Advances in Medical Therapy of CCA, Part 1: New Therapeutic Paradigms

December 2022, Vol 3, No 4

Pictured left to right: Richard Kim, MD; Katie Kelley, MD; Gentry King, MD; Vaibhav Sahai, MD, MBBS, MS

The cholangiocarcinoma (CCA) tumor microenvironment is heterogeneous. However, it has been historically thought of as immunologically “cold” and is predicted to be nonresponsive to immunotherapy. Indeed, as monotherapy, treatment with an immune checkpoint inhibitor (ICI) has shown low rates of response in biliary tract cancer (BTC), as demonstrated in the KEYNOTE-158 trial.1 Despite a lack of efficacy, ICIs have proven safe and well-tolerated in patients across tumor types, raising the question of whether combining chemotherapy with an ICI can improve immunogenicity and have the potential for a positive clinical response.

Katie Kelley, MD, from UCSF Helen Diller Family Comprehensive Cancer Center, addressed this topic at the 4th annual CCA Summit. Small single-arm or single-center studies have shown early efficacy and safety with ICI and chemotherapy combinations, in particular, gemcitabine/cisplatin (GemCis). The objective response rate (ORR) in a small single-center study of nivolumab plus GemCis was 36.7%,2 which is slightly higher than what was demonstrated with GemCis alone; in addition, it is interesting to note that responses were not limited to patients positive for programmed death-ligand 1 (PD-L1). Efficacy was further demonstrated in a phase 2 trial of GemCis plus durvalumab with or without tremelimumab in patients with advanced BTC. Response rates were similar with and without tremelimumab (72% with GemCis and durvalumab vs 70% with GemCis and durvalumab plus tremelimumab),3 demonstrating no clear clinical need for the addition of a cytotoxic T-lymphocyte-associated protein 4 antagonist to an anti–PD-L1–blocking antibody.

More recently, the phase 3 TOPAZ-1 trial demonstrated significant improvement in overall survival (OS), progression-free survival (PFS), and ORR with the addition of durvalumab to GemCis. Patients were randomly assigned to receive GemCis and durvalumab or GemCis and placebo for up to 8 cycles where durvalumab or placebo was then continued until disease progression. Median PFS was 7.2 months with GemCis and durvalumab versus 5.7 months for GemCis and placebo (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.63-0.89; P = .001).4 Median OS was 12.8 months in the durvalumab arm versus 11.5 months in the placebo arm (HR, 0.80; 95% CI, 0.66-0.97; P = .021), and ORR was 26.7% versus 18.7% for durvalumab versus placebo (odds ratio, 1.60; 95% CI, 1.11-2.31; P = .011).4 Efficacy was seen across all key subgroups, with the greatest benefit seen in Asian patients.

Immune-related adverse events occurred in 12.7% of the durvalumab arm versus 4.7% for the placebo arm.4 This trial led to the recent approval of durvalumab plus GemCis as first-line therapy for locally advanced or metastatic BTC.

Trials investigating various ICI therapy combination regimens in first-line advanced BTC are ongoing. KEYNOTE-966 is a phase 3 trial investigating GemCis with or without pembrolizumab in first-line advanced BTC. Contrary to the TOPAZ-1 design, gemcitabine can be continued as maintenance instead of placebo. In addition, IMbrave151 is an ongoing double-blinded, randomized, phase 2 trial investigating GemCis plus atezolizumab with or without bevacizumab in advanced BTC. The recent approval of durvalumab has established a new standard of care for first-line therapy; however, outcomes from ongoing studies may influence future ICI use.

Angela Lamarca, MD, PhD, MSc

New IDH1 Inhibitors

Isocitrate dehydrogenase (IDH) is an enzyme involved in cell metabolism, and mutations in the IDH1 and IDH2 genes block normal cell differentiation and promote tumorigenesis. IDH1 mutations are especially prevalent in intrahepatic CCA (iCCA), accounting for 10% to 20% of iCCAs, and are more prevalent in cluster 4, hepatitis-negative iCCA, young female patients, and more advanced disease at presentation. IDH-mutated tumors have also been shown to have a downregulation of immune-related pathways.

