Editor’s Note: Although biliary tract cancer (BTC) is relatively rare, it has a higher incidence in the Southeast Asian population, with 50% of patients already in advanced stages at diagnosis and a survival period of less than one year. Its impact cannot be ignored. In 2023, China saw the approval and market launch of the first-line immunotherapy for BTC, instilling confidence in clinical treatment and ushering in a new era of research exploration. To shed light on this, our journal invited Dr. Haitao Zhao, Director of the Hepatology Department at Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, to review the latest developments in the molecular characteristics, clinical diagnosis and treatment, and new drug research of BTC. He also provides a macroscopic perspective, outlining directions worth exploring, such as precision and personalized treatment. Additionally, he selects three promising treatment clues, aiming to provide important guidance for future clinical practice and research exploration.

  • Molecular Characteristics and Advances in Pathogenesis Research

Cholangiocarcinoma (CCA) is a heterogeneous disease with multiple pathobiological imbalances, including disruptions in cancer gene dependencies, epigenomic dysregulation, reactivation of development, metabolic reprogramming, microenvironment reshaping, and immune escape. High-throughput genomic sequencing analysis shows different mutation characteristics in intrahepatic cholangiocarcinoma (iCCA), perihilar cholangiocarcinoma (pCCA), and distal cholangiocarcinoma (dCCA), indicating biological differences among different anatomical subtypes. Targetable gene mutations are carried by 40%-50% of iCCA patients and 15%-20% of pCCA and dCCA patients. In BTC patients, TP53, CDKN2A/B, KRAS, and SMAD4 have the highest mutation frequencies, while the frequencies of targetable IDH1/2, FGFR2, BRAF, PIK3CA, and NTRK mutations are lower (<5%).

As previously mentioned, different subtypes have different mutation spectra. For example, mutations in BAP1, CDKN2A, ARD1A, FGFR1-3, and MET are more common in iCCA, while HER2 amplification (17.4%) and KRAS mutations are more common in pCCA and dCCA. TP53, PIK3CA, HER2, BRAF, and EGFR mutations are more common in gallbladder cancer (GBC). Furthermore, IDH1/2 mutations are likely unique to iCCA, while FGFR1-3, MET, and EGFR mutations are likely unique to extrahepatic cholangiocarcinoma (EHCC). The mutation frequencies of CCA vary by region and etiology; the IDH1 mutation frequency in Asians is lower than in non-Asians, and the mutation rate of IDH1 in liver fluke-related CCA is lower, while TP53, SMAD4, MLL3, and GNAS mutation rates are higher. In patients with hepatitis B-related iCCA, the TP53 mutation rate is higher, while the KRAS mutation rate is higher in hepatitis B-negative patients.

In 2021, we conducted a comprehensive analysis of the genomic profiles of 803 Chinese BTC patients and found that TP53, KRAS, ARID1A, and LRP1B had the highest mutation frequencies. IDH1 and IDH2 mutations are common in Western populations with CCA (25%), but in Chinese BTC patients, they are only 7% and 2%, respectively. TP53 mutations are more common in GBC patients, and KRAS mutations are more abundant in advanced BTC (stage III-IV) and extrahepatic cholangiocarcinoma (ECC) patients. iCCA patients are more likely to carry IDH1 and PBRM1 mutations, as well as MYC and MDM2 amplifications. DNA damage repair (DDR) defects are a hallmark of BTC, with 65.5% of BTC patients having DDR mutations, of which TP53 is the most common DDR gene mutation in three different BTC subtypes. In 242 patients with non-TP53 DDR mutations, the most common DDR genes are ATM, BRCA2, PRKDC, ATR, and POLE. Therefore, in different BTC subtypes, patients with DDR gene mutations have significantly higher tumor mutation burdens than those with wild-type DDR genes.

In the same year, the team led by Academician Fan Jia from Fudan University, based on multi-omics data such as genomics, transcriptomics, proteomics, and phosphorylated proteomics, drew a multidimensional molecular map of iCCA. They found that TP53, KRAS, FGFR2, IDH1/2, and BAP1 mutations (fusion) are the main driver gene mutations in Chinese iCCA. In addition, the study found a large number of aflatoxin mutation fingerprints in Chinese iCCA samples, and these carcinogen fingerprints are significantly correlated with higher tumor mutation loads and high infiltration of NK cells. The researchers further analyzed the multi-omics features of chromosomal copy number variations in iCCA and found that the loss of tumor suppressor genes (such as ARID1A, MAP2K4, MLH1) and the amplification of oncogenes (such as STK19, HIST1H1E, MCL1, MDM4) are the main events, and nearly 40% of iCCA have gene changes that can be targeted by drugs. The study established a molecular classification of iCCA patients based on the core of the proteomics: inflammatory type (S1), stromal type (S2), metabolic type (S3), and differentiated type (S4). These four subtypes have unique features in genomics, immune microenvironment, treatment strategies, clinical prognosis, etc., and are expected to guide clinical personalized diagnosis and treatment.

