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Is durvalumab a breakthrough treatment for gallbladder cancer?

Gallbladder cancer (GBC) is one of the most prevalent among biliary tract duct cancers globally. It develops within the lining of the gallbladder. The majority of the patients are diagnosed at an advanced stage of the illness, leaving themselves with fewer therapeutic options and a grim prognosis. Thus, early detection of this cancer and cutting-edge treatment options are required to boost survival prospects.


What is the prognosis for GBC?


Despite the breakthroughs in diagnostics and therapeutics, the majority of patients are still diagnosed at an advanced stage, and the currently accessible first-line treatments for this stage have limited effectiveness in terms of efficacy. Have poor efficacy. Current limitations in chemotherapy and targeted therapies make it difficult for the median overall survival to surpass five years. Furthermore, the global 5-year survival rate for advanced gallbladder cancer is only between 15-20%.


Surgery is still the sole curative option for advanced gallbladder cancer, despite the exceedingly low survival rate. Additionally, patients with gall bladder cancer may benefit from receiving chemotherapy, radiation treatment, adjuvant chemotherapy, or chemotherapy during surgery. Immunotherapy, particularly monoclonal antibodies, has been a promising therapeutic option for gallbladder cancer in recent years. Currently, patients with gallbladder cancer are prescribed nivolumab and pembrolizumab as routine third-line therapies [1].


Rationale behind the use of durvalumab


Durvalumab is a human anti-PD-L1 monoclonal antibody that has received FDA approval for the treatment of advanced urothelial carcinoma and unresectable non-small cell lung cancer. Durvalumab has shown a tolerable safety profile and long-lasting anticancer efficacy in phase 1 and 2 studies on a variety of advanced malignancies[2].


The following are some benefits of using durvalumab to treat solid tumors in people with gallbladder cancer:

  • Durvalumab blocks the interaction of programmed death (PD-1), disabling T-cell inhibition and thereby eliminating the suppression of T-cell activity.

  • Durvalumab also prevents PD-L1 from interacting with inhibitory receptor that is expressed on T-cells and antigen-presenting cells.

  • This causes the reactivation of T-cells and the release of cytokines into the tumor microenvironment.

  • This mechanism of action of durvalumab to enhance immune interactions against tumor cells justifies its use in ongoing clinical trials[3].


What is the clinical efficacy of durvalumab in GBC?


Durvalumab has been studied in more extensive clinical settings because early-phase clinical studies have shown it to be effective in treating gallbladder cancer. It is currently the subject of clinical research to see if it can improve the prognosis of gallbladder cancer. The following are the clinical trials that are being done for durvalumab:

  • On September 2, 2022, the Food and Drug Administration approved durvalumab (Imfinzi®) for adult patients with locally advanced or metastatic biliary tract cancer (BTC).It has to be used in combination with gemcitabine and cisplatin[4].

  • Durvalumab demonstrated persistent anti-tumor effectiveness in a phase III randomized controlled trial called TOPAZ (ClinicalTrials.gov identifier - NCT03875235). Durvalumab showed acceptable safety in patients with advanced or recurrent biliary duct cancer including gall bladder cancer when given along with gemicitabine and cisplatin as first-line therapy[5].

  • Another randomized, Phase Ib trial (ClinicalTrials.gov identifierNCT03257761) proved that the efficacy of a combination of guadecitabine and durvalumab improved the overall survival in patients with liver, pancreatic, bile duct, or gallbladder cancer in general or in a predetermined PD-L1-positive population[6].


Future directions!


The results of ongoing clinical trials evaluating durvalumab and other immunotherapies are eagerly awaited to assess if checkpoint inhibitors can improve clinical outcomes for patients with advanced gallbladder cancer. In the future, precise predictive biomarkers will be necessary to help the clinicians decide whether a patient will respond to checkpoint inhibitors. The relevance of tumor load as a biomarker for predicting the efficacy of immunotherapy in gallbladder cancer may also prove valuable in the future. Due to the ongoing development and improvement of clinical monoclonal antibody research, an increasing number of monoclonal antibodies are being enlisted in the army of advanced therapy for gallbladder cancer.


References


1. Z. I. Hu and K.-H. Lim, “Evolving Paradigms in the Systemic Treatment of Advanced Gallbladder Cancer: Updates in Year 2022,” Cancers (Basel), vol. 14, no. 5, p. 1249, Feb. 2022, doi: 10.3390/cancers14051249.

2. Durvalumab Improves Survival in Bile Duct Cancers - NCI,” Feb. 10, 2022. https://www.cancer.gov/news-events/cancer-currents-blog/2022/biliary-tract-cancer-durvalumab-improves-survival (accessed May 26, 2023).

3. A. Rizzo, A. D. Ricci, and G. Brandi, “Durvalumab: an investigational anti-PD-L1 antibody for the treatment of biliary tract cancer,Expert Opin Investig Drugs, vol. 30, no. 4, pp. 343–350, Apr. 2021, doi: 10.1080/13543784.2021.1897102.

4. C. for D. E. and Research, “FDA approves durvalumab for locally advanced or metastatic biliary tract cancer,” FDA, Sep. 2022, Accessed: May 26, 2023. [Online]. Available: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-durvalumab-locally-advanced-or-metastatic-biliary-tract-cancer

5. AstraZeneca, “A Phase III Randomized, Double-Blind Placebo Controlled, Multi-Regional, International Study of Durvalumab in Combination With Gemcitabine Plus Cisplatin Versus Placebo in Combination With Gemcitabine Plus Cisplatin for Patients With First-Line Advanced Biliary Tract Cancers,” clinicaltrials.gov, Clinical trial registration NCT03875235, Mar. 2023. Accessed: May 25, 2023. [Online]. Available: https://clinicaltrials.gov/ct2/show/NCT03875235

6. University of Southern California, “A Phase Ib Study of Guadecitabine (SGI-110) and Durvalumab (MEDI 4736) in Patients With Advanced Hepatocellular Carcinoma, Pancreatic Adenocarcinoma, and Cholangiocarcinoma/Gallbladder Cancer,” clinicaltrials.gov, Clinical trial registration NCT03257761, Apr. 2023. Accessed: May 25, 2023. [Online]. Available: https://clinicaltrials.gov/ct2/show/NCT03257761

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Collaborators

IIT Guwahati
University of Manchester
Rhenix Lifesciences
American university of Sharjah
IIT Delhi
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