In an interview with Targeted Oncology, Ghassan K. Abou-Alfa, MD, discusses the efficacy of tislelizumab in HCC in greater detail, along with safety and the agent’s mechanism of action.
Tislelizumab (BGB-A317), an investigational PD-1 antibody, shows efficacy in patients with unresectable hepatocellular carcinoma (HCC).1
A phase 2 study (NCT03419897) of the agent in HCC had an actual enrollment of 249 participants and an estimated completion date of February 2022. The primary end point was objective response rate. Secondary end points include duration of response, progression-free survival, disease control rate, clinical benefit rate, overall survival, percentage of participates with adverse events, and health-related quality of life.2
During the study, patients received 200mg of tislelizumab once every 3 weeks. The agent proved to be well tolerated and showed preliminary antitumor activity across a range of solid tumors in addition to HCC.
In an interview with Targeted Oncology, Ghassan K. Abou-Alfa, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, discusses the efficacy of tislelizumab in HCC in greater detail, along with safety and the agent’s mechanism of action.
Targeted Oncology: Can you give me a brief overview of your presentation?
ABOU-ALFA: It's a great honor on behalf of all your colleagues and coauthors to present the results of the global phase 2 study of tislelizumab, an investigational PD-1 antibody, in patients with unresectable hepatocellular carcinoma. In brief, we're quite excited that tislelizumab as another anti-PD-1, but with a very important specificity and regard to its mechanisms of action have been evaluated in this phase2 study and led to the finding of important results, among which is an increase response rate of close to about 13%. With importantly, 2 complete responses and 29 partial responses. And if anything, this translated into improvement in outcome, over a medium follow up close to about 9 to 10 months. Median overall survival was 12.4 months and medium progression- free survival was 2.7 months. It is important to note the 1-year overall survival was close to 52%. No doubt that this is very encouraging, especially that the therapy was tolerable. And of course, we look forward for the results of the ongoing randomized phase 3 trial evaluating tislelizumab compared to the standard, sorafenib, as first line therapy for patients with advanced unresectable HCC
What is tiselizumab’s mechanism of action?
Tislelizumab has certain particularities, and it really does. If everything yes, it's an anti-PD-1, but intriguingly, it has a very high affinity and specificity to PD-1, which is engineered because of the minimization of the binding of the FC gamma receptor on macrophages to limit the antibody dependent phagocytosis. So, as we all know, the PD-1 is like sitting in a chair where the T cells will come in and they are invited to sit on and that's why they don't attack the cell membrane of the cancer cell. And all an oral anti PD-1 does is kick this chair. So, the T cells can fall into play. Interestingly, however, with the FC gamma, this might become a little bit more of a laborious process. And if anything, the tie end of the binding of the FC gamma to the macrophages, which means the T cells are bound to the macrophage, will prevent that interaction from happening as powerful as it can be. With this extra acid that tislelizumab provided by minimizing the binding of the FC gamma receptor to the macrophages invite the direct attack of the T cells onto the tumor.
What were the results of the study? Did anything surprise you?
In details the Rational208 study, which was the global phase 2 of tislelizumab in HCC, of course, permitted patients with advanced HCC, with at least one prior line of systemic therapy and no prior exposure to anti PD-1 and PD-L1 therapy. The drug is given every three weeks, and the demographics were appropriate and equal to what we know about the disease. Even though we note here that about 50/50 of the patients was either from Asia, especially in mainland China and Taiwan, and the other 50 were in Europe. The surprises were that the response rates were rather impressive. They were about 13% overall, but more importantly, the response was almost equal if it was 1 prior line of therapy, or more than equal to prior to 2 prior lines of therapy. It was 13.8% for the 1 prior line therapy, as overall response rate, and 1.6% for the more than equal to 2 prior lines of therapy. Regardless, we had the three CRs and we also had 30 PRS. as I mentioned beforehand. The duration of response was also appealing and intriguing. We have here again, another fact that we have seen with the anti PD-1 activity, which is that the duration of responses are prolonged, enough that in the case of our study of tislelizumab, the median duration of response was not reached, despite a median response follow-up of close to 1 year: 11.7 months. It's important here to know that the response rate was displayed among all different subgroup analyses independent of gender, performance, stage, etc. More importantly, though, this translated into an overall median survival of 13.2 months, and at the same time, is this was the spring further into 13.8 months for 1 prior line of therapy, and 12.4 months for more than equal to 2 lines of therapy. The adverse events were the standard that we would see in this line of therapy, and they were thankfully limited. And they were noted for the grade 3 fatigue 0.8% and rash at 0.4%. We're happy with the increased response of 13.3% as I mentioned, duration of response with a median that's not reached, but with a follow-up of up to 1 year and add to this we had a median overall survival of 13.2 months and we will look forward for the phase 3 trial as I mentioned, which is looking at tislelizumab versus for sorafenib comparison as first-line treatment for patients with advanced HCC.
What are the next steps in this research?
The next step is the phase 3 study that's comparing tislelizumab to sorafenib in the first line setting in advanced HCC which is already ongoing. Sadly, liver cancer, as we all know, is still a dreadful disease that most of patient will die from. There is an urgent need for further therapeutic intervention. We are definitely way happier and more satisfied and grateful for all the great efforts have been done in regard to many therapies, but no doubt we still need more.