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Single tremelimumab priming dose exhibits acceptable safety for advanced HCC

Audrey Abella
14 Sep 2020

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.

 

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Most Read Articles
29 Jul 2020
Adjunctive perampanel appears to be safe and effective for long-term treatment of patients with tonic‐clonic seizures, according to a posthoc analysis.
11 Aug 2020
During the Allergic Rhinitis (AR) Boot Camp held in conjunction with the Bayer Pharmacist Congress 2020, Professor Dr Baharudin Abdullah discussed the management of AR in the primary care setting and the importance of using patient profiles to guide the choice of antihistamines.
Elaine Soliven, 18 Sep 2020
Adding mepolizumab to standard of care treatment significantly reduces nasal polyp size and obstruction in adults with chronic rhinosinusitis with nasal polyps (CRSwNP), according to the SYNAPSE* study presented at ERS 2020.
Jairia Dela Cruz, 18 Feb 2020
Administering daily oral doses of adjunctive perampanel is safe and well tolerated in the treatment of young and older children with focal seizures or generalized tonic‐clonic seizures, in addition to yielding about 40–70 percent reduction in seizure frequency, according to data from the open-label 311 Core Study.