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Systemic therapy is currently the main treatment for biliary tract malignant tumors (BTC), and chemotherapy is still the basis of systemic therapy for advanced BTC. However, with the development of the concept of precision therapy and the advancement of genetic testing technology, more therapeutic targets of BTC have been discovered, bringing new breakthroughs to the field of BTC therapy. This article will review the first-, second-, and late-line treatment recommendations and related research progress of advanced BTC based on the "BTC: Clinical Practice Guidelines for the Diagnosis, Treatment, and Follow-up of ESMO" issued by the Guidelines Committee of the European Society for Medical Oncology (ESMO) in 2023 [1].
First-line treatment
Currently, chemotherapy is the standard of care for first-line treatment for BTC, and is associated with improved overall survival (OS) compared with best supportive care alone [2,3], and the OS benefit of cisplatin-gemcitabine dual therapy is more pronounced than gemcitabine monotherapy [4,5].
In international randomized controlled trials, the median OS for cisplatin-gemcitabine in patients with a performance status score (PS score) of 0-1 was 13.0 months [6]. There is insufficient evidence to recommend continuous therapy for more than 6 months, and treatment decisions should be based on individual patient tolerability and tumor response. Oxaliplatin may be considered as an alternative to cisplatin when renal function is problematic, while gemcitabine monotherapy is preferred in patients with PS 2 [7].
As an emerging treatment method, immunotherapy has been widely used in the clinical treatment of tumors. The addition of immune checkpoint inhibitors to chemotherapy has shown promising results in the first-line treatment of BTC. The phase III TOPAZ-1 study compared durvalumab plus chemotherapy (gemcitabine plus cisplatin) with placebo plus chemotherapy (gemcitabine plus cisplatin) as first-line therapy. The results showed that durvalumab plus chemotherapy improved OS compared with chemotherapy alone (HR=0.76; 95% CI 0.64 -0.91), progression-free survival (PFS), and objective response rate (ORR). It was safe and well tolerated, with no additional grade 3 to 4 treatment-related adverse events [8]. Based on this positive outcome, the cisplatin-gemcitabine-durvalumab combination has become the standard of care for first-line patients with advanced BTC.
Another phase III study, KEYNOTE-966, evaluated the efficacy and safety of pembrolizumab in combination with chemotherapy in the first-line treatment of advanced BTC. The primary endpoint was also met with pembrolizumab plus chemotherapy significantly improving OS compared with chemotherapy (HR 0.83; 95% CI 0.72–0.95, p=0.0034) with a favorable safety profile [9].
■ Recommendations
- Cisplatin-gemcitabine is recommended as first-line standard therapy for patients with PS 0-1 [I,A].
- First-line therapy should consider cisplatin-gemcitabine-durvalumab [I,A; ESMO-clinical benefit amplitude (MCBS) v1.1 score: 4].
- When renal function is problematic, oxaliplatin can be used instead of cisplatin [II,B].
- For patients with a PS of 2, gemcitabine monotherapy can be used [IV,B].
Second-line and post-line therapy
In the ABC-06 study in the United Kingdom, 5-fluorouracil-leucovorin-oxaliplatin (FOLFOX) showed some superiority in OS compared with aggressive symptomatic treatment (HR 0.69) [10]. Therefore, after first-line cisplatin-gemcitabine therapy, the use of FOLFOX in second-line therapy is recommended.
Nearly 40% of patients with BTC have genetic alterations, which can be used as potential targets for precision therapy. Therefore, molecular analysis should be performed before or during first-line therapy to guide late-line second-line or post-line therapy.
Clinically relevant mutations in isocitrate dehydrogenase (IDH) 1 and IDH2 account for approximately 10% to 20% of patients with iCCA (intrahepatic cholangiocarcinoma). Ivosidenib is an oral inhibitor of the IDH1 mutant enzyme. In the ClarIDHy study, ivosidenib significantly improved PFS in patients who progressed on first-line therapy (primary endpoint, HR 0.37, 95% CI 0.25-0.54, P < 0.0001) [11].
A phase II trial demonstrated the efficacy of fibroblast growth factor receptor (FGFR) inhibitors in patients with FGFR2 fusion-positive CCA, with objective response rates (ORRs) of 20 to 40 percent, median PFS of approximately seven months, and median OS of approximately 12 to 17 months [12,13].
In 5%-10% of patients with CCA and 20% of patients with gallbladder cancer (GBC), HER2/neu (ERBB2) may be referred to as a predictive biomarker and therapeutic target for targeted therapy. In the MyPathway basket trial, the pertuzumab-trastuzumab combination achieved an ORR of 23 percent, with a median PFS of four months and a median OS of 10.9 months [14].
BRAF mutations are detectable in about 5% of patients with CCA. In the ROAR basket trial, the BRAF inhibitor dabrafenib in combination with the MEK inhibitor trametinib achieved an ORR of 51 percent in treatment-experienced patients with the BRAF V600E mutation, with a median PFS of nine months and a median OS of 14 months [15].
It is more sensitive to therapies such as platinum-based and polyadenosine diphosphate ribose polymerase (PARP) inhibitors in patients with BTC who carry pathogenic variants in homologous recombinant DNA damage repair genes. Therefore, patients with BRCA1/2 or PALB2 mutations who respond to platinum-based therapy can be treated with PARP inhibitors and should be considered for clinical trials.
