95MO: Efficacy of Tinengotinib in Treating Advanced Fibroblast Growth Factor Receptor (FGFR) Inhibitor Resistant/Recurrent Cholangiocarcinoma Patients

 

Background

Fibroblast Growth Factor Receptor inhibitors (FGFRi) have been shown to play a role in the treatment of cholangiocarcinoma (CCA) with FGFR alterations after chemotherapy. However, disease progression occurs after 6-8 months. Secondary multiclonal mutations in the FGFR2 kinase domain represent a notable acquired resistance mechanism. Tinengotinib is identified as a novel FGFRi with high efficacy against various FGFR2 kinase domain mutations and has shown promising clinical results in CCA patients previously treated with FGFRi. This study presents summary data from three trials.

 

Methods

Patients received oral Tinengotinib once daily in 28-day cycles. A summary analysis was conducted for treatment-related adverse events (TRAEs), overall response rate (ORR), disease control rate (DCR), and median progression-free survival (mPFS) in stratified CCA populations.

 

Results

From December 2019 to March 2023, 73 advanced CCA patients were included in the study. The median age was 60 years (24-81), 60% were female, all had undergone first-line or more treatments, and 47% had received FGFRi treatment. 97% of patients were at stage IV CCA at enrollment.

 

A total of 63 patients (86.3%) reported TRAEs (see Figure 1), with 28 cases (38.4%) grade 1-2, 32 cases (43.8%) grade 3, and 3 cases (4.1%) grade 4; no grade 5 events were observed. The most common TRAEs (≥20%) included hypertension (43.8%, grade 3 19.2%), oral mucositis (32.9%, grade 3 4.1%), diarrhea (30.1%, grade 3 4.1%), and palmar-plantar erythrodysesthesia (24.7%, grade 3 2.7%).

In 58 evaluable patients, ORR and DCR were 20.7% and 75.9%, respectively. In 29 patients previously treated with FGFRi and with FGFR2 mutations, ORR and DCR were 34% and 89.7%, respectively. In 21 patients resistant to previous FGFRi, ORR was 38.1%, DCR was 95.2%, and mPFS was 6.90 months (95% CI: 4.90-9.20). Among 10 patients with FGFR2 kinase domain mutations (N549D/H/K/T, V564F/I/L, E565A/G/K) detected in baseline liquid biopsy, ORR was 50%, DCR was 90%, and mPFS was 7.03 months (95% CI: 0.95-11.86).

 

Conclusion

These summary results indicate that Tinengotinib has manageable safety in CCA patients. Tinengotinib shows significant clinical benefits in CCA patients with FGFR alterations resistant to previous FGFRi. A global Phase III clinical trial is planned to further evaluate the efficacy and safety of Tinengotinib in FGFRi-resistant CCA patients.

 

Expert Commentary

The study of this drug is quite interesting, exploring the efficacy of the drug in patients resistant to frontline FGFR inhibitors. After frontline treatment with FGFR inhibitors, patients develop new mutations in the FGFR2 kinase domain, leading to resistance to previous FGFR inhibitors. This study focused on this subset of patients and found that Tinengotinib not only has good efficacy in advanced CCA but also performs better in patients resistant to FGFR inhibitors. In patients resistant to FGFR inhibitors and with confirmed FGFR2 kinase domain mutations, the efficacy is particularly remarkable.

This study is the first to investigate second-line treatment targeting the same pathway, suggesting that even after the development of secondary mutations causing resistance, the target remains valuable. Second-line treatment may have a higher objective response rate. In the future, patients with FGFR mutations in CCA, even after developing secondary resistance, may still benefit from Tinengotinib, potentially extending their overall survival. This brings a new perspective and represents a new direction in drug development.

 

97P: Comparison of Durvalumab Plus Gemcitabine and Cisplatin (D+GemCis) vs. Gemcitabine and Cisplatin (GemCis) as Neoadjuvant Treatment for Localized Biliary Tract Cancer (BTC): Results from a Randomized, Multicenter, Open-Label, Phase II Trial (DEBATE)

 

Background

Compared to using GemCis alone, D+GemCis has shown significantly improved efficacy in advanced/metastatic BTC patients. However, the efficacy of D+GemCis in neoadjuvant treatment has not been studied.

 

Methods

This multicenter, open-label, non-comparative, randomized Phase II trial included locally staged biliary tract cancer patients confirmed by histology or cytology, randomized in a 2:1 ratio to receive 4 cycles of D+GemCis or GemCis as neoadjuvant treatment. If patients underwent surgery, both groups received 6 cycles of postoperative durvalumab. The primary endpoint was the R0 resection rate. ctDNA analysis was performed using the GuardantOmni platform.

 

Results

The study included 45 patients (D+GemCis group: 31; GemCis group: 14). Intrahepatic cholangiocarcinoma (18 cases, 40%) was the most common primary tumor site, and 69% of patients (31 cases) were clinically staged as stage III. The response rates for D+GemCis and GemCis were 36% (11 cases) and 7% (1 case), respectively. In the D+GemCis and GemCis arms, 68% (21 cases) and 36% (5 cases) of patients underwent surgery, with 61% (19 cases) and 36% (5 cases) achieving curative resection (R0+R1), and R0 resection rates were 48% (15 cases) and 36% (5 cases), respectively. The median progression-free survival for the two arms was 15.1 months (95% CI: 4.5-25.8) and 3.6 months (0-13.0). Patients who could undergo curative resection after treatment showed a significantly improved overall survival (P<0.001). No new safety signals were identified in the D+GemCis arm.

