Session V: New Molecular Targets/Pathways in CCA

December 2023, Vol 4, No 4

Moderator Milind Javle, MD, with Shubham Pant, MD, MBBS, Renuka Iyer, MD, and Vaibhav Sahai, MBBS, MS

Panelists participating in Session V discussed new molecular targets and pathways in cholangiocarcinoma (CCA). Shubham Pant, MD, MBBS, began the session with a discussion of HER2 in biliary tract cancer (BTC). HER2 is an established therapeutic target in patients with breast and gastric cancer, and a number of novel HER2-targeted therapies are being evaluated in gastrointestinal malignancies.1 Given that HER2 amplification/overexpression is observed in a subset of BTCs, including resected BTC, investigators suspect that the role of HER2-directed therapies being studied in gastrointestinal cancers may extend to patients with BTC.1 The MyPathway trial evaluated the combination of anti-HER2 antibodies pertuzumab and trastuzumab in patients with HER2-positive metastatic BTC. In this trial, the overall response rate (ORR) was 29%, median progression-free survival (PFS) was 4 months, and overall survival (OS) was 10.9 months.2 In the phase 2b HERIZON-BTC-01 study, zanidatamab, a HER2-targeted bispecific antibody, demonstrated meaningful clinical benefit in patients with HER2-amplified BTC.3 The ORR was 41.3%, and the median PFS was 5.5 months, with a manageable safety profile.3 Dr Pant also discussed a multi-institutional phase 2 trial, the Korean Cancer Study Group HB19-14 study, which evaluated the clinical activity of trastuzumab plus gemcitabine/cisplatin combination therapy as initial treatment in patients with HER2-positive BTC.4 This treatment regimen resulted in a 12-month OS rate of 39.1% and median OS of 9.96 months.4 The 12-month PFS rate was 17.6%, and the median PFS was 7 months.4 Dr Pant concluded that these data support the continued development of HER2-targeted therapies as a future treatment option in patients with HER2-positive BTC.

Renuka Iyer, MD, presented on antibody–drug conjugates (ADCs), which are complex molecules that combine the specificity of monoclonal antibodies with the potency of chemotherapy.5 Many variants of ADCs are known, including antibody–steroid conjugates, antibody–antibody conjugates, antibody–oligonucleotide conjugates, immune-stimulating–antibody conjugates, antibody–degrader conjugates, alternative scaffold protein/peptide–drug conjugates, small-molecule drug conjugates, and aptamer drug conjugates.6 According to Dr Iyer, 103 clinical trials are registered in that are investigating the use of ADCs in solid tumors.6 In BTC, ADC targets currently in preclinical and clinical development include HER2, FGFR2, MUC1, glypican-1, and CD133/prominin-1. Two phase 2 clinical trials used ADCs in patients with CCA: the KAMELEON study investigated trastuzumab emtansine (T-DM1) in patients with HER2-positive advanced urothelial bladder cancer or pancreatic cancer/CCA.7 Although this study was terminated early due to recruitment difficulties, the adverse events observed were generally consistent with the known safety profile of T-DM1.7 Dr Iyer also discussed the HERB trial, which investigated trastuzumab deruxtecan in patients with HER2-positive unresectable or recurrent BTC.8 In this trial, the ORR in HER2-positive patients was 36.4%, which was a significant improvement (P=.01).8 Although several targets have been identified or investigated, they are not universally applicable and are limited to certain types of CCA. Several ADCs are in preclinical studies; however, additional novel molecular targets need to be studied; furthermore, understanding resistance to therapies will be important to optimize sequencing and combination strategies.