Angela Lamarca, MD, PhD, MSc, of the Fundación Jiménez Díaz University Hospital, University of Madrid, discussed IDH1 inhibitor therapy, which was initially studied in a phase 1 trial. The CCA cohort showed promising benefits with ivosidenib used as second-line therapy, with a median PFS of 3.8 months, a 6-month PFS of 40.1%, and a 12-month PFS of 21.8%.5 However, response rates were low, with an ORR of 5%.5 This study was the basis for more advanced studies, including the ClarIDHy trial.

ClarIDHy was a phase 3, placebo-controlled study that investigated ivosidenib versus placebo in second- or third-line treatment of patients with CCA who have specific pathogenic alterations in IDH1. The median PFS was 2.7 months with ivosidenib compared with 1.4 months with placebo (HR, 0.37; 95% CI, 0.25-0.54),6 and an improvement in OS was seen in favor of ivosidenib.7 This trial led to the approval of ivosidenib in patients with IDH1-mutated locally advanced or metastatic CCA who have been previously treated with systemic therapy.

Much is still unknown regarding targeting IDH1, including access to matched treatment, determination of IDH, primary and secondary resistance, response rates, combination strategies, and the role of IDH inhibitors in the adjuvant or first-line setting. To address some of these issues, investigational strategies are being studied in ongoing trials. It is hypothesized that traditionally “cold” tumors may become “hot” with IDH-inhibitor therapy and, therefore, patients may benefit from combination treatment with immunotherapy. In addition, the presence of IDH mutations may lead to accumulation of DNA damage, so it has been theorized that IDH inhibitors in combination with poly-ADP ribose polymerase (PARP) inhibitors may make sense. Therefore, translational research is currently investigating various monotherapy and combination regimens, including IDH-inhibitor monotherapy, IDH inhibitor plus immunotherapy with or without chemotherapy, PARP-inhibitor monotherapy, and IDH inhibitor plus PARP inhibitor.

Novel HER2 Strategies

The incidence of HER2 alterations varies in BTC by anatomic type: it is 5% in iCCA, 16% in extrahepatic CCA (eCCA), and 14% to 19% in gallbladder carcinoma. With the growing systemic therapy landscape, HER2-targeted therapies are approved for second-line treatment in BTC, but it is still necessary to better understand how they integrate into treatment regimens where immunotherapy is now standard of care in the first-line setting. Gentry King, MD, from Fred Hutchinson Cancer Center, explored this issue in his presentation.

The HER2-targeted therapies pertuzumab and trastuzumab were studied in HER2-positive metastatic BTC in a multicenter, phase 2, open-label, multiple basket study. The BTC cohort achieved significant responses, especially in eCCA and gallbladder cancer; median PFS was 4 months, and the median OS was 10.9 months.8 Although these are promising data, durability of response and outcomes needs improvement; therapeutic strategies to improve HER2-directed therapy are based on approaches currently being used in breast and gastric cancers. One strategy is to use multi-domain HER2 blockade with trastuzumab and pertuzumab. In addition, the biparatopic antibody zanidatamab has been studied in a phase 1 trial as a novel HER2-targeted bispecific antibody simultaneously binding ECD4 and ECD2 on HER2.9 The pan-HER, oral tyrosine kinase inhibitor neratinib has also demonstrated activity in several HER2-mutated solid tumors. Another method is to combine a small-molecule inhibitor, tucatinib, with an anti-HER2 monoclonal antibody, trastuzumab, which demonstrated some success in breast cancer. The antibody–drug conjugate trastuzumab deruxtecan, currently used in gastric cancer, was studied in the HERB trial, a single-arm phase 2 study of HER2-expressing advanced BTC. In HER2-positive patients, the confirmed ORR was 36.4%.10 It is interesting to note that HER2-positive patients experienced a longer median PFS whereas HER2-low–expressing patients had a longer median OS.

