member of the Urothelial Cancer Expert Committee, Chinese Society of Clinical Oncology (CSCO)
- Member of the Liver Cancer Expert Committee, Chinese Society of Clinical Oncology (CSCO)
- Chairman of the First Melanoma Committee, Fujian Anti-Cancer Association
- Class C High-level Talent in Fujian Province, engaged in multidisciplinary comprehensive treatment of tumors, particularly melanoma, bone and soft tissue tumors, urologic tumors, and hepatobiliary and pancreatic tumors, with clinical and translational research. Over the past five years, has published more than 26 SCI papers as the first or corresponding author, with a total impact factor of over 100, and has participated in compiling six books. Lead author of the National Health Commission’s 2022 “Melanoma Diagnosis and Treatment Guidelines,” and the 2018-2023 “CSCO Melanoma Diagnosis and Treatment Guidelines,” “CSCO Urothelial Cancer Diagnosis and Treatment Guidelines,” and “CSCO Primary Liver Cancer Diagnosis and Treatment Guidelines.” Expert in quality control for single-disease melanoma for the National Health Commission.
