Tremelimumab plus durvalumab demonstrated encouraging safety and efficacy data compared with single agent durvalumab and tremelimumab in patients with unresectable hepatocellular carcinoma.
The combination of tremelimumab plus durvalumab (Imfinzi) produced the most promising risk/benefit profile in patients with unresectable hepatocellular carcinoma (uHCC) compared with single agent tremelimumab or durvalumab, according to results from a phase 1/2 expansion trial (NCT02519348) published in the Journal of Clinical Oncology; however, investigators noted that all regimens included in this research demonstrated tolerability and were clinically active.
In terms of safety, the study’s primary end point, investigators reported that grade 1/2 cutaneous toxicities were the most common treatment-related adverse effect (TRAE) for patient,. The most common grade 3 or higher TRAEs included aspartate aminotransferase, increased lipase, increased amylase, and diarrhea.
Serious TRAEs were observed in 24.6% of patients in the tremelimumab group, 17.6% of patients treated with 300 mg of intravenous tremelimumab for 1 cycle (T300) plus 1500 mg of durvalumab, 10.9% of patients in the durvalumab arm, and 14.6% of patients treated with 75 mg of intravenous tremelimumab once every 4 weeks for a total of 4 cycles (T75) plus 1500 mg of durvalumab. Immune-mediated AEs (imAEs) were more common in the 3 tremelimumab-containing arms (T300 plus durvalumab, 31.1%; tremelimumab, 24.6%; T75 plus durvalumab, 26.8%) compared with the durvalumab monotherapy arm (15.8%).
Additionally, in terms of efficacy outcomes, investigators reported that the confirmed overall response rate (ORR) was highest for the T300 plus durvalumab group at 24.0% (95% CI, 14.9%-35.3%), with confirmed complete responses observed in 1 patient in the T300 plus durvalumab cohort and 2 in the T75 plus durvalumab cohort.
“The encouraging safety profile and clinical activity of a single priming dose of tremelimumab combined with durvalumab once every 4 weeks suggest that this regimen may provide improved safety and durable responses versus either agent alone or versus a combination (including a lower, repeated dose of tremelimumab) in patients with uHCC,” the investigators wrote.
This expansion study was conducted in 4 parts. In part 1, patients received T75 plus durvalumab at 1500 mg intravenously once every 4 weeks (n = 75). Part 2A randomized patients to receive durvalumab monotherapy at 1500 mg intravenously once every 4 weeks (n = 104), tremelimumab monotherapy at 750 mg intravenously in 7 doses every 4 weeks and once every 12 weeks after (n = 69), or the T75 plus durvalumab combination (n = 84). Part 2B subsequently analyzed the safety of T300 plus durvalumab, and part 3 randomized patients to 1 of 4 groups: T300 plus durvalumab, durvalumab monotherapy, tremelimumab monotherapy, or T75 plus durvalumab.
Eligible patients were aged 18 years or older (or 20 years or older in Japan) and had confirmed uHCC by previous histologic diagnosis or radiologic criteria. Patients were immunotherapy naïve and had progressed on or were intolerant to sorafenib. Additionally, a class A Child-Pugh Score and an ECOG performance status of 0 or 1 were required.
Key secondary end points of the study were ORR, duration of response (DoR), time to response, progression-free survival (PFS), and overall survival (OS).
Parts 2 and 3 of enrolled 332 patients to the T300 plus durvalumab group (n = 75), durvalumab group (n = 104), tremelimumab group (n = 69), and T75 plus durvalumab group (n = 84) as of February 28, 2020. The median duration of treatment exposure was 3.7 months (range, 0.8-27.1) for the T300 plus durvalumab, 3.7 (range, 0.7-34.3) months for the durvalumab group, 3.7 months (range, 0.9-31.2) for the tremelimumab group, and 2.4 months (range, 0.6-31.4) for the T75 plus durvalumab group.
The median DoR was not reached for the T300 plus durvalumab group, and was 11.17 months for the durvalumab group, 23.95 months for the tremelimumab group, and 13.21 months for the T75 plus durvalumab group.
In terms of survival outcomes, investigators reported a median PFS of 2.17 (95% CI, 1.91-5.42) months, 2.07 (95% CI, 1.84-2.83) months, 2.69 (95% CI, 1.87-5.29) months, and 1.87 (95% CI, 1.77-2.53) months in the T300 plus durvalumab, durvalumab, tremelimumab, and T75 plus durvalumab groups, respectively. Additionally, the median OS was 18.73 months (95% CI, 10.78-27.27), 13.57 months (95% CI, 8.74-17.64), 15.11 months (95% CI, 11.33-20.50), and 11.30 months (95% CI, 8.38-14.95) in each cohort, respectively.
Regarding future efforts, the investigators concluded, “The T300 plus durvalumab regimen and durvalumab monotherapy are being evaluated versus sorafenib [Nexavar] in the ongoing phase III HIMALAYA study [NCT03298451].”
Kelley RK, Sangro B, Harris W, et al. Safety, efficacy, and pharmacodynamics of tremelimumab plus durvalumab for patients with unresectable hepatocellular carcinoma: randomized expansion of a phase I/II study. J Clin Oncol. 2021;39(27):2991-3001. doi:10.1200/JCO.20.03555