Incorporating HER2 therapies with ICIs in the first-line setting is also an important area of interest. In KEYNOTE-811, the addition of pembrolizumab to chemotherapy and trastuzumab in HER2-positive gastric cancer improved ORR by 22.7%.11 The innate immune system is also an area of interest where a CD47 blocker is currently being studied in combination with trastuzumab as a blocker fusion protein designed to enhance activity of targeted antibodies. Although many new therapies have been investigated for this rare cancer, the challenge will be moving through drug development quickly.

PARP Inhibitors in BTC

To date, many druggable gene targets in BTC have been identified, and Vaibhav Sahai, MBBS, MS, of the University of Michigan, described the safety and efficacy of PARP inhibitors that are being investigated in a variety of mutations. First, PARP inhibitors may be able to target BRCA 1/2 or PALB2, whose interaction is necessary for DNA repair. Approximately 8% of patients with BTC harbor DNA damage repair mutations, including BRCA1/2 and PALB2. PARP inhibitors trap PARP at sites of the DNA, leading to the accumulation of double-stranded breaks, and in patients with these mutations where the homologous repair pathway is no longer effective, nonhomologous end-joining repair pathways are used that eventually lead to apoptosis or cancer-cell death. In addition, PARP inhibitors can be used to target IDH1 or IDH2 mutations, which occur in about 5% of patients with BTC and 15% of patients with iCCA. It has been seen that 2-hydroxyglutarate accumulates in the presence of IDH mutations and leads to ineffective DNA damage repair and increased sensitivity to PARP inhibitors. Finally, it has been previously thought that BAP1 mutations, which occur in about 20% to 25% of patients, may also respond to PARP inhibitors.

Many trials are currently investigating PARP inhibitors in BTC, including a phase 2 trial investigating niraparib in patients with BAP1 or other DNA damage repair mutations, and thus far, 1 patient has had a response to therapy. Although the efficacy of PARP inhibitors in a variety of mutations is unknown, several ongoing trials studying PARP inhibitors specifically in IDH mutations either alone or in combination with ICIs and ATR inhibitors are providing insight.


  1. Piha-Paul SA, Oh D-Y, Ueno M, et al. Efficacy and safety of pembrolizumab for the treatment of advanced biliary cancer: results from the KEYNOTE-158 and KEYNOTE-028 studies. Int J Cancer. 2020;147(8):2190-2198.
  2. Ueno M, Ikeda M, Morizane C, et al. Nivolumab alone or in combination with cisplatin plus gemcitabine in Japanese patients with unresectable or recurrent biliary tract cancer: a non-randomised, multicentre, open-label, phase 1 study. Lancet Gastroenterol Hepatol. 2019;4(8):611-621.
  3. Oh DY, Lee K-H, Lee D-W, et al. Gemcitabine and cisplatin plus durvalumab with or without tremelimumab in chemotherapy-naive patients with advanced biliary tract cancer: an open-label, single-centre, phase 2 study. Lancet Gastroenterol Hepatol. 2022;7(6):522-532.
  4. Oh DY, He AR, Qin S, et al. Durvalumab plus Gemcitabine and Cisplatin in Advanced Biliary Tract Cancer. NEJM Evidence. 2022;1(8).
  5. Lowery MA, Burris HA, Janku F, et al. Safety and activity of ivosidenib in patients with IDH1-mutant advanced cholangiocarcinoma: a phase 1 study. Lancet Gastroenterol Hepatol. 2019;4(9):711-720.
  6. Abou-Alfa GK, Macarulla T, Javle MM, et al. Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21(6):796-807.
  7. Zhu AX, Macarulla T, Javle MM, et al. Final overall survival efficacy results of ivosidenib for patients with advanced cholangiocarcinoma with IDH1 mutation: the phase 3 randomized clinical ClarIDHy trial. JAMA Oncology. 2021;7(11):1669-1677.
  8. Javle M, Borad MJ, Azad NS, et al. Pertuzumab and trastuzumab for HER2-positive, metastatic biliary tract cancer (MyPathway): a multicentre, open-label, phase 2a, multiple basket study. Lancet Oncol. 2021;22(9):1290-1300.
  9. Meric-Bernstam F, Hanna DL, El-Khoueiry AB, et al. Zanidatamab (ZW25) in HER2-positive biliary tract cancers (BTCs): results from a phase 1 study. J Clin Oncol. 2021; 39(suppl 3):299-299.
  10. Ohba A, Morizane C, Kawamoto Y, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients (pts) with HER2-expressing unresectable or recurrent biliary tract cancer (BTC): an investigator-initiated multicenter phase 2 study (HERB trial). J Clin Oncol. 2022;40(suppl 16):4006-4006.
  11. Janjigian YY, Kawazoe A, Yañez P, et al. The KEYNOTE-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer. Nature. 2021;600(7890):727-730.

