Nivolumab challenges sorafenib as first-line treatment in advanced hepatocellular carcinoma: improved response rate and trend towards longer survival
Results of the phase III CheckMate 459 trial identify nivolumab as a potential new standard of care in the first-line treatment of patients with advanced hepatocellular carcinoma. Notwithstanding the fact that the moderate increase in overall survival seen with nivolumab compared to sorafenib did not meet the predefined threshold of statistically significance (p= 0.0419), nivolumab was associated with a higher rate of better quality responses. Moreover, compared to sorafenib, nivolumab also has a more favourable and manageable toxicity profile resulting in an improved quality of life and a reduced treatment burden.
Currently, few effective treatment options are available for patients with aHCC whose tumours are not amenable to surgical resection or local therapy. Even though sorafenib is approved as a first-line treatment option in this patient group, there still remains an unmet need to improve tolerability and improve survival outcome (i.e. median overall survival [OS] with sorafenib was 10.7 months in the SHARP trial). In the phase I/II CheckMate 040 trial nivolumab previously proved to be safe and effective and as a result it was compared to sorafenib in randomized, multicentre phase III CheckMate 459 study.
Systemic therapy-naive patients with aHCC aged ≥18 years were randomized (1:1) to receive either nivolumab (240 mg IV Q2W, n=371) or sorafenib (400 mg oral BID, n=372). Stratification factors included aetiology (HCV versus non-HCV), vascular invasion and/or extrahepatic spread and geography (Asia versus non-Asia). Patients were treated until unacceptable toxicity or disease progression. The primary endpoint of this trial was OS, with objective response rate (ORR), efficacy by tumour programmed death ligand 1 (PD-L1) expression and safety as key secondary study objectives.
The median age of patients included in the trial was 65 years and all patients had an ECOG performance status of 0 or 1. PD-L1 expression levels were ≥ 1% in 19% of the patients in the nivolumab arm versus 18% of the patients in the sorafenib arm. At the time of the analysis, 10% of patients in the nivolumab arm continued treatment as compared to 2% in the sorafenib group. The main reasons for treatment discontinuation were disease progression (67% and 66% respectively), study-drug toxicity and unrelated adverse events. In both study groups, one patient died.
The median OS in the nivolumab arm was reported at 16.4 months, which was almost 2 months longer than the 14.7 months in the sorafenib arm (HR [95% CI]: 0.85 [0.72-1.02]; p=0.0752). However, this difference did not meet the predefined threshold for statistical significance (HR 0.84, p=0.0419) and as such, the study did not meet its primary endpoint. At 12 months 60% of patients in the nivolumab arm were still alive as compared to 55% in the sorafenib arm, dropping to 37% and 33%, respectively, after 24 months. In a subgroup analysis, the OS benefit seen with nivolumab was observed across all predefined subgroups. Of note, the OS data in this trial are the longest ever seen in a frontline phase III trial in aHCC patients. This ‘better than expected survival’ in the control arm might in part explain why the OS difference did not reach statistical significance.
The OS of patients treated with nivolumab was longer than what was seen with sorafenib, regardless of the baseline PD-L1 expression. However, the investigators did see a trend for a better ORR in patients with PD-L1 ≥1% (28% vs 12%). In the overall study population, the ORR increased from 7% in the sorafenib group (of which 5 patients achieved a complete response) to 15% among nivolumab treated patients (14 patients achieved a complete response).
Grade 3/4 treatment-related adverse events were reported in 22% in the nivolumab arm and 49% in the sorafenib arm and led to discontinuation in 4% and 8%, respectively. Treatment-related adverse events of the skin (28% versus 64% in the sorafenib group) and gastrointestinal adverse events (9% versus 47% in the sorafenib group) were less common in the nivolumab group. On the other hand, patients who were treated with nivolumab suffered more from endocrine adverse events (13% versus 2% in the sorafenib group). As assessed by FACT-Hep, a disease specific questionnaire that measures the effects of HCC and its treatments on patients’ QoL, fewer patients treated with nivolumab (7-29%) experienced a worsening of treatment side effects, compared to 32-53% of patients in the sorafenib group.
In summary, although CheckMate 459 did not meet its primary endpoint, nivolumab could demonstrate a clinically meaningful improvement in OS, objective response rate and complete response rate in first-line treatment of aHCC. This OS benefit was observed regardless of the PD-L1 status and across the majority of predefined subgroups. This study confirms the findings observed with second-line nivolumab in CheckMate 040. Moreover, nivolumab was associated with a favourable and manageable safety profile consistent with previous reports.
Yau T, Park JW, Finn RS, et al. CheckMate 459: A randomized, multi-center phase III study of nivolumab versus sorafenib as first-line treatment in patients with advanced hepatocellular carcinoma. Presented at ESMO 2019; AbstractLBA38.