Sequential or up-front triple combination with durvalumab, tremelimumab, and bevacizumab for patients with unresectable hepatocellular carcinoma (HCC): MONTBLANC.

Abstract

TPS574 Background: Escalation of treatment from one to two combined immune checkpoint inhibitors (CPI) has dramatically increased objective and clinical response in advanced hepatocellular carcinoma (HCC) patients. Establishing strategies with more than two CPI agents to further increase response while maintaining a manageable toxicity is therefore a top priority. The upfront simultaneous use of three or more CPI can yield a strong initial response to treatment, but it may also increase treatment-related toxicity. An alternative approach, which prioritizes safety over immediate response, involves utilizing different CPI doublets in a sequential manner. However, this design entails switching to a different combination only after radiological progression is observed, and recurrent progressions may lead to deteriorating liver function and treatment resistance. Trials of immunotherapy of HCC conducted in recent years showed that the efficacy of CPI, when used simultaneously, outweighs the drawbacks of their combined toxicity and that early radiological response to treatment, or the lack thereof, is a predictor of clinical outcome. In addition, failure of trials using broad-spectrum tyrosine kinase inhibitors (TKI) and CPI suggest that antibodies or narrow-spectrum TKI should be used for future CPI-based combinations in HCC studies. Based on these considerations, the MONTBLANC study is the first trial to assess the effectiveness of up-front triple treatment with a combination of the three currently approved immunological agents for HCC and to implement the concept of treatment escalation determined by lack of early radiological response (as opposed to treatment progression). Methods: The MONTBLANC study is a randomized, 2-arm phase II study on the efficacy of combinations of durvalumab, tremelimumab, and bevacizumab in patients with advanced HCC. Patients with preserved liver function (Child-Pugh A) with unresectable tumors or not amenable to local or locoregional treatment are randomized to an early escalation arm (A) or a triple treatment arm (B). Patients in arm A receive combined durvalumab and tremelimumab (STRIDE regimen). Treatment is escalated by the addition of bevacizumab upon detection of disease progression or in the absence of radiological response by the 4th month of treatment. Patients in arm B receive up-front STRIDE and bevacizumab. Treatment will continue until unacceptable toxicity or progression under the Bev-containing regimen. The primary endpoint is overall response rate (ORR). Clinical trial information: NCT05844046 .