  • Recent Advances in Clinical Diagnosis and Treatment: Mainly Covering Advanced-Stage Patients

Advancements in the diagnosis and treatment of BTC are primarily focused on patients in advanced stages.

  1. International Advances in Systemic Treatment for Advanced Biliary Tract Cancer
  2. Standard First-Line Treatment

The ABC-02 study in 2010 established the GC chemotherapy regimen, which has been used for over a decade, but with limited benefits, showing a median survival time of only 11.7 months. In 2022, the era of immunotherapy for biliary tract cancer (BTC) began, breaking the bottleneck of a median survival of less than a year over the past 12 years. A Phase III, randomized, double-blind, placebo-controlled global multicenter clinical trial (TOPAZ-1 study) evaluated the safety and efficacy of the combination of durvalumab and chemotherapy in the first-line treatment of advanced BTC. This study yielded excellent results in overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). The combination was recommended by major guidelines globally. In July 2022, the WCGIC released sub-group data, showing benefits across different subtypes, with a 44% reduction in the risk of death for postoperative recurrence patients. It was recommended as a neoadjuvant treatment in the NCCN Guidelines for Malignant Tumors of the Biliary Tract, and in 2023, the ASCO-GI reported characteristics of long-term survival patients from the TOPAZ-1 study. Notably, on November 7, 2023, China’s CDE formally approved durvalumab for first-line treatment of locally advanced or metastatic BTC in adult patients.

In 2023, the results of the Phase III clinical study KEYNOTE-966 were announced at the American Association for Cancer Research (AACR) annual meeting. After a median follow-up of 25.6 months, first-line treatment with pembrolizumab plus gemcitabine and cisplatin (GC) significantly improved the median OS for advanced BTC compared to placebo plus GC. The median OS in the pembrolizumab group was 12.7 (11.5–13.6) months, while the control group had a median OS of 10.9 (9.9–11.6) months, with a 17% reduction in the risk of death (HR 0.83; 95% CI 0.72–0.95, P=0.0034). Additionally, 25% of patients in the pembrolizumab group were still alive at 24 months (compared to 18% in the control group). Based on this study, the “CSCO Guidelines for Diagnosis and Treatment of Biliary Tract Cancer 2023” recommended this regimen as the first-line treatment for BTC in April 2023, and the “NCCN Clinical Practice Guidelines in Oncology for Hepatobiliary Cancers (2023.V3)” made the same recommendation on November 8, 2023. This study confirmed that the combination of immunotherapy and chemotherapy is the standard first-line treatment for advanced BTC, with the highest level of evidence to date.

  • Atezolizumab ± Bevacizumab + GC in First-Line Treatment of BTC

IMbrave151 is the world’s first randomized, double-blind, Phase II study exploring VEGF and PD-L1 dual inhibition in combination with chemotherapy as first-line treatment for advanced bile duct cancer. The results reported at the 2023 ASCO meeting showed no significant difference in PFS: 8.3 vs. 7.9 months, HR 0.76 (0.51, 1.14). The addition of bevacizumab (experimental group) moderately improved PFS in patients with advanced bile duct cancer, and the median PFS of control group and experimental group was similar, but the PFS of experimental group was higher at 6 months. At 6 months, the experimental group had a longer duration of response (DOR), but there was no significant difference in OS between the two groups.

  • Gemcitabine and cisplatin combined with Nab-paclitaxel

Gemcitabine, Cisplatin, and Nab-Paclitaxel (GCN) with Improved Efficacy Results from the Phase III SWOG 1815 study comparing GCN vs. GC were reported at the 2023 ASCO meeting. The study showed negative results overall, but a surprising subgroup analysis revealed higher ORR (50% vs. 24%) and longer survival trends (OS: 17.0 months vs. 9.3 months; PFS: 9.6 months vs. 5.6 months) for gallbladder cancer patients receiving GCN. The CSCO guidelines recommend this regimen for first-line treatment of GBC, and the latest version of the NCCN guidelines still cites Phase II trial results as a 2B category recommendation for first-line treatment of BTC.

  1. Domestic Advances in Advanced Biliary Tract Cancer

BTC is rare in Western countries, but it is more common in China. China has made rapid progress in BTC diagnosis and treatment, although much of it is exploratory and based on small sample studies.

  1. Targeted Immunotherapy Combination

In 2021, a team from Peking Union Medical College Hospital first reported an ORR of 25.0%, a disease control rate (DCR) of 78.1%, and median progression-free survival (mPFS) and median overall survival (mOS) of 4.9 months and 11.0 months, respectively, with the combination of pembrolizumab and lenvatinib in the treatment of advanced BTC. In 2022 and 2023, the team continued to report on the real-world clinical study of the largest cohort of patients treated with lenvatinib combined with a PD-1 antibody for iCCA and GBC in the Cancer Immunology, Immunotherapy international journal, confirming the effectiveness and safety of targeted immunotherapy combination treatment for BTC subtypes. Several other centers in China, including Zhejiang University Affiliated Second Hospital and Eastern Hepatobiliary Hospital, have also published studies confirming the effectiveness.

  • Gemcitabine, Oxaliplatin, and Lenvatinib (Triple Quadruple Therapy)

Academician Jia Fan conducted a Phase II study evaluating the efficacy of Gemox combined with PD-1 monoclonal antibody and lenvatinib (“triple quadruple therapy”) in the treatment of unresectable iCCA. The ORR reached 80%, DCR reached 93.3%, and the median OS, PFS, and DOR were 2.1 months, 22.5 months, and 10.2 months, respectively. Grade ≥3 adverse events occurred in 66.7% of cases, and 3 out of 30 patients achieved curative surgery. The team at Tianjin Medical University Cancer Institute and Hospital reported the results of a Phase II study on the conversion treatment of potentially resectable local advanced BTC with the combination of Gemox, camrelizumab, and lenvatinib at the ESMO conference in 2022. The ORR was 56%, and the R0 resection rate after conversion treatment was as high as 52%. Another real-world study from Peking Union Medical College Hospital involving 57 BTC patients showed an ORR of 64% and a DCR of 96% for the “triple quadruple therapy,” with 3 patients undergoing conversion surgery, including 1 patient who received second-line treatment. The “triple quadruple therapy” demonstrated excellent efficacy and controllable safety, providing a powerful option for Chinese BTC patients, but it still lacks support from Phase III clinical trial results.

  • Immuno-Oncology 3.0

The team at Peking Union Medical College Hospital first proposed the strategy of immuno-oncology 3.0 – combining local therapy with full-course multimodal stereotactic treatment based on PD-1 or PD-L1 inhibitors. They conducted a series of studies and published related SCI papers. The evaluation of the efficacy and safety of combined local treatment with ICI and lenvatinib in the salvage treatment of BTC showed significantly extended OS (13.7 vs. 11.1 months) and PFS (7.9 vs. 5.6 months) after combined local treatment, with an impressive ORR of 32% and no new adverse reactions observed. Three patients achieved curative conversion surgery. They further assessed the efficacy of different local treatment methods combined with targeted immunotherapy and the timing of combination use. The study found that the combination of radiotherapy as a local treatment resulted in a high ORR of 35%, DCR of 85%, significantly prolonged PFS (10.8 months vs. 4.6 months), and OS (13.7 months vs. 9.2 months) compared to no radiotherapy, with overall manageable adverse events.

In addition, early combination of local treatment may increase ORR. In the synchronous radiotherapy group (interval between combined targeted and immunotherapy ≤6 weeks) compared to the salvage radiotherapy group (interval between the two >6 weeks), although the ORR (33.3% vs. 31.6%, P=0.61) difference was not statistically significant, the synchronous radiotherapy group had significantly extended PFS (10.8 months vs. 4.6 months, P<0.001) and OS (13.7 months vs. 9.2 months, P=0.008). They also conducted a retrospective study, confirming the effectiveness of PD-1 antibody combined with HAIC as salvage treatment for BTC, and early combination with HAIC was more favorable for extending OS. This concept has now been recognized and practiced in the field of hepatobiliary.

  • Transformational Treatment for Advanced Biliary Tract Cancer

There have been sporadic reports on transformational treatment for BTC internationally. Currently, more and more domestic centers are exploring BTC transformational treatment. Peking Union Medical College Hospital has completed 19 cases of advanced biliary system tumor transformational treatment. An analysis of 14 patients who received immunotherapy from January 29, 2019, to May 19, 2022, showed that compared to those who achieved partial response (PR)/complete response (CR) without transformational surgery, the median PFS in the non-transformational surgery group was 11.7 months, which was not reached in the transformational surgery group. The difference was significant (P<0.0001), and the 3-year PFS rate in the transformational surgery group was 50%. The median OS was 22.4 months in the non-transformational surgery group, which was not reached in the transformational surgery group, and survival was significantly better than that of non-transformative patients during the same period (P=0.023). The 3-year OS rate in the transformational surgery group was 60%, and as of the latest follow-up, 7 patients are alive without recurrence.

