Durvalumab/Tremelimumab for HCC in Patients Undergoing Liver Transplant
Promising efficacy has been seen with the use of immunotherapy for the management of patients with hepatocellular carcinoma, Now, durvalumab and tremelimumab combination therapy is being studied for this patient population listed for a liver transplant.
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A phase 2 study (NCT05027425) is investigating durvalumab (Imfinzi) and tremelimumab (Imjudo) for the treatment of patients with hepatocellular carcinoma (HCC) listed for a liver transplant.1
According to researchers at the National Institutes of Health, National Cancer Institute, HCC is the third leading cause of cancer mortality worldwide and the disease has an overall 5-year survival rate of less than 20%. While a standard part of treatment for patients with HCC is total hepatectomy and liver transplantation, adjustments were made in 2015 to the exception points for patients listed for transplantation. This adjustment resulted in a 1.79-fold higher transplant waitlist dropout within the first 6 months.
To avoid the long wait list times, clinicians have been using bridging therapy with locoregional treatment given the lack of efficacy of sorafenib (Nexavar), which was previously the only systemic option available for HCC. Recently completed randomized, controlled trials have shown there to be an overall survival (OS) benefit for patients with unresectable HCC when treated with the combination of tremelimumab and durvalumab vs sorafenib alone.
There has been demonstrable efficacy seen with the use of immunotherapy for the management of patients with HCC, and it is believed that immunotherapy has potential to bridge transplantation with accompanying improved disease-specific survival in this patient population.
In the HIMALAYA phase 3 trial (NCT03298451), treatment with durvalumab plus tremelimumab demonstrated a significant improvement in OS compared with sorafenib as frontline therapy. These data led to the approval of the combination by the FDA in October 2022 for patients with unresectable HCC.
The combination of durvalumab and tremelimumab is being further evaluated in a single-arm, open-label, phase 2, multicenter clinical trial. Here, investigators are assessing the safety of dual checkpoint inhibition prior to transplantation in patients with HCC.2 The trial plans to enroll 30 patients with HCC and cirrhosis or portal hypertension who meet UCSF criteria, have a Child–Pugh scores of less than 8, and an ECOG performance status of 0-1.
Patients aged 18 years and older are eligible for enrollment in the study if they have received no prior therapy for HCC at any time, have a body weight of >30 kg, and have adequate organ and marrow function. If patients have extrahepatic disease, recent variceal bleed, active hepatitis B or C infection, or any autoimmune or inflammatory disease, they will be excluded from the study.
After enrollment, patients will be treated with the combination of durvalumab and tremelimumab for up to 4 months. Durvalumab will be administered via intravenous (IV) infusion at 1500 mg and tremelimumab will be given via IV infusion at 300 mg, only dosed on day 1 of the first cycle. After a minimum 28-day washout, they will undergo locoregional therapy per institutional standards, and after a minimum 72-day washout from the end of immunotherapy, patients will undergo liver transplant.
Investigators are assessing the primary end point of acute cellular rejection rates. Secondary end points include adverse events during treatment, graft loss, mortality rates, radiologic responses via RECIST criteria to assess the efficacy of the immunotherapy, pathologic responses via explanted liver assessment, recurrence-free survival, and OS.
After the first ten patients are treated, there will be an interim safety analysis, and if the study can establish safety, experts hope future studies will focus on examining the efficacy of the combination.
REFERENCES:
Ryan CE, Lambdin J, Shah S, et al. Durvalumab and tremelimumab for hepatocellular carcinoma in patients listed for a liver transplant. Ann Surg Oncol. 2023;30(2):686-687. doi:10.1245/s10434-022-12811-7.
Durvalumab (MEDI4736) and tremelimumab for hepatocellular carcinoma in patients listed for a liver transplant. ClinicalTrials.gov. Updated April 6, 2023. Accessed April 18, 2023. https://clinicaltrials.gov/ct2/show/NCT05027425
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