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Novel tremelimumab plus durvalumab regimen improves OS in advanced HCC

Dr. Robin Kate Kelley
University of California San Francisco, San Francisco
California
US
03 Aug 2020
Monotherapy with the immune checkpoint inhibitors (ICIs) durvalumab (anti–PD-L1) or tremelimumab (anti–CTLA-4) has demonstrated clinical responses in patients with hepatocellular carcinoma (HCC). At the American Society of Clinical Oncology 2020 Virtual Scientific Programme (ASCO 2020), Dr Robin Kate Kelley of the University of California San Francisco in San Francisco, California, US, presented results of the phase II Study 22, which demonstrated that a novel regimen containing a single priming dose of tremelimumab plus monthly durvalumab provided a favourable benefit-risk profile in patients with advanced HCC.

Immune checkpoint inhibition in advanced HCC

“Inhibition of both PD-L1 and CTLA-4 immune checkpoints can achieve deep and durable immune responses in subsets of patients with advanced HCC,” said Kelley. In particular, combination therapy or monotherapy with the anti–PD-L1 durvalumab and/or the anti–CTLA-4 tremelimumab has demonstrated clinical activity in patients with HCC. [Lancet 2017;389:2491-2502; J Clin Oncol 2020;38:193-202; J Hepatol 2013;59:81‐88; J Clin Oncol 2017, doi: 10.1200/JCO.2017.35.15_suppl.4073; J Clin Oncol 2017, doi: 10.1200/JCO.2017.35.15_suppl.4071; J Clin Oncol 2019, doi: 10.1200/JCO.2019.37.15_suppl.4012; Cheng A, et al, ESMO 2019, abstract LBA3]

“In the HCC cohort of a phase I study, durvalumab was associated with an objective response rate [ORR] of 10.3 percent and a median overall survival [OS] of 13.2 months,” Kelley noted. [J Clin Oncol 2017, doi: 10.1200/JCO.2017.35.15_suppl.4071] “Meanwhile, a small study involving 21 HCC patients with hepatitis C infection showed that tremelimumab was associated with an ORR of 17.6 percent and a median OS of 8.2 months.” [J Hepatol 2013;59:81‐88]

“Anti–PD-L1 agents, in combination with other agents including anti–CTLA-4, have shown potential in augmenting the immune response of patients with HCC, resulting in improved clinical outcomes,” she continued. “In the initial phase I safety run-in cohort of Study 22, an open-label, multicentre, global randomized trial involving patients with unresectable HCC, the combination of durvalumab plus tremelimumab [intravenous 20 mg/kg and 1 mg/kg Q4W, respectively for four doses, followed by 20 mg/kg Q4W durvalumab alone] demonstrated acceptable safety and early activity, with a confirmed ORR of 17.5 percent, prompting expansion of the study.” [J Clin Oncol 2017, doi: 10.1200/JCO.2017.35.15_suppl.4073]

Phase II Study 22: Tremelimumab plus durvalumab vs monotherapies

Increasing the dose of an anti–CTLA-4 combined with an anti–PD-L1 may induce a stronger immune response and enhanced antitumour activity, which may improve OS but also increase toxicity. [J Clin Oncol 2019, doi: 10.1200/JCO.2019.37.15_suppl.4012; Naumann RW, et al, ESMO 2019, abstract 5630; J Clin Oncol 2017, doi: 10.1200/JCO.2017.35.15_suppl.8503; J Clin Oncol 2019;37:1608-1616; J Clin Oncol 2018;36:2836-2844; J Clin Oncol 2012;30:2691-2697] In particular, high-dose tremelimumab combined with durvalumab was reported to be associated with an initial, dose-dependent burst of peripheral CD4+ and CD8+ T cells in patients with non-small-cell lung cancer. However, this burst did not recur with repeated dosing of tremelimumab. [Lancet Oncol 2016;17:299-308]

The phase II randomized expansion cohorts of Study 22 investigated whether a single priming dose of tremelimumab in combination with durvalumab would improve immune-mediated clinical activity in patients with advanced HCC while minimizing toxicity. [J Clin Oncol 2020, doi: 10.1200/JCO.2020.38.15_suppl.4508]