Vaibhav Sahai, MBBS, MS, presented on new molecular targets and pathways in CCA. In general, research has suggested that identifying actionable or potentially actionable mutations can improve survival in patients with advanced BTC, supporting the concept of molecular analysis for a personalized approach to treatment.9 Dr Sahai discussed several novel targets and drugs under active preclinical and clinical investigation, including a study evaluating KIN-3248, a next-generation, irreversible pan-FGFR inhibitor in patients with advanced CCA and other tumors that harbor FGFR2 and/or FGFR3 gene alterations. A phase 1b multicenter clinical trial investigated devimistat (CPI-613), a novel inhibitor of tumor mitochondrial metabolism, in combination with gemcitabine/cisplatin in patients with BTC. This study yielded an ORR of 45%, and the median PFS was 14.9 months.10 Clinical trials are also currently underway to investigate poly (ADP-ribose) polymerase (PARP) inhibitors, including a phase 2 study of olaparib and durvalumab in patients with IDH-mutated CCA. Dr Sahai also discussed other phase 2 clinical trials of PARP inhibitors, including a study of olaparib plus pembrolizumab in patients with advanced BTC and the BilT-02 study, a multicenter trial of rucaparib and nivolumab as maintenance therapy following first-line platinum-based chemotherapy in patients with advanced BTC.11 Several larger phase 2/3 studies are also planned or ongoing, including an ongoing phase 2/3, randomized, controlled study of the antibody CTX-009 in combination with paclitaxel versus paclitaxel alone in adult patients with unresectable, advanced, metastatic or recurrent BTC who have received 1 prior systemic chemotherapy regimen.12 CTX-009 simultaneously inhibits Delta-like 4-Notch and VEGF/VEGF-R receptor signaling pathways, thereby reducing tumor growth, which makes this a promising therapeutic target.12 The primary objective for this study is efficacy, and the primary end point is best ORR.12 Dr Sahai also discussed the SPOTLIGHT trial, a multicenter, double-blind, phase 3 trial that evaluated zolbetuximab (a monoclonal antibody) plus mFOLFOX6 in patients with claudin18.2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma.13 Patients treated with zolbetuximab plus mFOLFOX6 had a higher median OS, 18.2 months, compared with 15.5 months in patients treated with placebo and mFOLFOX6.13


  1. Oh DY, Bang YJ. HER2-targeted therapies - a role beyond breast cancer. Nat Rev Clin Oncol. 2020 Jan;17(1):33-48.
  2. 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;22:1290-1300.
  3. Harding JJ, Fan J, Oh D-Y, et al. Zanidatamab for HER2-amplified, unresectable, locally advanced or metastatic biliary tract cancer (HERIZON-BTC-01): a multicentre, single-arm, phase 2b study. Lancet Oncol. 2023;24(7):P772-P782.
  4. Ostwal VS, Mandavkar S, Bhargava PG, et al. Trastuzumab (T) plus gemcitabine-cisplatin (GC) for treatment naïve HER2 positive biliary tract adenocarcinomas (BTC): a multicentre open-label, phase II study (TAB). J Clin Oncol. 2023;41(suppl 16):abstr 4089.
  5. Dumontet C, Reichert JM, Senter PD, et al. Antibody-drug conjugates come of age in oncology. Nat Rev Drug Discov. 2023;22:641-661.
  6. Iyer R. Antibody-drug conjugates. Presented at: 5th Anniversary Cholangiocarcinoma Summit, October 19-21, 2023; Scottsdale, Arizona.
  7. de Vries EGE, Rüshoff J, Lolkema M, et al. Phase II study (KAMELEON) of single-agent T-DM1 in patients with HER2-positive advanced urothelial bladder cancer or pancreatic cancer/cholangiocarcinoma. Cancer Med. 2023;12(11):12071-12083.
  8. Ohba A, Morizane C, Ueno M, et al. Multicenter phase II trial of trastuzumab deruxtecan for HER2-positive unresectable or recurrent biliary tract cancer: HERB trial. Future Oncol. 2022;18(19):2351-2360.
  9. Oh DY, He AR, Qin S, et al. Updated overall survival (OS) from the phase III TOPAZ-1 study of durvalumab (D) or placebo (PBO) plus gemcitabine and cisplatin (+ GC) in patients (pts) with advanced biliary tract cancer (BTC). Ann Oncol. 2022;33(suppl_9):S1454-S1484.
  10. Mohan A, Griffith KA, Wuchu F, et al. Devimistat in combination with gemcitabine and cisplatin in biliary tract cancer: preclinical evaluation and phase Ib multicenter clinical trial (BilT-04). Clin Cancer Res. 2023;29(13):2394-2400.
  11. Sahai V, Griffith KA, Goff LW, et al. Phase 2 multicenter trial of rucaparib and nivolumab as maintenance therapy following first-line platinum-based chemotherapy in patients with advanced biliary tract cancer (BTC): BilT-02. J Clin Oncol. 2023;41(16_suppl):4113-4113.
  12. Fontaine M, Pilgrim S, Schuetz T. A phase 2/3 randomized, controlled study of CTX-009 in combination with paclitaxel versus paclitaxel alone in adult patients with unresectable advanced, metastatic or recurrent biliary tract cancers who have received one prior systemic chemotherapy regimen. J Clin Oncol. 2023;41(4_suppl):TPS640-TPS640.
  13. Shitara K, Lordick F, Bang YJ, et al. Zolbetuximab plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (SPOTLIGHT): a multicentre, randomised, double-blind, phase 3 trial. Lancet. 2023;401(10389):1655-1668.

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