  1. (3) New Neoadjuvant Treatment for Local Advanced Biliary Tract Cancer

Currently, there is a lack of Phase III RCT studies proving the benefits of neoadjuvant treatment for BTC. There are two prominent studies, with immunotherapy + chemotherapy showing potential as a neoadjuvant treatment option.

  1. Durvalumab Combined with Gemcitabine and Cisplatin

The DEBATE study is a randomized, multicenter, open-label, Phase II trial that evaluated the neoadjuvant treatment of local BTC with durvalumab combined with gemcitabine and cisplatin (D+GemCis) compared to gemcitabine and cisplatin (GemCis). The results showed that in the D+GemCis arm and GemCis arm, 68% (21 cases) and 36% (5 cases) of patients underwent surgery, respectively. R0 resection rates were 48% (15 cases) and 36% (5 cases) for the two arms. The median PFS for the two arms was 15.1 months and 3.6 months, respectively. Patients who could undergo curative surgery after treatment had significantly improved OS (P<0.001). Neoadjuvant D+GemCis can increase the surgical resection rate of local BTC patients, and surgical resection is associated with better survival benefits. It has been recommended as a 2B category in the NCCN Guidelines but is not recommended in the CSCO Guidelines.

  • Gemcitabine + Cisplatin + Nab-Paclitaxel

A Phase II clinical study for unresectable BTC showed an ORR of 45%, and a PFS of 11.8 months. In the NEO-GAP Phase II study, 30 high-risk iCCA patients who could undergo resection received this regimen, and 22 underwent surgery, with an ORR of 23% and a DCR of 90%.

  • 03 Recent Advances in Drug Development: Focusing on Targeted Immunotherapy
  1. Targeting Fibroblast Growth Factor Receptor (FGFR)

1.Pemigatinib

The Phase II FIGHT-202 trial assessed the efficacy of pemigatinib in the second-line treatment of FGFR2 fusion or rearrangement cholangiocarcinoma (CCA) patients. The results showed an ORR of 35.5% and a median OS of 21.1 months. Therefore, pemigatinib may be considered as a choice for patients progressing after platinum-based therapy.

2. Infigratinib (FGFR Inhibitor)

Phase II trials explored another FGFR inhibitor, infigratinib, specifically enrolling intrahepatic cholangiocarcinoma (iCCA) patients with FGFR2 fusions or rearrangements. The study revealed a median overall survival (mOS) of 12.2 months and an objective response rate (ORR) of 23%. In May 2021, it received accelerated FDA approval.

3. Erdafitinib (Pan-FGFR Inhibitor)

Erdafitinib, a pan-FGFR inhibitor, gained FDA approval in 2019 for treating locally advanced or metastatic urothelial carcinoma with FGFR3 or FGFR2 mutations. Recent data from the LUC2001 trial, presented at ASCO 2022, included 232 advanced cholangiocarcinoma (CCA) patients, with 39 carrying FGFR mutations. After a median follow-up of 22.4 months, the ORR was 40.9%, with mOS and mPFS at 40.2 and 5.6 months, respectively.

4. Derazantinib and Futibatinib

The FIDES-01 trial, presented at ASCO’s 2022 Gastrointestinal Cancers Symposium, showcased results for derazantinib, a potent FGFR 1-3 kinase inhibitor. In FGFR-mutated or amplified iCCA patients progressing after standard chemotherapy, the disease control rate (DCR) was 75.7%, with mPFS and mOS of 8 and 16 months, respectively. Futibatinib, a highly selective FGFR 1-4 inhibitor, demonstrated meaningful results with a DCR of 78.6%, an ORR double that of derazantinib (42% vs. 21%), and mPFS and mOS of 9 and 21.7 months, respectively.

5. Tinengotinib

Tinengotinib, identified as a novel FGFR inhibitor, exhibited promising clinical results in patients with FGFR inhibitor-resistant or recurrent cholangiocarcinoma. Reported at the 2023 ESMO Congress, tinengotinib for advanced fibroblast growth factor receptor (FGFR) inhibitor resistant/recurrent cholangiocarcinoma had an ORR and DCR of 20.7% and 75.9%, respectively, with a mPFS of 6.90 months. Plans are underway for a global Phase III clinical trial to further evaluate tinengotinib in FGFR inhibitor-resistant CCA patients.

6. Combination Therapy

A clinical trial (NCT05174650) is ongoing, investigating the combination of derazantinib and atezolizumab in first-line or second-line treatment for advanced iCCA with FGFR fusions or rearrangements.