Study design

“Study 22 is the first head-to-head trial comparing ICIs used as monotherapy and in combination,” said Kelley. “We also evaluated the safety and efficacy of a novel regimen comprising a single priming dose of tremelimumab added to the backbone treatment of durvalumab in patients with advanced HCC.” [J Clin Oncol 2020, doi: 10.1200/JCO.2020.38.15_suppl.4508]

Study 22 included patients with unresectable HCC who progressed on, were intolerant to, or refused sorafenib and had not previously received ICIs. They were randomly assigned to one of four treatment arms: tremelimumab 750 mg Q4W monotherapy, durvalumab 1,500 mg Q4W monotherapy, or tremelimumab 75 mg Q4W plus durvalumab 1,500 mg Q4W (four doses) followed by durvalumab Q4W (T75+D arm), or the novel regimen of a single priming dose of tremelimumab 300 mg plus durvalumab 1,500 mg followed by durvalumab 1,500 mg Q4W (T300+D arm).

The primary endpoint was safety, while key secondary endpoints included OS, ORR and duration of response.

Highest median OS and ORR with T300+D

Results of Study 22 presented at ASCO 2020 were for 332 patients at data cut-off on 28 February 2020. Among the four treatment arms, median OS was the longest in the T300+D arm, at 18.73 months, demonstrating its promising clinical activity in patients with advanced HCC. (Figure)

AST-403_01

“There was also early and maintained separation of OS curves with the two regimens with higher tremelimumab dosing, namely, the T300+D and tremelimumab monotherapy arms,” noted Kelley.

ORR was also the highest with T300+D, at 24.0 percent. Patients treated with T300+D had a median time to response of 1.86 months, while the median duration of response was not yet reached at the time of data cut-off. (Table 1)

AST-403_02

“These encouraging responses were observed regardless of PD-L1 or viral status,” said Kelley.

“The study’s pharmacodynamic biomarker analysis also demonstrated a unique association between the T300+D regimen and proliferative T-cell profile,” she added. “Results suggest that the T300+D regimen has an additive biologic activity as demonstrated by the acute proliferation of CD8+ T cells in patients who exhibited an objective response, providing a strong biologic rationale for the observed treatment response.”

Tolerable AEs across all arms

“In Study 22, adverse events [AEs] were tolerable across all arms,” said Kelley. “Treatment-related serious AEs occurred in approximately 11–25 percent of patients across the four treatment arms, with the highest rate reported in the tremelimumab monotherapy arm. Treatment-related AEs requiring discontinuation occurred in 6–13 percent of patients, with the highest rate also reported in the tremelimumab monotherapy arm.” (Table 2)

AST-403_03

T300+D under evaluation in first line

The T300+D regimen is currently being investigated in the first-line setting vs sorafenib in the phase III HIMALAYA trial (Study of Durvalumab and Tremelimumab as First-line Treatment in Patients with Advanced Hepatocellular Carcinoma); OS is the primary endpoint. The study has recruited patients with unresectable, advanced HCC who have not been treated with prior systemic therapy and are not eligible for locoregional therapy. HIMALAYA is the first trial investigating dual immune checkpoint inhibition in the first-line setting for advanced HCC. [https://clinicaltrials.gov/ct2/show/NCT03298451; https://www.astrazeneca.com/media-centre/press-releases/2020/imfinzi-and-tremelimumab-granted-orphan-drug-designation-in-the-us-for-liver-cancer-20012020.html]

Summary

Study 22, conducted in a predominately second-line setting, demonstrated acceptable safety profiles in all tremelimumab/durvalumab treatment arms. No new safety signals were identified beyond the established safety profile of each agent, whether as monotherapy or in combination. Meanwhile, the novel regimen featuring a single priming dose of tremelimumab plus monthly durvalumab showed promising clinical activity in patients with advanced HCC, with the T300+D regimen providing a favourable benefit-risk profile vs the T75+D regimen and the two ICIs as monotherapies. T300+D is currently being investigated in the first-line setting vs sorafenib in patients with HCC in the phase III HIMALAYA trial.

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