CheckMate 459: A randomized, multi-center phase III study of nivolumab (NIVO) vs sorafenib (SOR) as first-line (1L) treatment in patients (pts) with advanced hepatocellular carcinoma (aHCC)

Abstract

Abstract Background SOR is approved as 1L therapy for pts with aHCC, but there is still an unmet need to prolong survival and improve tolerability. This phase III study compared clinical efficacy and safety of NIVO with SOR as 1L therapy in pts with aHCC. Methods Systemic therapy–naive pts aged ≥18 years with aHCC were randomized 1:1 to NIVO (240mg IV Q2W) or SOR (400mg oral BID). Primary endpoint was overall survival (OS). Additional endpoints were objective response rate (ORR) and progression-free survival (PFS) by blinded independent central review per RECIST v1.1, efficacy by tumor programmed death ligand 1 (PD-L1) expression, and safety. Results 743 pts with aHCC were randomized to NIVO (n=371) or SOR (n=372) with minimum follow-up of 22.8 months at data cutoff. OS did not meet the predefined threshold of statistical significance (HR 0.84, P=0.0419). Median OS (mOS) was 16.4mo for NIVO and 14.7mo for SOR (HR 0.85 [95% CI: 0.72–1.02]; P=0.0752). Clinical benefit was observed across predefined subgroups, including hepatitis infection status, presence of vascular invasion and/or extrahepatic spread, and region (Asia vs non-Asia). ORR was 15% for NIVO (14 pts with complete response [CR]) and 7% for SOR (5 pts with CR; Table). Grade 3/4 treatment-related adverse events were reported in 81 pts (22%) in the NIVO arm and 179 pts (49%) in the SOR arm and led to discontinuation in 16 (4%) and 29 (8%) pts, respectively. No new safety signals were observed with NIVO. 140 pts (38%) in the NIVO arm and 170 pts (46%) in the SOR arm received subsequent therapy. Additional OS analyses and patient-reported outcomes will be presented to support the benefit of NIVO.Table: LBA38_PREfficacy resultsTable: LBA38_PRNIVOSORn=371n=372Median OS (95% CI), mo16.4 (13.9–18.4)14.7 (11.9–17.2)12-mo OS rate, % (95% CI)59.7 (54.4–64.6)55.1 (49.8–60.1)24-mo OS rate, % (95% CI)36.8 (31.8–41.8)33.1 (28.3–38.0)Median PFS, mo (95% CI)3.7 (3.1–3.9)3.8 (3.7–4.5)ORR, n (%)57 (15)26 (7)BOR, n (%)Complete response14 (4)5 (1)Partial response43 (12)21 (6)ORR by baseline tumor PD-L1 expression, n/n (%)PD-L1 ≥1%20/71 (28)6/64 (9)PD-L1 Conclusions Though the primary endpoint of OS did not achieve statistical significance vs SOR, NIVO showed clinically meaningful improvements in OS, ORR, and CR rate as 1L treatment for aHCC. NIVO demonstrated a favorable safety profile consistent with previous reports. Clinical trial identification NCT02576509. Editorial acknowledgement Writing and editorial assistance was provided by Andrea L. Hammons of Parexel International (Waltham, MA, USA) and funded by Bristol-Myers Squibb. Legal entity responsible for the study Bristol-Myers Squibb. Funding Bristol-Myers Squibb. Disclosure T. Yau: Honoraria (institution), Advisory / Consultancy: Bristol-Myers Squibb. R.S. Finn: Honoraria (self), Speaker Bureau / Expert testimony: AstraZeneca; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (self): Bayer; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution): Eisai; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution): Eli-Lilly; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution): Merck; Honoraria (self), Speaker Bureau / Expert testimony: Novartis; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (self): Pfizer; Honoraria (self), Speaker Bureau / Expert testimony: Roche/ Genentech. A. Cheng: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Ono Pharmaceutical; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Nucleix Ltd.; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche/Genentech; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: IQVIA; Advisory / Consultancy: Merck Sharp Dohme; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bayer Yakuhin; Speaker Bureau / Expert testimony: Amgen Taiwan; Advisory / Consultancy: Ispen; Advisory / Consultancy: Bayer Schering Pharma; Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Eisai; Advisory / Consultancy: Merck Serono; Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Novartis. P. Mathurin: Honoraria (self), Speaker Bureau / Expert testimony: Ipsen; Honoraria (self), Speaker Bureau / Expert testimony: Eisai; Honoraria (self), Speaker Bureau / Expert testimony: MSD; Honoraria (self), Speaker Bureau / Expert testimony: Bayer Healthcare ; Honoraria (self), Speaker Bureau / Expert testimony: AbbVie; Honoraria (self), Speaker Bureau / Expert testimony: Gilead; Honoraria (self), Speaker Bureau / Expert testimony: Servier; Honoraria (self), Speaker Bureau / Expert testimony: Sanofi. J. Edeline: Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Speaker Bureau / Expert testimony: MSD; Honoraria (self), Speaker Bureau / Expert testimony: AstraZeneca; Honoraria (self), Speaker Bureau / Expert testimony: IPSEN; Honoraria (self), Speaker Bureau / Expert testimony: Eisai; Honoraria (self), Speaker Bureau / Expert testimony: Bayer; Travel / Accommodation / Expenses: Amgen. M. Kudo: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Eisai; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Advisory / Consultancy: Ono; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Medico s Hirata; Research grant / Funding (institution): Otsuka; Research grant / Funding (institution): Taiho; Research grant / Funding (institution): Astellas Pharma; Research grant / Funding (institution): Chugai; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): EA Pharma; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): Gilead. J.J. Harding: Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Speaker Bureau / Expert testimony: Eisai; Honoraria (self), Speaker Bureau / Expert testimony: Exelexis; Honoraria (self), Speaker Bureau / Expert testimony: Elly Lilly ; Honoraria (self), Speaker Bureau / Expert testimony: CytomX; Honoraria (self), Speaker Bureau / Expert testimony: QED. P. Merle: Advisory / Consultancy: Bayer; Advisory / Consultancy, Research grant / Funding (institution): IPSEN; Advisory / Consultancy: Eisai; Advisory / Consultancy: Lilly; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Merck; Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy: AstraZeneca. O. Rosmorduc: Honoraria (self): Bayer; Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy: Sirtex; Honoraria (self): Eisai. L. Wyrwicz: Research grant / Funding (self): Bristol-Myers Squibb; Research grant / Funding (self): Beigene; Research grant / Funding (self): Eisai. E. Schott: Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Bayer. S.P. Choo: Honoraria (self), Speaker Bureau / Expert testimony: Bayer; Honoraria (self), Speaker Bureau / Expert testimony: Lilly; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: BMS; Honoraria (self), Advisory / Consultancy: Sirtex; Honoraria (self), Advisory / Consultancy: Eisai; Honoraria (self), Advisory / Consultancy: Ipsen. R.K. Kelley: Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Adaptimmune; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Exelixis; Honoraria (self), Speaker Bureau / Expert testimony, IDMC membership: Genentech/Roche; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Regeneron; Research grant / Funding (institution): AstraZeneca. D. Begic: Full / Part-time employment: Bristol-Myers Squibb. J. Neely: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. J. Anderson: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. B. Sangro: Advisory / Consultancy: Adaptimmune; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy: BTG; Advisory / Consultancy: H3 Biomedicine; Advisory / Consultancy, Speaker Bureau / Expert testimony: Ipsen; Advisory / Consultancy: Lilly; Advisory / Consultancy: Merck; Advisory / Consultancy: Onxeo; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Sirtex Medical; Advisory / Consultancy: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: Terumo. All other authors have declared no conflicts of interest.