Related Items

Surgical Approaches to CCA, Part 1: Integration with Medical Therapy
December 2022, Vol 3, No 4
A multidisciplinary approach to treating localized disease in cholangiocarcinoma (CCA) is important, and management strategies for advanced disease have the potential to be used in patients who undergo surgical resection.
Surgical Approaches to CCA, Part 2: Innovations in Surgical Techniques
December 2022, Vol 3, No 4
Improving early return to function and minimizing complications are important considerations for patients with resectable cholangiocarcinoma (CCA), but data on minimally invasive liver surgery have been limited to single or multi-institutional retrospective studies. Of note, 2 randomized studies have shown that laparoscopic removal of colorectal liver metastases improved outcomes in complication rates, length of stay, and pain burden without compromising margin status compared with open surgery.
Surgical Approaches to CCA, Part 3: Liver Transplant
December 2022, Vol 3, No 4
Historically, liver transplantation in patients with cholangiocarcinoma (CCA) was considered a contraindication at most US medical centers; however, with recent advances, the United Network for Organ Sharing (UNOS) liver intestine committee now recognizes that transplantation is indicated in hilar CCA when performed under institutional protocols with neoadjuvant chemoradiation. Maria Majella Doyle, MD, MBA, of Washington University School of Medicine and Mid America Transplant Services, discussed liver transplant in her presentation, detailing protocols and efficacy results from the Mayo Clinic and other centers in hilar CCA and beyond.
Advances in Medical Therapy of CCA, Part 2: Treatment Challenges
December 2022, Vol 3, No 4
Systemic control has always been the mainstay in the treatment of advanced biliary tract cancer (BTC), with several first- and second-line therapies approved by the US Food and Drug Administration.
Keynote: Crossfire Debates on the Management of CCA
December 2022, Vol 3, No 4
Teresa Macarulla, MD, PhD, of the Vall d’Hebron University Hospital in Barcelona, Spain, and Mark Yarchoan, MD, from Johns Hopkins Medicine, debated the question, “Should immunotherapy be standard of care in cholangiocarcinoma (CCA)?”
Panelists Discuss Emerging Therapies in BTCs
December 2022, Vol 3, No 4
Milind Javle, MD, of the MD Anderson Cancer Center, led off the roundtable dialogue on emerging therapies in biliary tract cancers (BTCs) with a discussion around methylthioadenosine phosphorylase (MTAP) loss in cholangiocarcinoma (CCA). MTAP is located on the 9p21 chromosome, where CDKN2A/B is also located.
Supportive Care and Management of Complications in BTC: A Multidisciplinary Team Approach
December 2022, Vol 3, No 4
Mark Schattner, MD, FASGE, AGAF, of Memorial Sloan Kettering Cancer Center, discussed endoscopic biliary drainage (EBD) in cholangiocarcinoma (CCA), specifically in hilar obstruction, emphasizing the different goals and techniques in patients with resectable versus unresectable disease. The ultimate goals for management of obstruction in patients with resectable CCA are to optimize them for surgery and avoid perioperative complications and unnecessary procedures.

Subscribe Today!

To sign up for our newsletter or print publications, please enter your contact information below.

I'd like to receive: