Abstract 982P
Background
Donafenib, a deuterated sorafenib derivative, has demonstrated efficacy and safety in phase Ia/Ib studies in advanced hepatocellular carcinoma (HCC). This phase II/III trial assessed efficacy of donafenib to determine noninferiority/superiority vs sorafenib as a first-line therapy for advanced HCC.
Methods
This was an open-label, randomized, parallel-controlled, and multicentre trial. Patients with unresectable/metastatic HCC, a Child-Pugh score ≤ 7 and no prior systemic therapy were randomized 1:1 oral donafenib (0.2 g): sorafenib (0.4 g) bid, until intolerable toxicity/disease progression. The primary endpoint was overall survival (OS). Secondary endpoints included specified time-point survival rates and time to progression (TTP). Efficacy analysis was primarily based on the full analysis set (FAS); predefined subgroups were analysed.
Results
Patients (668; intention-to-treat [ITT] set) were randomized to donafenib, 334: sorafenib, 334. The FAS included 659 patients (328 vs 331, respectively). Survival rates for donafenib and sorafenib at 6, 9, 12, and 18 months (FAS) were 73.5% and 72.5% (p = 0.7562), 62.2% and 57.7% (p = 0.2279), 50.6% and 45.0% (p = 0.1489), 35.4% and 28.1% (p = 0.0460). Median TTP was 3.7 vs 3.7 months (donafenib vs sorafenib; HR 0.931, 95% CI 0.777–1.117). Subgroup analysis showed median OS with donafenib was significantly longer than with sorafenib among patients with no prior locoregional treatment, no portal vein invasion ± extrahepatic metastasis, no later use of systemic chemotherapy (ITT and FAS), and among those with Barcelona clinic liver cancer stage C HCC or no later use of immune checkpoint inhibitor therapy (FAS). Table: 982P
Subgroup comparison of donafenib vs sorafenib in OS
| Subgroup | ITT | FAS | ||
| Median (months) | HR (95% CI) | Median (months) | HR (95% CI) | |
| BCLC stage C | 10.8 vs 9.7 | 0.840 (0.701, 1.007) | 11.4 vs 9.8 | 0.832 (0.693, 0.998) |
| No prior locoregional therapy | 9.7 vs 7.5 | 0.618 (0.421, 0.908) | 9.7 vs 7.5 | 0.618 (0.421, 0.908) |
| Absence of portal vein invasion ± extrahepatic metastasis | 21.7 vs 15.6 | 0.655 (0.451, 0.953) | 21.7 vs 15.6 | 0.655 (0.451, 0.953) |
| No later immune checkpoint inhibitors | 10.4 vs 9.2 | 0.835 (0.697, 1.000) | 10.5 vs 9.3 | 0.827 (0.690, 0.992) |
| No later systemic chemotherapy | 11.6 vs 9.8 | 0.818 (0.684, 0.979) | 12.0 vs 9.8 | 0.810 (0.677, 0.971) |
Conclusions
Donafenib is an effective first-line therapy for advanced HCC, with a better survival benefit than sorafenib demonstrated by this subgroup analysis.
Clinical trial identification
NCT02645981.
Editorial acknowledgement
Dr Rachael Profit of Nucleus Global.
Legal entity responsible for the study
Suzhou Zelgen Biopharmaceuticals Co., Ltd.
Funding
Suzhou Zelgen Biopharmaceuticals Co., Ltd.
Disclosure
X. Wu: Full/Part-time employment: Suzhou Zelgen Biopharmaceuticals Co., Ltd. All other authors have declared no conflicts of interest.