Patients previously untreated for hepatocellular carcinoma (HCC) tolerated nivolumab better than the currently approved first-line therapy, sorafenib, and also demonstrated higher response rates with nivolumab, investigators reported at the ESMO Congress 2019 in Barcelona, Spain.
Thomas Yau, Oncology, the University of Hong Kong in Pokfulam, Hong Kong PRC, explained that survival was longer with nivolumab compared to sorafenib, even though statistical significance was not reached and clinical benefit favouring nivolumab was consistent across preplanned subgroup analyses.
The randomised, multi-centre phase CheckMate 459 study (NCT02576509) enrolled 743 patients aged 18 or more years with advanced HCC that had received no previous systemic therapy. Following 1:1 randomisation 371 patients were treated with nivolumab at 240 mg i.v. every 2 weeks and 372 patients received oral sorafenib at 400 mg twice daily.
The primary endpoint was overall survival (OS) and additional endpoints included objective response rate (ORR) and progression-free survival (PFS) by blinded independent central review per RECIST v1.1, efficacy according to tumour expression of the programmed death ligand 1 (PD-L1), and safety.
Nivolumab therapy prolonged OS but missed statistical significance for the primary endpoint
At minimum follow-up of 22.8 months, the OS analysis showed that it did not meet the predefined threshold of statistical significance (p = 0.0419).
However, OS was improved with nivolumab over sorafenib. Median OS was 16.4 months with nivolumab compared to 14.7 months with sorafenib (p = 0.0752). The 12-month OS rates were 59.7% (95% confidence interval [CI], 54.4–64.6) with nivolumab versus 55.1% (95% CI, 49.8–60.1) with sorafenib and the 24-month OS rates were 36.8% (95% CI, 31.8–41.8) versus 33.1% (95% CI, 28.3–38.0) respectively.
Median PFS was similar with both treatments; median PFS was 3.7 months (95% CI, 3.1–3.9) with nivolumab versus 3.8 months (95% CI, 3.7–4.5) with sorafenib.
Higher response rates were achieved with nivolumab especially in patients with PD-L1 tumour expression
Fifty-seven patients (15%) achieved response with nivolumab; of these 14 (4%) showed complete response (CR) and 43 patients (12%) showed partial response (PR). With sorafenib, just 26 patients showed response for an ORR of 7% that included 5 CR (1%) and 21 PR (6%).
Evaluation according to PD-L1 tumour expression showed higher response rates with nivolumab. In patients with low PD-L1 <1% tumour expression, 36 (12%) of nivolumab versus 20 (7%) of patients on sorafenib showed response. The response with nivolumab increased in patients with PD-L1 ≥1% where 20 patients (28%) on nivolumab versus 6 patients (9%) on sorafenib achieved response.
In addition, nivolumab provided clinical benefit across predefined subgroups, including hepatitis infection status, presence of vascular invasion and/or extrahepatic spread, and region (Asia versus non-Asia).
Safety profile favoured nivolumab
No new safety signals were observed with nivolumab.
Grade 3/4 treatment-related adverse events (AE) were reported in 81 patients (22%) in the nivolumab arm compared to 179 (49%) in the sorafenib arm.
Treatment discontinuation due to an AE was reported for 16 (4%) nivolumab versus 29 (8%) sorafenib patients.
More patients receiving sorafenib required post-study therapy; subsequent systemic treatment was required for 140 patients (38%) with nivolumab versus 170 patients (46%) with sorafenib.
The patient-reported findings suggest that patients in the nivolumab arm experienced better quality of life and further support clinical data that demonstrated a treatment benefit for nivolumab versus sorafenib in advanced HCC.
Arndt Vogel of theGastroenterology & Hepatology, Hannover, Germany who discussed the study findings said that formally it is another negative phase III immunotherapy study, but again with clinically meaningful safety/efficacy data. Efficacy is in line with previous reports (CheckMate-040, Keynote-224, Keynote-240). mOS has increased in first-line treatment of HCC; quality and quantity of subsequent therapies has improved. The “package” (efficacy, safety, and QoL) is in favour of nivolumab. Biomarkers are needed to identify patients that benefit from immuno(mono)therapy.
The authors noted that, although sorafenib is currently approved as first-line therapy for patients with advanced HCC, an unmet need exists to prolong survival and improve tolerability.
Nivolumab demonstrated greater tolerability and clinically meaningful improvements in OS, as well as in the overall and complete response rates as first-line treatment compared to sorafenib, despite not achieving statistical significance for the primary endpoint.
This study was funded by Bristol-Myers Squibb.
LBA38_PR – Yau T, Park JW, Finn RS, et al. CheckMate 459: A Randomized, Multi-Center Phase 3 Study of Nivolumab (NIVO) vs Sorafenib (SOR) as First-Line (1L) Treatment in Patients (pts) With Advanced Hepatocellular Carcinoma (aHCC).