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Toripalimab, Lenvatinib, plus Chemotherapy a Promising Combination in Advanced Unresectable Intrahepatic CCA

2020 Year in Review: Cholangiocarcinoma — December 19, 2020

The multidrug combination of toripalimab, lenvatinib plus chemotherapy with gemcitabine and oxaliplatin showed promising efficacy and tolerability in patients with intrahepatic CCA.

In patients with advanced, unresectable intrahepatic CCA, the multidrug combination of toripalimab, a new PD-1 inhibitor, plus lenvatinib (Lenvima), a multikinase inhibitor, and the chemotherapy drugs gemcitabine and oxaliplatin showed promising efficacy according to phase 2 clinical trial results presented at this year’s virtual meeting of the European Society for Medical Oncology. Results were presented by Jian Zhou, MD, PhD, Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China, and colleagues.

This phase 2, open-label, single-arm study evaluated 30 patients with advanced unresectable intrahepatic CCA. Patients received 240 mg toripalimab intravenously every 3 weeks, 8 mg lenvatinib once daily orally, and 1 g/m2 gemcitabine on days 1 and 8, and 85 g/m2 of oxaliplatin every 3 weeks intravenously for 6 cycles.

The primary end point was objective response rate (ORR) based on the Response Evaluation Criteria in Solid Tumors version 1.1; secondary outcomes included progression-free survival (PFS), overall survival (OS), and safety. Whole-exome sequencing was performed on the tumor tissue, and immunohistochemistry staining determined PD-L1 expression.

Overall, 43.3% of patients had stage IIIB CCA, 40% had stage IV disease, and 53.3% had no PD-L1 expression. In addition, 80% of the patients had a positive blood test result for hepatitis B. None of the patients had received previous therapy. The majority (70%) of patients had DNA damage repair (DDR) gene mutations.

With this multidrug combination, the ORR was 80% (95% confidence interval [CI], 61.4%-92.3%), including 1 complete response. The disease control rate was 93.3% (95% CI, 77.9%-99.2%). In 2 patients, the tumor was downstaged and subsequently resected.

The 6-month OS rate was 90%. Median PFS, median OS, and median duration of response were not reached.

The ORR was significantly associated with DDR mutations and PD-L1 expression. In patients with CCA and DDR mutations but no PD-L1, the ORR was 95% compared with 55.6% in patients without DDR mutations (P = .022). In patients with PD-L1 expression, ORR was 100% versus 68.8% (P = .048) in patients with no PD-L1 expression.

Vomiting, abnormal electrocardiogram, elevated aspartate transaminase levels, neutropenia, fatigue, nausea, and numbness were the most common (>10%) adverse events. Thirteen (43%) of the 30 patients in the study had a grade ≥3 adverse event. The most common adverse events were neutropenia, rash, and jaundice.

An important breakthrough in the treatment of multiple solid tumor cancers has recently been immune checkpoint inhibitors that target PD-1 or PD-L1.1-3 Multikinase inhibitors hold a prominent place in chemotherapy. However, the combination of PD-1 and PD-L1 inhibitors and chemotherapy can lead to significant improvements in OS and PFS in some cancers.4-7

Predictors of response to PD-1 and PD-L1 inhibitors include PD-L1 expression, tumor mutational burden, microsatellite instability, and mismatch repair-deficiency.8-10 The number of patients in this study was small. However, Zhou and colleagues have shown that patients with a high PD-1 expression and the presence of DDR mutations responded favorably to the addition of chemotherapy and an anti–PD-1 antibody to a multikinase inhibitor.

Investigators in this study concluded that in patients with intrahepatic CCA, the combination of toripalimab, lenvatinib, and chemotherapy with gemcitabine and oxaliplatin was tolerable and showed promising efficacy. Further review of this treatment combination based on these study results is warranted.

Source: Zhou , et al. Ann Oncol. 2020;38(4_suppl). Abstract 56P.


  1. Rijnders M, de Wit R, Boormans JL, et al. Systematic review of immune checkpoint inhibition in urological cancers. Eur Urol. 2017;72:411-423.
  2. Lehman JM, Gwin ME, Massion PP. Immunotherapy and targeted therapy for small cell lung cancer: there is hope. Curr Oncol Rep. 2017;19:49.
  3. Emens LA, Ascierto PA, Darcy PK, et al. Cancer immunotherapy: opportunities and challenges in the rapidly evolving clinical landscape. Eur J Cancer. 2017;81:116-129.
  4. Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016;387:1540-1550.
  5. Ribas A, Hamid O, Daud A, et al. Association of pembrolizumab with tumor response and survival among patients with advanced melanoma. JAMA. 2016;315:1600-1609. Erratum in: JAMA. 2016;315:2472.
  6. Overman MJ, Lonardi S, Wong KYM, et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair–deficient/microsatellite instability–high metastatic colorectal cancer. J Clin Oncol. 2018;36:773-779.
  7. Motzer RJ, Tannir NM, McDermott DF, et al; for the CheckMate 214 investigators. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018;378:1277-1290.
  8. Viale G, Trapani D, Curigliano G. Mismatch repair deficiency as a predictive biomarker for immunotherapy efficacy. Biomed Res Int. 2017;2017:4719194.
  9. Vareki SM, Garrigós C, Duran I. Biomarkers of response to PD-1/PD-L1 inhibition. Crit Rev Oncol Hematol. 2017;116:116-124.
  10. Chalmers ZR, Connelly CF, Fabrizio D, et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med. 2017;19:34.

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