Safety of Atezolizumab-Bevacizumab in Liver Transplanted Patients With Advanced Hepatocellular Carcinoma
The prognosis of liver transplanted (LT) patients with recurrence of hepatocellular carcinoma (HCC), especially those with progression after locoregional treatment or advanced HCC, remains poor. Current treatment modalities involve tyrosine kinase inhibitors (TKIs) characterized by a low response rate and often poor tolerability. Encouraging findings from the Imbrave 150 study, demonstrating increased survival rates coupled with favorable treatment tolerance, prompt the investigators to consider the potential of offering the combination of treatment with Atezolizumab-Bevacizumab (Atezo-Beva) to patients with LT. No data regarding the safety and efficacy of this new combination are available for patients with LT as they were not included in Imbrave 150. Immunosuppression after LT is low when compared to essentially all other organ recipients, liver recipients are considered with lower immunological risk. However, the use of ICIs has been associated with a risk of hepatic rejection in LT patients. In this study, in order to prevent acute cellular rejection (ACR) occurrence, we propose to adopt a standardized immunosuppressive regimen closed to the one used immediately after LT but with lower therapeutic goals for tacrolimus and everolimus to allow immunotherapy treatment to be effective. The better tolerance of liver grafts will probably lead to less risk of rejection with Atezo-Beva than in other organ transplants.
• All patients over 18 and under 90 years old:
• who underwent LT more than 6 months ago (to prevent the higher risk of ACR which exists within the first months after LT and to deal with populations with a lowered immunosuppressive regimen long after LT)
• with HCC recurrence diagnosis according to the EASL diagnostic criteria (33)
• with advanced HCC not accessible to surgery and locoregional treatment
• with at least one measurable untreated lesion
• With a proposal for Atezo-Beva in first line treatment made in a multidisciplinary meeting
• Adequate hematologic and end-organ function, defined by the following laboratory test results, obtained within 14 days prior to initiation of study treatment, unless otherwise specified:
‣ ANC ≥ 1.5 x 109/L (1500/µL) without granulocyte colony-stimulating factor support
⁃ Lymphocyte count ≥ 0.5 x 109/L (500/µL)
⁃ Platelet count ≥ 75 x 109/L (75,000/µL) without transfusion
⁃ Hemoglobin ≥ 90 g/L (9 g/dL). Patients may be transfused to meet this criterion.
⁃ AST, ALT ≤ 5 x upper limit of normal (ULN)
⁃ Serum bilirubin ≤ 3x ULN
⁃ creatinine clearance≥40 mL/min (calculated using the Cockcroft-Gault formula)
⁃ For patients not receiving therapeutic anticoagulation: INR or aPTT ≤ 2x ULN
⁃ Urine dipstick for proteinuria \< 2+ (within 7 days prior to initiation of study treatment). Patients discovered to have ≥ 2+ proteinuria on dipstick urinalysis at baseline should undergo a 24-hour urine collection and must demonstrate \<1 g of protein in 24 hours
• ECOG Performance Status of 0 or 1
• For women of childbearing potential and men: agreement to remain abstinent or use effective contraception during treatment and at least :
‣ 5 months after the end of the treatment with atezolizumab,
⁃ 6 months after the end of the treatment with bevacizumab
• Child-Pugh class A