The frequency of mismatch repair defects (dMMR) in BTC is less than 1%. In the case of MSI-H, the use of ICIs for the treatment of BTC has shown clinical benefit. In the prospective, nonrandomized, phase II KEYNOTE-158 trial, 22 patients with CCA and MSI-H/dMMR were treated with pembrolizumab with an ORR of 40.9 percent, a median PFS of 4.2 months, and a median OS of 24.3 months [16].
Neurotrophin receptor tyrosine kinase (NTRK) gene fusions occur in < 0.1 percent of cases of BTC, and targeted therapy with larotrectinib or entetinib may be considered [17,18].
■ Recommendations
- FOLFOX is the standard of care in second-line therapy following cisplatin-gemcitabine therapy [I,A; ESMO-MCBS v1.1 score: 1].
- Treatment with ivosidenib is recommended for patients with CCA and IDH1 mutations who have progressed on prior ≥1-line systemic therapy [I, A; ESMO-MCBS v1.1 score 2; ESCAT score I-A; FDA approved, EMA not approved].
- FGFR inhibitor therapy is recommended for patients with FGFR2 fusions who have progressed on ≥1 prior line of systemic therapy [III,A; ESMO-MCBS v1.1 score 3; ESCAT score I-B].
- Pembrolizumab is recommended for patients with MSI-H/dMMR (high microsatellite instability/mismatch repair deficiency) who have progressed on or are intolerant to prior therapy [III,A; ESMO-MCBS v1.1 score 3; ESCAT score I-C].
- Dabrafenib + trametinib is recommended for patients with BRAFV600E mutations who have progressed on ≥1 line of systemic therapy [III,A; ESMO-MCBS v1.1 score: 3; ESCAT score: I-B; FDA approved, EMA not approved].
- PARP inhibitors may be considered for patients with BRCA1/2 or PALB2 mutations who respond to platinum-based therapy [V,B; ESCAT score: III-A].
- NTRK inhibitor therapy is recommended for patients with NTRK fusions who have progressed on or have been intolerant to prior therapy [III,A; ESCAT score: I-C].
- HER2-targeted therapy is recommended for patients with HER-2 gene alterations who have progressed on or are intolerant to prior therapy [III,A; ESCAT score: I-C].
- For patients with advanced disease who are treated with systemic and local therapy, follow-up should be performed at a frequency of 8 to 12 weeks. In addition to CT or MRI, CA 19-9 or CEA levels can be measured to observe the course of disease [IV,A].
Original source:
[1] Vogel A, Bridgewater J, Edeline J, et al. Biliary tract cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023; 34(2):127-140. doi:10.1016/j.annonc.2022.10.506
[2] survival and quality of life in advanced pancreatic and biliary cancer. Ann Oncol. 1996; 7(6):593-600.
[3] Sharma A, Dwary AD, Mohanti BK, et al. Best supportive care compared with chemotherapy for unresectable gall bladder cancer: a randomized controlled study. J Clin Oncol. 2010; 28(30):4581-4586.
[4] Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010; 362(14):1273-1281.
[5] Okusaka T, Nakachi K, Fukutomi A, et al. Gemcitabine alone or in combination with cisplatin in patients with biliary tract cancer: a comparative multicentre study in Japan. Br J Cancer. 2010; 103(4):469-474.
[6] Valle JW, Vogel A, Denlinger CS, et al. Addition of ramucirumab or merestinib to standard first-line chemotherapy for locally advanced or metastatic biliary tract cancer: a randomised, double-blind, multicentre, phase 2 study. Lancet Oncol. 2021; 22(10):1468-1482.
[7] Sharma A, Kalyan Mohanti B, Pal Chaudhary S, et al. Modified gemcitabine and oxaliplatin or gemcitabine þ cisplatin in unresectable gallbladder cancer: results of a phase III randomised controlled trial. Eur J Cancer. 2019;123:162-170.
[8] Oh DY, et al. Poster presented at 2022 ESMO Congress.
[9] Kelley RK et al., Pembrolizumab in combination with gemcitabine and cisplatin for the treatment of advanced biliary tract carcinoma: Phase 3 KEYNOTE-966 study. 2023 AACR Clinical Trial Plenary Sessions (CTPL) 02.
[10] Lamarca A, Palmer DH, Wasan HS, et al. Second-line FOLFOX chemotherapy versus active symptom control for advanced biliary tract cancer (ABC-06): a phase 3, open-label, randomised, controlled trial. Lancet Oncol. 2021; 22(5):690-701.
[11] 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.
[12] Abou-Alfa GK, Sahai V, Hollebecque A, et al. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study. Lancet Oncol. 2020; 21(5):671-684.
[13] Javle M, Lowery M, Shroff RT, et al. Phase II study of BGJ398 in patients with FGFR-altered advanced cholangiocarcinoma. J Clin Oncol. 2018; 36(3):276-282.
[14] 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.
[15] Subbiah V, Lassen U, Élez E, et al. Dabrafenib plus trametinib in patients with BRAF(V600E)-mutated biliary tract cancer (ROAR): a phase 2, open-label, single-arm, multicentre basket trial. Lancet Oncol. 2020; 21(9):1234-1243.
[16] Marabelle A, Le DT, Ascierto PA, et al. Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair-deficient cancer: results from the phase II KEYNOTE-158 study. J Clin Oncol. 2020; 38(1):1-10.
[17] Doebele RC, Drilon A, Paz-Ares L, et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials. Lancet Oncol. 2020; 21(2): 271-282.
[18] Hong DS, Shen L, van Tilburg CM, et al. Long-term efficacy and safety of larotrectinib in an integrated dataset of patients with TRK fusion cancer. J Clin Oncol. 2021; 39(suppl_15):3108.
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