Editor’s Note: From September 25 to 29, 2024, the highly anticipated 27th National Clinical Oncology Conference and CSCO Annual Meeting was successfully held in Xiamen. This prestigious event brought together top experts in the field of oncology from across China, focusing on standardized pathways for diagnosis and treatment of malignant tumors and exploring the latest frontiers. During the conference, Dr. Jun Zhou from Peking University Cancer Hospital delivered a presentation titled “Advances in the Application of New Anticancer Drugs in Biliary Tract Cancer” at the dedicated session on targeted therapy for cholangiocarcinoma. Oncology Frontier had the opportunity to conduct an in-depth interview with Professor Zhou, delving into the current progress in drug treatments for biliary tract cancers and exploring future research directions.

Oncology Frontier: Cholangiocarcinoma is a rare and highly heterogeneous malignancy originating from the epithelial cells of the bile ducts, characterized by strong invasiveness and poor prognosis. In your presentation at this year’s CSCO conference, you discussed the “Advances in New Anticancer Drugs for Biliary Tract Cancer.” Could you briefly outline the current status of cholangiocarcinoma treatment?

Dr. Jun Zhou: The range of drug treatments for biliary tract cancers (BTC) is quite broad, as outlined in the CSCO guidelines, which provide a framework for drug therapy. Here, we will focus on standard first- and second-line treatments for advanced disease.

For first-line treatment in advanced BTC, the standard regimens are gemcitabine-cisplatin (GC) combined with durvalumab or GC combined with pembrolizumab. These recommendations are based on the successful outcomes of two phase III clinical trials. We believe that chemotherapy combined with immunotherapy should be the standard first-line approach for BTC. However, within this broad framework, is there room to further enhance efficacy? Domestic researchers have explored combining chemotherapy and immunotherapy with tyrosine kinase inhibitors (TKIs) like anlotinib and lenvatinib, and small-scale studies have shown significant improvements in efficacy. The key question is whether this increase in efficacy can be validated in phase III clinical trials and whether it can extend overall survival (OS). We eagerly await further clinical data, particularly from the four-drug combination trial being led by Academician Fan Jia’s team at Zhongshan Hospital, Fudan University.

Moreover, under the framework of first-line chemotherapy and immunotherapy, we also need to explore whether there is room for personalized targeted therapies for specific patient subgroups. For instance, HER2-positive cholangiocarcinoma patients make up 8% to 10% of the total population. Should their first-line treatment include anti-HER2 therapy? I believe it should, but clinical research and data are currently lacking. Similarly, should patients with FGFR mutations receive a combination of FGFR inhibitors and immunotherapy as part of their first-line treatment? These are questions we are actively exploring.

Another key consideration is whether we need to explore chemotherapy-free options within the first-line framework of combined chemotherapy and immunotherapy. For some patients who are not suitable for or do not wish to undergo chemotherapy, can we provide a treatment regimen combining targeted therapy with immunotherapy that offers similar efficacy and safety? I believe this could be a promising direction, and there are ongoing studies combining anlotinib or lenvatinib with PD-1/PD-L1 antibodies.

Under the current standard of first-line treatment focused on immunotherapy and chemotherapy combined with immunotherapy, the second-line treatment framework can be divided into two key parts. First, for patients with clear targets, we should prioritize targeted treatment options, such as anti-HER2 therapy, FGFR inhibitors, IDH1 inhibitors like ivosidenib, BRAF inhibitors combined with MEK inhibitors for BRAF V600 mutations, and potentially PARP inhibitors for BRCA2 mutations. These options should be actively explored and prioritized. Patients with actionable targets tend to have significantly improved survival outcomes compared to those without targets. Therefore, second-line treatment must take targeted therapy into account. For patients without any actionable targets, standard chemotherapy should be considered for both first- and second-line treatments.

Second, there is still debate surrounding the standard second-line chemotherapy regimen. While guidelines recommend the FOLFOX regimen, I believe further discussions and studies will continue in the future.

This, in my view, is the current framework for first- and second-line drug treatments in advanced biliary tract cancers.

Oncology Frontier: What are the current challenges in targeted therapy for cholangiocarcinoma? What do you see as the key research directions for the future?

Dr. Jun Zhou: I believe there are several key research directions moving forward:

First, regarding perioperative treatment for biliary tract cancers, the current standard involves combining chemotherapy with immunotherapy. But should we consider adding neoadjuvant treatment to this approach in the perioperative period? Is there potential for implementing this regimen preoperatively? This is a highly relevant topic for surgeons and requires collaborative discussion.

Second, can immunotherapy drugs be used as adjuvant therapy after surgery? Postoperative immunotherapy is not yet a standard treatment for cholangiocarcinoma, so clinical application should be cautious. However, we are aware that phase III clinical trials on postoperative immunotherapy are already underway, indicating that adjuvant treatment could become a significant research area in the future.

Third, in oncology, we already have several effective treatment options. Can we transform unresectable cases into resectable ones? In other words, we need to identify patient groups suitable for conversion therapy. If we can find a highly effective treatment strategy, such as a four-drug combination, FGFR inhibitors, hepatic artery infusion chemotherapy, or combined immunotherapy, the field of conversion therapy could become a major area of focus.

Fourth, for more advanced patients, the spotlight should be on new anticancer drugs, particularly various antibody-drug conjugates (ADCs) for gallbladder cancers. ADCs targeting HER2, CHOP2, B7 molecules, and the EGFR pathway are currently under investigation in this context. The entire ADC field could be seen as a major research hotspot, with more studies expected for later-line treatments.

Finally, mature targeted therapies for later-line treatments will also remain a key area of research in biliary tract cancers. For instance, for patients with IDH1 mutations who fail ivosidenib treatment, what are the subsequent treatment options? For patients with FGFR fusion mutations who fail FGFR inhibitors, what should be the next steps in FGFR-targeted treatment? These questions are currently being explored. I believe that precision-targeted therapy will advance into deeper and more complex lines of treatment, making this a promising area for future research.

Dr. Jun Zhou

• Chief Physician, Department of Gastrointestinal Oncology, Peking University Cancer Hospital
• Executive Director, Hepatobiliary Oncology, Beijing Tsinghua Changgung Hospital
• Standing Member, CSCO Expert Committee on Biliary Tract Cancer
• Standing Member, CSCO Expert Committee on Pancreatic Cancer
• Member, CSCO Expert Committee on Liver Cancer
• Vice President, Tumor Branch of the Chinese Association of Geriatrics
• Deputy Director, Youth Committee on Digestive Tract Oncology, Chinese Research Hospital Association
• Member, Precision Medicine and Oncology MDT Professional Committee, Chinese Research Hospital Association
• Member, Cancer Immunotherapy Branch, Chinese Association for the Promotion of Healthcare
• Member, Young Experts Committee on Hepatobiliary and Pancreatic Oncology, Beijing Health Promotion Association