 

ctDNA analysis revealed actionable genetic changes in 5 patients (11%), including 4 with IDH1 R132C mutation and 1 with ERBB2 amplification. Two patients (4%) had MSI-H.

Conclusion

Neoadjuvant D+GemCis increases the surgical resection rate in localized BTC patients, and surgical resection is associated with better survival benefits. The study demonstrates that ctDNA analysis is a feasible method for assessing target gene changes in early-stage BTC.

 

Expert Commentary

In neoadjuvant treatment, the response rate of durvalumab combined with GC chemotherapy is higher than that of GC chemotherapy alone. This is similar to the results of a Phase III clinical study (TOPAZ-1) of durvalumab combined with GC chemotherapy for unresectable/metastatic BTC, but the response rate has increased fivefold, indicating significant differences. The results suggest that neoadjuvant treatment with GC chemotherapy combined with immunotherapy significantly improves the efficacy of local BTC treatment compared to traditional chemotherapy. First, the overall tumor shrinkage rate is significantly increased, and second, there is a significant benefit in long-term survival for patients.

 

In tumors that can undergo surgery, the combination of immunotherapy and chemotherapy in the neoadjuvant stage shows overall good efficacy. This may be because patients in this stage have better physical conditions and intact immune systems, making them more likely to benefit from immunotherapy. After neoadjuvant treatment with immunotherapy combined with chemotherapy, more patients can undergo curative surgery, with greater survival benefits. This suggests that in the neoadjuvant stage, immunotherapy combined with chemotherapy is a promising treatment strategy.

 

125P: Real-World Treatment Patterns of Biliary Tract Cancer (BTC) Patients: A European Retrospective Chart Review (GARNET-2)

 

Background

BTC is a group of malignant tumors in the liver and perihepatic area, with a 5-year survival rate of less than 20%. This study describes the real-world treatment patterns and outcomes of patients with advanced and/or unresectable (aBTC) in France, Germany, Italy, Spain, and the United Kingdom (UK).

 

Methods

In this web-based chart review retrospective survey, physicians reported anonymized patient-level data for adult patients diagnosed with aBTC between May 2018 and October 2021 who started first-line systemic treatment (index date). Patients were followed from the index date until death or the last available date. Descriptive summaries were provided for patient characteristics, treatment patterns, and clinical outcomes.

 

Results

Data were extracted for 196 patients from 792 who started first-line systemic treatment for aBTC. Intrahepatic cholangiocarcinoma (CCA; 34.8%) was the most common, followed by extrahepatic CCA (29.9%), gallbladder (23.5%), and ampullary cancer (10.2%); information was missing for 1.5% of patients. During a median follow-up of 12.4 months, less than half of the patients received first-line gemcitabine plus cisplatin (GemCis; 47.9%), and the median duration of first-line treatment was 5.3 months, with disease progression (49.2%) being the most common reason for treatment discontinuation. Only 33.1% of patients received second-line treatment, and 4.1% received third-line or higher treatment. The median real-world overall survival (rwOS) from the index date was 13.4 months, with regional variability (see Table 1).

 

Conclusion

This study highlights unmet needs in aBTC patients, with less than half receiving the standard recommended treatment according to ESMO guidelines—gemcitabine plus cisplatin. The median rwOS slightly exceeds one year, indicating the necessity to seek new treatment approaches to extend survival. Recently, immunotherapy has been approved for aBTC patients, and it is essential to explore its benefits in the real world, emphasizing the importance of early detection for improving survival rates in BTC.

 

Expert Commentary

This is a large-scale European retrospective study that provides an overview of the current treatment status of BTC. It found that less than half of the patients received the recommended standard first-line chemotherapy according to ESMO guidelines, and the remaining half may have undergone other treatments. Only one-third of the patients received second-line treatment, and even fewer received third-line treatment. The overall survival period is only 13 months. This suggests that for advanced BTC patients, including cholangiocarcinoma, gallbladder cancer, and ampullary cancer patients, there is a limited opportunity to receive comprehensive treatment, severely impacting their overall survival. Therefore, standardized treatment for these patients is necessary, and it is crucial to standardize and popularize second-line, third-line, or immunotherapy to benefit more patients.

 

Expert Biography

 

 

Peking Union Medical College Hospital

Director, Liver Surgery Department

Doctoral Supervisor

National “Ten Thousand Talents Program” Expert (Leading Talent)

Recipient of the 23rd Wu Yang Award

Founder of the China Social Welfare Foundation-Tumor Precision Immunotherapy Public Welfare Fund

Executive Committee Member, Liver Cancer Expert Committee of the Chinese Society of Clinical Oncology (CSCO)

Secretary-General and Deputy Director, Liver Committee of the Chinese Society for Microcirculation

Alumni Council Member, Peking University

Deputy Secretary-General, Medical Association of Chinese Students and Scholars in the U.S.

Chairman, Youth Committee, Medical Association of Chinese Students and Scholars in the U.S.

Secretary-General and Deputy Chairman, Liver and Gallbladder Branch, Medical Association of Chinese Students and Scholars in the U.S.

Expert Reviewer, Major Projects of the Ministry of Science and Technology

Expert Reviewer, National Medical Products Administration

Deputy Editor-in-Chief, HBSN (SCI IF: 8.265) Journal

Editorial Board Member, WJG (SCI IF: 5.742) Journal

Principal Investigator for 19 national, provincial, and university-level fund projects, published 148 SCI academic papers as the corresponding author, with a total impact factor exceeding 1252.6, total citation count exceeding 7948, and an H-index of 45.