Novel tremelimumab-durvalumab regimen safe, effective in advanced liver cancer
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A single 300 mg priming dose of tremelimumab in combination with durvalumab appeared safe and active among patients with advanced hepatocellular carcinoma, according to study results presented during the ASCO20 Virtual Scientific Program.
The results suggest the regimen has a better benefit-risk profile than tremelimumab administered in 75 mg doses with durvalumab or monotherapy with either drug, researchers noted.
“Immune checkpoint inhibition with anti-PD-L1 and anti-CTLA-4 antibodies drive antitumor activity and have demonstrated durable immune responses in subsets of patients with advanced hepatocellular carcinoma,” Robin Kate Kelley, MD, associate professor of clinical medicine at UCSF Helen Diller Family Comprehensive Cancer Center, said during a presentation. “Recent data suggest improved clinical outcomes using combination regimens with anti-PD-L1 agents as backbone therapy.”
Previous studies of patients with solid tumors treated with increasing doses of tremelimumab (MedImmune/AstraZeneca) showed higher priming doses of the anti-CTLA-4 agent may induce a stronger immune response and enhance antitumor activity.
Kelley and colleagues randomly assigned 332 immunotherapy-naive patients with advanced HCC to one of four treatment groups that received:
one dose of tremelimumab at 300 mg plus the anti-PD-L1 agent durvalumab (Imfinzi, AstraZeneca) at 1,500 mg, followed by durvalumab dosed at 1,500 mg every 4 weeks (T300 group; n = 75);
tremelimumab dosed at 75 mg every 4 weeks and durvalumab dosed at 1,500 every 4 weeks (four doses), followed by durvalumab at 1,500 mg every 4 weeks (T75 group; n = 84);
durvalumab dosed at 1,500 mg every 4 weeks (n = 104); or
tremelimumab dosed at 750 mg every 4 weeks (n = 69).
Safety served as the primary endpoint. Overall response rate by blinded, independent central review, duration of response, circulating lymphocytes and OS served as secondary endpoints.
Median follow-up was 11.7 months for the T300 group, 14.6 months for the T75 group, 8.9 months for the durvalumab monotherapy group and 15.8 months for the tremelimumab monotherapy group.
Results showed the T300 group had a higher confirmed ORR (22.7%; 95% CI, 13.8-33.8) than the T75 group (9.5%; 95% CI, 4.2-17.9), the durvalumab monotherapy group (9.6%; 95% CI, 4.7-17) and the tremelimumab monotherapy group (7.2%; 2.4-16.1).
Median OS was 18.7 months (95% CI, 10.8 to not reached) in the T300 group, 11.3 months (95% CI, 8.4-14.6) in the T75 group, 11.7 months (95% CI 8.5-16.9) in the durvalumab monotherapy group and 17.1 months (95% CI, 10.9 to not reached) in the tremelimumab monotherapy group.
Median duration of response was not reached in the T300 group, 13.2 months in the T75 group, 14.8 months with durvalumab monotherapy and 24 months with tremelimumab monotherapy.
Serious treatment-related adverse events occurred among 13.5% of patients in the T300 group, 11% of patients in the T75 group, 10.9% of patients in the durvalumab group and 21.7% of patients in the tremelimumab group. No deaths attributed to treatment-related adverse events occurred in the T300 or tremelimumab monotherapy groups.
Researchers identified a unique proliferative T-cell profile for patients in the T300 group. This suggests additive biologic activity in this combination.
“All groups demonstrated an acceptable safety profile, [however], T300 in combination with durvalumab provides the best benefit-risk profile,” Kelley said. “T300 in combination with durvalumab and durvalumab monotherapy are being evaluated vs. sorafenib in an ongoing phase 3 study in first-line HCC.”
Perspective
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Thomas Karasic, MD
I don’t think this study is directly practice changing. The ongoing randomized phase 3 HIMALAYA trial is looking at this combination in a larger population to see if it is better than sorafenib.
This study offered some preliminary data showing the different dosing regimens being studied in the HIMALAYA trial and could be a preview of that whenever it gets published.
It’s an interesting approach with the large induction dose instead of four doses, and results suggest it may be better to do the high dose first instead of the standard regimen.
I understand that the HIMALAYA trial has the single high dose in two of its four groups. When that study is published, we will really get a good idea about what the right approach is. We know that CTLA-4 inhibitors may work at higher doses, but they are more toxic. We need to find that right balance. I think it varies from cancer to cancer. What works in melanoma may not work in HCC.
This was an interesting approach of trying to improve efficacy without adding too much toxicity.
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Kelley RK, et al. Abstract 4508. Presented at: ASCO20 Virtual Scientific Program; May 29-31, 2020.
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