Single tremelimumab priming dose exhibits acceptable safety for advanced HCC

The novel combination regimen comprising the immune checkpoint inhibitors (ICIs) durvalumab (anti-PD-L1) and tremelimumab (anti-CTLA-4) showed a favourable safety profile and clinical activity for advanced hepatocellular carcinoma (HCC), according to detailed safety data presented at ESMO GI 2020.

“Combining tremelimumab with durvalumab enhances antitumour activity by targeting two different immune mechanisms,” noted Dr Bruno Sangro from the Clinica Universidad de Navarra in Pamplona, Spain, in his presentation.

“[However,] in solid tumours, ICI regimens incorporating higher doses of anti-CTLA-4 combined with anti-PD-L1 are often associated with improved [overall survival (OS)] but with increased toxicity,” he pointed out. [J Clin Oncol 2019;37(suppl):4012; Ann Oncol 2019; 30(suppl):v851-v934; J Clin Oncol 2018;36:2836-2844]

Sangro and colleagues therefore sought to evaluate whether a single priming dose of tremelimumab with durvalumab can improve immune-mediated clinical activity in HCC patients while minimizing toxicity.

The team evaluated 332 ICI-naïve individuals (median age 63.5 years, 85.3 percent male) with advanced HCC who progressed on, were intolerant to, or refused sorafenib. Participants were randomized to four arms comprising two durvalumab 1,500 mg Q4W and tremelimumab (D+T) combination regimens (D+T300* [n=75] or D+T75** [n=84]) or two monotherapy regimens (durvalumab [n=104; D-mono] or tremelimumab*** [n=69; T-mono]). [ESMO GI 2020, abstract O-6]

The T-mono regimen was associated with the highest grade 3/4 treatment-related adverse event (TRAE) rate (43.5 percent), followed by the D+T300 (35.1 percent), D+T75 (24.4 percent), and D-mono regimens (19.8 percent).

Treatment-related discontinuation rate was also highest with T-mono (13.0 percent), followed by D+T300 (10.8 percent), D-mono (7.9 percent), and D+T75 (6.1 percent).

Five treatment-related deaths occurred in the D+T300, D+T75, and D-mono arms (n=1, 1 and 3, respectively).

Despite the high grade 3/4 TRAE rate associated with the D+T300 regimen, participants receiving this regimen had a better objective response rate (24.0 percent) compared with the other three regimens (9.5 percent [D+T75], 10.6 percent [D-mono], and 7.2 percent [T-mono]).

Median OS was longest with D+T300 (18.7 months), followed by the T-mono (15.1 months), D-mono (13.6 months), and D+T75 regimens (11.3 months).

“[Moreover, a] unique association [was observed with] the D+T300 regimen with proliferative CD8+ T-cells, [which] provides a biologic rationale for the observed treatment response,” said Sangro. This observation appears to align with evidence reflecting an initial burst of peripheral T-cells among patients with non-small-cell lung cancer who were on high-dose tremelimumab plus durvalumab. [Lancet Oncol 2016;17:299-308]

Although all regimens demonstrated acceptable safety profiles, the encouraging safety profile and clinical activity seen with D+T300 underlines the potential of this combination to provide the best benefit-risk profile compared with the other regimens, noted the researchers.

“A single, priming dose of tremelimumab combined with monthly durvalumab … showed promising clinical activity in a predominantly second-line HCC population,” said Sangro. Also, the distinctive pharmacodynamic activity observed with D+T300 further supports its use in this patient setting.

D+T300 and durvalumab are being evaluated against sorafenib for first-line HCC therapy in the ongoing phase III HIMALAYA study.