  1. Targeting HER2 Amplifications

1. Pertuzumab and Trastuzumab Combination

In 2021, the non-randomized, multicenter, multi-basket Phase IIa MyPathway study enrolled 39 previously treated metastatic biliary tract cancer (BTC) patients with HER-2 amplifications or/and overexpression. The combination of pertuzumab and trastuzumab demonstrated an ORR of 23%, with median PFS and OS of 4.0 and 10.9 months, respectively. The regimen showed good safety, with a Grade ≥3 adverse event rate of only 8%, surpassing historical second-line chemotherapy data.

2. Trastuzumab Deruxtecan (T-DXd/DS-8201)

Trastuzumab deruxtecan, a next-generation antibody-drug conjugate (ADC) with an drug-antibody ratio of 8, which can carry more drugs to the tumor site and play a good anti-tumor effect in a wider range of HER-2 expression levels or in heterogeneous tumors. The multi-center Phase II HERB study evaluated the efficacy of T-DXd as a second-line treatment for BTC with positive HER-2 (IHC +++, IHC ++, or ISH+) and low HER-2 expression (IHC or ISH 0 or +, +/+, +/-, ++/−) following standard chemotherapy. Data presented at the ASCO 2022 Congress showed that the overall patient ORR was 30% and DCR was 80%. In the HER-2 positive subgroup, the ORR was 36.4%, the DCR was 81.8%, the median PFS and OS were 5.1 and 7.1 months, respectively, and the median DOR was 7.4 months. 50% of patients achieved tumor remission for more than 6 months. In the low HER-2 expression group, ORR and DCR reached 12.5% and 75.0%, respectively, and the median PFS and OS were 4.2 months and 8.9 months, respectively. Compared with the previous advanced BTC first – and second-line standard therapy and anti-HER-2 targeted therapy, this regimen showed better efficacy, and also showed significant benefits for patients with low HER-2 expression.

3. Zanidatamab (ZW25)

Zanidatamab, a dual-specificity antibody targeting HER2, demonstrated effectiveness in second-line treatment for HER2-overexpressing advanced BTC patients. Results from 41 patients of the HERIZON-BTC-69 trial showed a 12% ORR, 9% DCR, and a median duration of response (DOR) of 12.9 months. Additionally, the ongoing Phase 2b HERIZON-BTC-01 trial (NCT04466891) is evaluating zanidatamab in patients previously treated with first-line gemcitabine-based chemotherapy, with anticipated encouraging results.

4. Laronidase

The SUMMIT trial, a Phase II basket study, included patients with HER2 alterations, treating them with laronidase, an irreversible pan-HER2 tyrosine kinase inhibitor. Among 25 BTC patients, there were improvements in median progression-free survival (mPFS) at 2.8 months, median overall survival (mOS) at 5.4 months, and an ORR of 12%, demonstrating moderate anti-tumor activity.

5. Tucatinib

Tucatinib, an oral HER2 tyrosine kinase inhibitor, in combination with trastuzumab, showed efficacy in 30 BTC patients with an ORR of 46.7%. The median duration of response (DOR) and progression-free survival (PFS) were 6.0 and 5.5 months, respectively.

  1. Targeting IDH Mutations

1. Ivosidenib (IDH1 Inhibitor)

In 2020, the global multicenter Phase III ClarIDHy study evaluated ivosidenib, a potent small-molecule inhibitor targeting IDH1 mutations, in unresectable or metastatic IDH1-mutated cholangiocarcinoma beyond the second line. The study demonstrated an ORR of 2.4%, improved progression-free survival (PFS) at a median of 2.7 months, and tolerable safety. Although overall survival (OS) was 10.3 months, there was no statistically significant difference. To date, this is the first and only multicenter, randomized Phase III trial to demonstrate clinical benefit of targeted IDH1 therapy in such patients. So ivosidenib received FDA approval in August 2021 for previously treated IDH1-mutated cholangiocarcinoma patients.

The IDH1 inhibitor BAY1436032 was evaluated in 12 patients with CCA, 42% of whom were stable but had no objective response. 52BAY1436032 is not planned for further clinical development in CCA. The only reported study of IDH2 in patients with cholangiocarcinoma included four patients and did not observe an objective response to enasidinib. Clinical trials targeting IDH1/2 mutations (NCT03212274, NCT03878095, etc.) are ongoing, with investigations into combination therapies (NCT04088188, NCT0368481) to enhance IDH1 inhibitor efficacy.

