The Lynx Group
Cholangiocarcinoma News

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.

References

  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.

Related Items

Accelerated Approval Granted for Infigratinib for the Treatment of Metastatic Cholangiocarcinoma
Web Exclusives
Infigratinib has been approved to treat adults with previously treated locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 fusion or other rearrangement.
The Latest Research in Biliary Tract Cancers Presented at ASCO GI 2021
March 2021, Vol 2, No 1
At the CCA Summit held during the 2021 ASCO Gastrointestinal (GI) Cancers Symposium, Rachna T. Shroff, MD, MS, Chief, Section of GI Medical Oncology, University of Arizona Cancer Center, Tucson, discussed 15 clinical trials that were presented at the ASCO GI Cancers Symposium on cholangiocarcinoma (CCA) and hepatobiliary diseases. She highlighted key advances related to chemotherapy, targeted therapies, and biomarkers in the management of biliary tract cancers, including CCA.
FGFR Inhibition in Cholangiocarcinoma: Overcoming Acquired Resistance
December 2020, Vol 1, No 3
In April 2020, the FDA granted accelerated approval to pemigatinib (Pemazyre), the first targeted therapy for cholangiocarcinoma (CCA). The FGFR inhibitor was approved for adults with CCA and FGFR2 fusion.
Emerging Molecular Targets in Cholangiocarcinoma: IDH1, HER2, BRAF, and Beyond
December 2020, Vol 1, No 3
Targeted therapy has improved survival for patients with cancer across a broad spectrum of disease sites, but until recently, progress has been slow in the treatment of patients with cholangiocarcinoma (CCA).
The Oncology Pipeline Offers Hope for Patients with Cholangiocarcinoma
December 2020, Vol 1, No 3
Despite the onslaught of the COVID-19 pandemic, researchers are hard at work to develop innovative therapies that will make a difference in the lives of patients with cancer.
Genomic Testing in Cholangiocarcinoma: Look for Actionable Molecular Alterations
December 2020, Vol 1, No 3
At the 2020 Cholangiocarcinoma Summit, Nabeel El-Bardeesy, PhD, Associate Professor, Medicine, Harvard Medical School, and Associate Geneticist, Center for Cancer Research, Massachusetts General Hospital Cancer Center, Boston, MA, moderated a session titled “Molecular Biomarkers in CCA: Focus on Current and Emerging Technologies.” The session focused on how best to integrate the array of genomic testing platforms into clinical practice. The session included 2 presenters who discussed this topic.
Increasing Number of Biomarkers Being Studied in Cholangiocarcinoma Clinical Trials
December 2020, Vol 1, No 3
At diagnosis, the majority of patients with intrahepatic cholangiocarcinoma (CCA) present with advanced disease and a poor prognosis. Comprehensive genomic profiling (CGP) of intrahepatic CCA has revealed multiple potential therapeutic targets, including FGFR2, ERBB2 (HER2), and IDH1. Therefore, performing CGP early in the disease course is critical to increasing first-line clinical trial enrollment and access to treatment with FGFR inhibitors.
Managing Cholangiocarcinoma in the Setting of COVID-19: Unique Challenges and Opportunities
By Ghassan K. Abou-Alfa, MD, MBA; Bruce Lin, MD; Farshid Dayyani, MD, PhD; Richard Kim, MD; Rachna T. Shroff, MD, MS; Melinda Bachini; Milind M. Javle, MD
December 2020, Special Issue: Managing CCA in the Setting of COVID-19
The first confirmed case in the United States of the 2019 novel coronavirus (COVID-19) was reported on January 21, 2020, and as of November 27, 2020, there were >63 million confirmed cases and >1.5 million deaths globally. Despite the global impact, certain populations have been identified as having a higher risk of developing severe COVID-19 infection, including patients with cancer. Various studies have shown that patients with cancer experience particularly poor outcomes after COVID-19 infection. As a result of the pandemic, care delivery has been disrupted to some degree based on the need for prioritization and limitations on resources. Therefore, healthcare providers and patients have been continually reassessing the balance between the benefits and risks of anticancer interventions in the context of the added risk of COVID-19 infection.
Cholangiocarcinoma Year in Review Introduction
2020 Year in Review: Cholangiocarcinoma
As a result of the COVID-19 pandemic, year 2020 has witnessed unprecedented changes in the practice of medicine. The effect on medical conferences has been equally dramatic, and several major meetings have been canceled or altered. Fortunately, the oncology community adapted quickly!
Comparison of the Clinical Features, Treatment Patterns, and Tumor Mutations of Patients with Intrahepatic and Extrahepatic CCA
2020 Year in Review: Cholangiocarcinoma
Retrospective chart review data indicate that intrahepatic CCA and extrahepatic CCA exhibit disparate clinical features and molecular profile, and divergent treatment patterns.

Subscribe to CCA News

Stay up to date with personalized medicine by subscribing to recieve the free CCA News print publication or weekly e‑Newsletter.

I'd like to recieve: