Ipilimumab with atezolizumab-bevacizumab in patients with advanced hepatocellular carcinoma: The PRODIGE 81-FFCD 2101-TRIPLET-HCC trial

International audienceA substantial proportion of patients with hepatocellular carcinoma have to face up, sooner or later, to systemic therapy. The current standards as first line systemic therapies are either atezolizumab (anti-PD-L1) plus bevacizumab (anti-VEGF), or durvalumab (anti-PD-L1) plus tremelimumab (anti-CTLA-4). However, the median overall survival remains below 20 months, and a minority of patients become long-term survivors. Of interest in immune-oncology strategies for hepatocellular carcinoma, the objective response seems to be the most reliable surrogate marker of better overall survival. TRIPLET-HCC (NCT05665348) is a multicentre, randomised, open-label phase II-III trial designed to evaluate efficacy and safety of the triple combination by the addition of ipilimumab (anti-CTLA-4) to atezolizumab/bevacizumab, versus the double atezolizumab/bevacizumab combination. The main inclusion criteria are histologically proven BCLC-B/C HCC without previous systemic therapy. The primary objective of the phase II is the objective response rate in the triple arm, and OS in the triple versus double arms in the phase III. Secondary endpoints common to the phases II and III are the comparisons of progression-free survival, objective response rates, tolerance and quality of life. In addition, genetic and epigenetic studies from tissue and circulating DNA/RNA will be conducted to assess their prognostic or predictive value

Preliminary safety data of the PRODIGE 81-FFCD 2101-TRIPLET-HCC trial assessing the triple combination atezolizumab-bevacizumab-ipilimumab in patients (pts) treated in systemic therapy for hepatocellular carcinoma (HCC).

Meeting abstract du 2024 ASCO Annual Meeting, Chicago, Ill., 31mai au 4 juin 2024International audienceBackground: TRIPLET-HCC is a French, multicentre, randomized 1:1, open-label phase II-III trial designed to evaluate efficacy and safety of the triple combination (Arm-A) by the addition of ipilimumab (1 mg/kg for the first 4 cycles) to atezolizumab/bevacizumab (Q3W), versus the double atezolizumab/bevacizumab combination (Arm-B) for HCC eligible to systemic therapy in first line setting. The primary objective of phase II is the objective response rate in Arm-A, and overall survival in Arm-A versus Arm-B in phase III. In phase II, the first 15 pts randomized in Arm-A were assessed for a safety-run in aim to detect a potential signal of overtoxicity after the first four cycles of triple therapy (induction phase), thus allowing or forbidding the continuation of the trial. Methods: The trial started on March 2023 the 9 th . Adverse events (AE) and their imputability to treatment were reported in the eCRF by investigators. An independent data safety monitoring board (DSMB) was gathered 4 weeks after the last injection of ipilimumab of the 5 th and the 15 th patient randomized in Arm-A of phase II. The second DSMB meeting took place on November 2023 after extraction of data in November 2023 the 9 th . These data are presented in the present abstract. Results: At the DSMB meeting date, 15 patients in Arm-A were analyzed for safety while 13 patients had been randomized in Arm-B and had reached at least 4 cycles of treatment. In Arm-A, 12 pts completed the first 4 cycles of triple therapy, 1 pt received 3 cycles (sepsis), 1 pt only 2 (prednisone > 10 mg/day for grade-1 myocarditis which recovered), and 1 pt only 1 (sepsis and death). In Arm-B, 11 pts received the first 4 cycles of double therapy, 2 pts only 3 (anemia, lithiasic cholangitis). Three deaths occurred: 2 in Arm-A (1 possible related to immune-related (iR) hepatitis (not biopsy-proven) associated with sepsis, and 1 sudden death of unknow etiology), and one in Arm-B (tumor progression). Three pts in Arm-A (2 radiologic progressions, 1 death) and 1 pt in Arm-B (1 tumor progression with death) were withdrawn of the trial. Regarding grade-3/4 treatment-related adverse events (TRAE), 3 were reported in Arm-A (1 ASAT increase, 1 arterial hypertension, 1 colitis), and 2 in Arm-B (1 tumor bleeding, 1 arterial hypertension). Conclusions: The preliminary safety data from the TRIPLET-HCC trial suggest that the triple combination therapy is associated with a manageable safety profile, showing no unexpected signs of over toxicity. The DSMB's decision to continue the trial underscores the potential of this innovative therapeutic approach in improving outcomes for HCC patients. These findings support further investigation into the efficacy and long-term safety of the triple combination therapy in a broader patient population. Clinical trial information: NCT05665348

Preliminary safety data of the PRODIGE 81-FFCD 2101-TRIPLET-HCC trial assessing the triple combination atezolizumab-bevacizumab-ipilimumab in patients (pts) treated in systemic therapy for hepatocellular carcinoma (HCC).

Meeting abstract du 2024 ASCO Annual Meeting, Chicago, Ill., 31mai au 4 juin 2024International audienceBackground: TRIPLET-HCC is a French, multicentre, randomized 1:1, open-label phase II-III trial designed to evaluate efficacy and safety of the triple combination (Arm-A) by the addition of ipilimumab (1 mg/kg for the first 4 cycles) to atezolizumab/bevacizumab (Q3W), versus the double atezolizumab/bevacizumab combination (Arm-B) for HCC eligible to systemic therapy in first line setting. The primary objective of phase II is the objective response rate in Arm-A, and overall survival in Arm-A versus Arm-B in phase III. In phase II, the first 15 pts randomized in Arm-A were assessed for a safety-run in aim to detect a potential signal of overtoxicity after the first four cycles of triple therapy (induction phase), thus allowing or forbidding the continuation of the trial. Methods: The trial started on March 2023 the 9 th . Adverse events (AE) and their imputability to treatment were reported in the eCRF by investigators. An independent data safety monitoring board (DSMB) was gathered 4 weeks after the last injection of ipilimumab of the 5 th and the 15 th patient randomized in Arm-A of phase II. The second DSMB meeting took place on November 2023 after extraction of data in November 2023 the 9 th . These data are presented in the present abstract. Results: At the DSMB meeting date, 15 patients in Arm-A were analyzed for safety while 13 patients had been randomized in Arm-B and had reached at least 4 cycles of treatment. In Arm-A, 12 pts completed the first 4 cycles of triple therapy, 1 pt received 3 cycles (sepsis), 1 pt only 2 (prednisone > 10 mg/day for grade-1 myocarditis which recovered), and 1 pt only 1 (sepsis and death). In Arm-B, 11 pts received the first 4 cycles of double therapy, 2 pts only 3 (anemia, lithiasic cholangitis). Three deaths occurred: 2 in Arm-A (1 possible related to immune-related (iR) hepatitis (not biopsy-proven) associated with sepsis, and 1 sudden death of unknow etiology), and one in Arm-B (tumor progression). Three pts in Arm-A (2 radiologic progressions, 1 death) and 1 pt in Arm-B (1 tumor progression with death) were withdrawn of the trial. Regarding grade-3/4 treatment-related adverse events (TRAE), 3 were reported in Arm-A (1 ASAT increase, 1 arterial hypertension, 1 colitis), and 2 in Arm-B (1 tumor bleeding, 1 arterial hypertension). Conclusions: The preliminary safety data from the TRIPLET-HCC trial suggest that the triple combination therapy is associated with a manageable safety profile, showing no unexpected signs of over toxicity. The DSMB's decision to continue the trial underscores the potential of this innovative therapeutic approach in improving outcomes for HCC patients. These findings support further investigation into the efficacy and long-term safety of the triple combination therapy in a broader patient population. Clinical trial information: NCT05665348