  1. Targeting BRAF Mutations
  2. Dabrafenib and Trametinib

The 2020 ROAR study, an open-label, single-arm, multicenter Phase II trial, marked the first prospective basket trial incorporating patients with BRAFV600E-mutated biliary tract cancer (BTC). It evaluated BRAF and MEK inhibitors, dabrafenib and trametinib, in unresectable or metastatic BRAFV600E-mutated BTC after ≥2 lines of therapy. With 43 patients, the study reported a 47% objective response rate (ORR), a median duration of response (DOR) of 9.8 months, and a 6-month progression-free survival rate of 63%. The regimen was deemed safe. In June 2022, FDA approved dabrafenib and trametinib for all non-colorectal solid tumors carrying the BRAFV600E mutation. While dabrafenib monotherapy showed objective responses in 3 out of 9 advanced BTC patients, data on other BRAF inhibitors for BTC are limited. No other BRAF/MEK inhibitors have gained approval, but ongoing trials (e.g., NCT03839342) are exploring additional options.

  • Targeting NTRK Gene Fusions
  • Entrectinib

Entrectinib, a broad-spectrum agent targeting ROS1, ALK, and NTRK fusions, demonstrated promising results in clinical trials (ALKA-372-001, STARTRK-1, and STARTRK-2). Combining data from these studies, the overall response rate (ORR) was 57%, with 7% achieving complete responses and a duration of response (DOR) of 10 months. Data from the Asia subgroup, reported at the 2022 ESMO ASIA conference, indicated an ORR of 69.2% in 13 Asian patients with NTRK fusion-positive solid tumors, a median DOR of 10.4 months, and a median progression-free survival (PFS) of 14.9 months.

  • Larotrectinib

Larotrectinib, based on three clinical trials (NCT02122913, NCT02637687, and NCT02576431), demonstrated a 75% ORR in 55 patients with NTRK fusion-positive solid tumors. The one-year response durability was 71%, and 55% of patients remained progression-free.

  • RET Fusion Mutations
  • Pralsetinib

The ARROW study, a Phase I/II, multicohort, open-label clinical trial, conducted by 71 centers from 13 countries, observed the clinical efficacy and safety of the RET inhibitor pralsetinib in treating RET-altered solid tumors. In 2022, data from 23 evaluable patients showed a 57% overall response rate (ORR), with 2 out of 3 cholangiocarcinoma patients achieving remission. Pralsetinib became the first potent, oral, selective RET inhibitor to be approved in China, effective across fusions and mutations, independent of tumor type.

  • Selpercatinib

The LIBRETTO-001 study (NCT03157128) is a non-blind (open), international, multicentre, basket phase I/II clinical trial of selpercatinib in patients with RET fusion positive stage IV solid tumors who have been previously treated and currently have no satisfactory treatment option. It is also the largest RET fusion/mutant solid tumor clinical trial in the world to date. Data reported in January 2022 focused on non-lung and non-thyroid cancers, revealing a 43.9% ORR, a median PFS of 13.2 months, a median OS of 18 months, and good safety. In September 2022, FDA granted approval for selpercatinib in locally advanced or metastatic RET fusion-positive solid tumors that progressed after prior systemic treatment or lacked acceptable treatment options.

  • Targeting HRD (Homologous Recombination Deficiency)
  • First-Generation PARP Inhibitors

Niraparib, a classic PARP inhibitor with approval for ovarian cancer, showed limited efficacy in a trial for BAP1-mutated solid tumors. The ongoing Phase II UF-STO-ETI-001 trial (NCT03207347) aims to evaluate niraparib’s efficacy in cholangiocarcinoma patients with BAP1 and other DNA repair deficiencies. Ongoing investigations also explore the effectiveness of olaparib in cholangiocarcinoma with DNA repair defects (NCT04042831).

  • Second-Generation PARP Inhibitors

The second-generation PARP inhibitors improve selectivity, solubility, and avoidance of drug interactions through clever pharmacochemical structure optimization, thereby providing a better safety profile for combination therapy with first-line immunoagents and chemotherapeutic agents in later clinical trials. In April 2023, the second-generation PARP inhibitor, mefuparib hydrochloride, developed in China, received orphan drug designation from the US FDA for the treatment of cholangiocarcinoma.

  • MDM2-p53 Inhibitors

Clinical studies of MDM2-p53 inhibitor BI907828, as monotherapy or in combination with PD-1 inhibitors (NCT03964233), showed good responses in a subset of 8 patients (5 cases with PR and 2 with SD). The Brightline-2 Phase II trial (NCT05512377) is currently assessing BI907828’s efficacy in cholangiocarcinoma.

  1. KRAS G12C Inhibitors

Initial studies on the KRAS G12C inhibitor adagrasib showed a 100% disease control rate in 8 BTC patients, including 4 with partial responses (50%). Ongoing research explores adagrasib’s monotherapy and combination approaches, with additional KRAS G12C inhibitors entering clinical development (e.g., GDC-6036: NCT04449874, JAB-21822: NCT05002270). Another approach involves combining the MEK inhibitor trametinib with the autophagy inhibitor hydroxychloroquine (NCT04566133) for treating KRAS-mutant BTC, a strategy previously shown to be clinically effective in pancreatic cancer and undergoing testing in various tumor types.

