Nivolumab (NIVO) + ipilimumab (IPI) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): Results from CheckMate 040.

Abstract

4012 Background: NIVO monotherapy (mono) is approved for sorafenib (SOR)-treated pts with HCC based on data from CheckMate 040 (NCT01658878), which reported an objective response rate (ORR) of 14% and median overall survival (mOS) of 16 months (mo). This is the first report of efficacy and safety of the NIVO + IPI combination in SOR-treated pts with aHCC. Methods: Pts were randomized to 3 arms: [A] NIVO 1 mg/kg + IPI 3 mg/kg Q3W (4 doses) or [B] NIVO 3 mg/kg + IPI 1 mg/kg Q3W (4 doses), each followed by NIVO 240 mg Q2W, or [C] NIVO 3 mg/kg Q2W + IPI 1 mg/kg Q6W. Treatment continued until intolerable toxicity or disease progression. Primary endpoints included safety and tolerability. Secondary endpoints included ORR (BICR per RECIST v1.1), duration of response (DOR), disease control rate (DCR), and OS. Cutoff was 25 Sep 2018. Results: 148 SOR-treated pts were randomized. Minimum follow-up for OS from last pt randomization date to data cutoff was 24 mo. At baseline: 88% had vascular invasion or extrahepatic spread, 91% had BCLC stage C, 84% discontinued SOR due to disease progression and 14% due to toxicity. Overall, ORR was 31% (7 had a complete response [CR]) with a median DOR of 17 mo; DCR was 49% and 24-mo OS rate was 40%. Pts in arm A had a mOS of 23 mo and 4 pts had a CR. The table shows additional efficacy results by arm. Overall, NIVO + IPI was well tolerated; 37% of pts had a grade 3–4 treatment-related adverse event (TRAE; most common: pruritus and rash); 5% had grade 3–4 TRAEs leading to discontinuation. Conclusions: NIVO + IPI led to clinically meaningful responses and had an acceptable safety profile in SOR-treated pts, with an ORR twice that of NIVO mono (31% and 14%, respectively). Pts in arm A had the most promising mOS of 23 mo. Clinical trial information: NCT01658878. [Table: see text]

Immune-based therapies for hepatocellular carcinoma

“…The discontinuation rate for toxicity was low at 5%. Analysis of efficacy revealed the combination to yield a 31% ORR, which compares favourably with the previous experience of nivolumab monotherapy within the same study (14%) [119].…”

Predictors of Response and Survival in Immune Checkpoint Inhibitor-Treated Unresectable Hepatocellular Carcinoma

“…Synergic benefits of combination therapy to advance-staged HCC have been explored recently [29]. Current ongoing clinical trials suggested that combination treatment with lenvatinib plus pembrolizumab, atezolizumab plus bevacizumab, or nivolumab plus ipilimumab had promising ORR higher than 30%, or even 60% [30][31][32]. As recently reported in ESMO Asia 2019, the phase 3 IMbrave 150 has demonstrated significant improvements with atezolizumab and bevacizumab over sorafenib in OS and RFS for unresectable HCC (ORR 27%, DCR 74% by RECIST 1.1).…”

Updates in immunotherapy for hepatocellular carcinoma

“…The first arm experienced a median overall survival of 22.8 months, the second and third arms reached 12 and 13 months respectively. Overall, the combination was well tolerated, with 37% of all patients experiencing grades 3-4 treatment-related adverse events [57] . Tremelimumab plus durvalumab was associated with 20% of grade 3-4 toxicities with no unexpected safety signals in an analysis from an a phase I/II trial with 40 patients who progressed on or were intolerant to sorafenib [58] .…”