  • Multi-Targeted Drugs

Surufatinib is a domestically developed small-molecule tyrosine kinase inhibitor (TKI) in China. Its main targets include vascular endothelial growth factor receptors 1/2/3 (VEGFR-1/2/3), fibroblast growth factor receptor 1 (FGFR-1), and colony-stimulating factor 1 receptor (CSF-1R). Surufatinib has shown preliminary clinical efficacy, manageable tolerability, and safety in related studies. In a real-world study presented by domestic scholars at the 2023 European Society for Medical Oncology and World Congress on Gastrointestinal Cancer (ESMO-WCGIC), the median progression-free survival (mPFS) for surufatinib in neoadjuvant, first-line, and second-line treatments was reported as 8.13 months (95% CI: 5.85–10.8), 9.66 months (95% CI: 5.59–NA), and 8.71 months (95% CI: 7.26–NA), respectively. Among 16 non-operated patients, 37.50% (6/16) achieved partial response (PR), 56.25% (9/16) achieved stable disease (SD), and 6.25% (1/16) experienced disease progression (PD), resulting in a disease control rate (DCR) of 93.75%.

  • Novel Immunotherapeutic Drugs
  • PD-L1/TGF-β Dual-Target Antibody (M7824):

M7824 is a PD-L1/TGF-β dual-target antibody, referred to as the “second-generation PD-1 or upgraded PD-1”. Initial data for first-line treatment of bile duct cancer presented at the October 2018 ESMO congress showed an objective response rate (ORR) of 23%, median progression-free survival (PFS) of 2.6 months, and median overall survival (OS) of 12.7 months. M7824’s orphan drug designation for treating BTC was granted by the FDA, but later-stage data review revealed an ORR of only 10.1%, led to the termination of the phase II INTR@PID BTC 055 trial (NCT04066491) in August 2021. On March 16, 2021, Merck announced data from a second-line study of M7824 for biliary tract tumors that also failed.

  • Cell Therapy:
    • SCG101 Injection: A first-in-class autologous T-cell receptor (TCR-T) cell therapy specifically targeting hepatitis B surface antigen (HBsAg). It obtained clinical trial approvals from the China National Medical Products Administration (NMPA), U.S. Food and Drug Administration (FDA), and Health Sciences Authority (HSA) in Singapore for treating HBV-related hepatocellular carcinoma. SCG101 demonstrated significant antiviral and antitumor activity in late-stage HBV-related liver cancer patients and has expanded its use to HBV-related intrahepatic cholangiocarcinoma (iCCA). In November 2023, SCG101 cell injection obtained the implied clinical trial approval of NMPA, becoming the world’s first cell therapy for bile duct cancer.
    • Adoptive Cell Transfer (ACT) with Tumor-Infiltrating Lymphocytes (TIL): Successful cases of treating bile duct cancer patients using ACT with TIL were reported. A study combining CTLA-4 and nivolumab with conventional TIL therapy demonstrated tumor regression in 30%-63% of treated patients with BTC.
    • ScTIL-v2 Therapy: A clinical study was conducted on open, single-cell infusion with ScTIL-v2 to evaluate its tolerability, pharmacokinetic characteristics, safety, and effectiveness in treating primary malignant tumors of the biliary system.
  • Future Exploration Directions

In the future, the goal is to achieve the maximum integration of precision immunotherapy and personalized treatment based on clear pathological conditions. This involves exploring hierarchical, well-ordered individualized plans considering pathological classification, clinical staging, previous treatments, patient preferences, genomic information, and other individual factors. The aim is to maximize the benefits for patients by closely monitoring and guiding the diagnosis and treatment processes through various platforms.

  1. Molecular Targeted Therapy for Biliary Tract Cancer:
    1. Continued research and development for IDH1, FGFR2 fusion and rearrangement, HER2, and other targeted therapies and focus on KRAS, G12C at the same time.
    1. Exploration of molecular mechanisms and drug development for specific targets.
    1. Investigation of combinations of targeted drugs with chemotherapy and immunotherapy, especially for specific targets like HER2, FGFR, BRCA, etc.
    1. Understanding and addressing resistance mechanisms for targeted therapies like FGFR and IDH inhibitors.
  2. Combination Therapy:
    1. Exploration of the effectiveness of various combination therapies.
    1. Investigation into the sequencing and timing of combination therapies.
  3. Second-Line and Beyond Treatment Strategies:
    1. Developing strategies for second-line treatment after the emergence of resistance to PD-1/PDL-1 in first-line treatment.
    1. Exploration of treatments for primary resistance to combined immune checkpoint inhibitors.
  4. Chemotherapy-Sparing Approaches:
    1. Assessing the role of targeted immunotherapy in first-line treatment, especially the value in second-line and subsequent treatments.
    1. Exploration of novel immune checkpoint inhibitors.
    1. Evaluation of the value of cell therapy, vaccine therapy, photodynamic therapy, especially their effectiveness in combination with other modalities and their value in later-line treatments.
  5. Neoadjuvant and Postoperative Adjuvant Treatment Strategies for Biliary Tract Cancer:
    1. Development of neoadjuvant and adjuvant treatments based on immunotherapy to improve postoperative recurrence-free survival and overall survival for surgical patients.
  6. Building a Transformational Treatment System:
    1. Establishment of a highly efficient and deep transformational treatment system to provide curative opportunities for advanced BTC.
  7. Surgery aspect
    1. Ongoing exploration of liver transplantation for advanced intrahepatic cholangiocarcinoma.
    1. Exploration of innovative surgical techniques beyond the limits, such as ex vivo liver resection and duct reconstruction techniques.
  8. Biomarker Exploration:
    1. Liquid biopsy exploration for monitoring and guiding treatment based on biological information from blood, urine, and other fluid samples.
    1. Imaging biomarkers: Assisting in image-based judgment and predicting treatment efficacy using AI technology.
  9. National Multicenter Information Platform for Biliary Tract Tumors:
    1. Establishment of a national multicenter information platform to elevate the level of clinical research and collectively explore BTC treatment strategies.
  10. Three Major Treatment Directions for Biliary Tract Cancer

Biliary tract cancer diagnosis and treatment are known to be highly complex, often requiring genetic testing for targeted drug selection. In 2023, first-line immunotherapy drugs for biliary tract cancer were approved and marketed in China, marking the beginning of the era of immunotherapy. Therefore, there is significant exploration space in the future. Based on the team’s years of practical experience, three promising treatment directions have been identified.

  1. Broad-Narrow Combination:

Utilizing a combination of broad-spectrum and narrow-spectrum drugs, known as “Broad-Narrow Combination,” shows promise in improving treatment outcomes, especially for HER2-positive or BRCA-positive patients.

  • Immunotherapy + Chemotherapy + Targeted Therapy:

Unlike hepatocellular carcinoma, biliary tract cancer has recently been approved for immunotherapy combined with chemotherapy. However, the overall survival rate improvement is limited, typically 1-2 months. The team suggests that combining immunotherapy with targeted therapy on the basis of immunotherapy combined with chemotherapy could significantly enhance treatment outcomes.

  • Immunotherapy + Targeted or Chemotherapy + Local Treatment:

Additionally, combining immunotherapy with targeted or chemotherapy and further adding local treatment has the potential to improve overall treatment effectiveness while overcoming immunotherapy resistance.

As new drugs and technologies continue to emerge, the landscape of biliary tract cancer treatment will undergo a transformation. Mixing and matching treatments based on existing technologies and drugs are expected to more effectively extend survival and improve the quality of life. The future of biliary tract cancer treatment promises to be exciting, but medical professionals still need to exert more effort.

Expert Introduction:

Haitao Zhao

  • Director Physician of Hepatic Surgery, Peking Union Medical College Hospital.
  • Doctoral Supervisor.
  • National Ten Thousand Talents Program expert (Leading Talent).
  • Recipient of the 23rd Wu Jieping Medical Foundation Award.
  • Founder of the China Social Welfare Foundation – Tumor Precision Immunotherapy Public Welfare Fund.
  • Executive Committee Member of the Chinese Society of Clinical Oncology (CSCO) Liver Cancer Expert Committee.
  • Secretary-General and Deputy Chairman of the Liver Specialized Committee of the Chinese Microcirculation Society.
  • Member of the Alumni Association of Peking University.
  • Deputy Secretary-General of the Association of Chinese Students and Scholars in the United States – Medical Association.
  • Secretary-General of the Liver and Gallbladder Sub-Committee of the Association of Chinese Students and Scholars in the United States – Medical Association.
  • Evaluation Expert for Major Projects of the Ministry of Science and Technology.
  • Expert in the Medical Device Review of the National Medical Products Administration.
  • Deputy Editor-in-Chief of the HBSN (Impact Factor: 8.265) Journal.
  • Editorial Board Member of the WJG (Impact Factor: 5.742) Journal.
  • Principal Investigator for 19 national, provincial, and university-level fund projects.
  • Published 148 SCI academic papers as corresponding author, with a total impact factor exceeding 1252.6 points, total citations exceeding 7948 times, and an H-index of 45.

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Last updated on 2024.03.22