HCC trial misses OS endpoint, but researchers report ‘clinically meaningful’ benefit with nivolumab
BARCELONA, Spain — Nivolumab did not significantly extend OS compared with sorafenib as first-line therapy for patients with advanced hepatocellular carcinoma, according to results of the randomized phase 3 CheckMate 459 trial presented at European Society for Medical Oncology Congress.
However, researchers concluded nivolumab (Opdivo, Bristol-Myers Squibb) demonstrated clinical benefit.
Median OS in this group was the longest achieved in any phase 3 trial to assess first-line therapy for patients with HCC, Thomas Yau, MBBS, MD, MRCP, FHKCP, FRCP, of University of Hong Kong, said during his presentation.
“Nivolumab also demonstrated clinically meaningful improvements in overall response rate and complete response rate, and patients had better quality of life,” Yau said.
Patients with advanced HCC whose tumors are not amenable to local therapy or surgical resection have few effective treatment options.
Sorafenib (Nexavar, Bayer), a multikinase inhibitor, is approved for first-line treatment of advanced HCC. However, efforts continue to identify therapeutic approaches that can extend survival and improve tolerability, according to study background.
Results of the CheckMate 040 trial showed the PD-1 inhibitor nivolumab induced durable responses, conferred a promising long-term survival benefit and exhibited a manageable safety profile for patients with advanced HCC regardless of tumor etiology or prior sorafenib treatment.
Yau and colleagues conducted the multicenter CheckMate 459 trial to compare the efficacy and safety of nivolumab with sorafenib for 743 adults with histologically confirmed advanced HCC who were not eligible for surgery or local therapy. All patients had Child-Pugh class A disease, as well as ECOG performance status of 0 or 1. No patients had received prior systemic therapy.
Researchers randomly assigned 371 patients to nivolumab dosed at 240 mg IV every 2 weeks. The other 372 patients received sorafenib (Nexavar, Bayer) dosed at 400 mg twice daily. Treatment continued until disease progression or unacceptable toxicity.
Baseline characteristics were well-balanced between treatment groups.
OS served as the primary endpoint. Objective response rate and PFS by blinded independent central review, efficacy by PD-L1 expression, and safety served as additional endpoints.
Minimum follow-up was 22.8 months.
Patients assigned nivolumab achieved longer median OS (16.4 months vs. 14.7 months; HR = 0.85; 95% CI, 0.72-1.02), but the difference did not reach the predefined threshold of statistical significance (P = .0419).
A numerically higher percentage of nivolumab-treated patients survived 12 months (59.7% vs. 55.1%) and 24 months (36.8% vs. 33.1%).
OS analysis by predefined subsets showed greater benefit among patients from Asia (HR = 0.74; 95% CI, 0.56-0.98), those with Barcelona Clinic Liver Cancer stage C disease (HR = 0.78; 95% CI, 0.65-0.95), and those with vascular invasion and/or extrahepatic spread (HR = 0.74; 95% CI, 0.61-0.9).
Researchers observed consistent treatment effect with nivolumab regardless of PD-L1 status, although they reported a trend toward improved OS among patients with PD-L1 expression of 1% or greater (median, 16.7 months vs. 15.2 months; HR = 0.84; 95% CI, 0.69-1.02).
Median PFS did not differ significantly between the nivolumab and sorafenib groups (3.7 months vs. 3.8 months; HR = 0.93; 95% CI, 0.79-1.1).
Researchers reported benefit with nivolumab with regard to ORR (OR = 2.41; 95% CI, 1.48-3.92), as well as rates of complete response (14% vs. 1%) and partial response (12% vs. 6%).
Nearly half of patients in both groups received subsequent therapy (49% for nivolumab and 53% for sorafenib), with 38% of those assigned nivolumab and 46% of those assigned sorafenib undergoing subsequent systemic therapy. Also, 20% of patients in the sorafenib group received subsequent immunotherapy.
The percentage of patients assigned sorafenib who received subsequent therapy may have contributed to the statistically negative trial results, Yau said.
Patients assigned sorafenib were more likely to experience grade 3/grade 4 treatment-related adverse events (49% vs. 22%) and discontinue therapy due to grade 3/grade 4 treatment-related adverse events (8% vs. 4%).
Sorafenib-treated patients also were more likely to experience skin events (any grade, 64% vs. 28%; grade 3/grade 4, 18% vs. 2%) and gastrointestinal events (any grade, 47% vs. 9%; grade 3/grade 4, 5% vs. 2%).
Researchers used FACT-Hep — a disease-specific questionnaire — to measure the effects of HCC and treatment on health care-related quality of life. Yau also reported “clinically meaningful differences” in favor of nivolumab through 113 weeks.
In addition, through 89 weeks, the rates of patients who reported experiencing worsening of treatment side effects was lower with nivolumab (range, 7% to 29%) than sorafenib (range, 32% to 53%).
“CheckMate 459 did not meet the predefined threshold of statistical significance for OS. However, nivolumab demonstrated clinically meaningful improvements in OS, ORR and complete response rate in first-line advanced HCC,” Yau said.
“Nivolumab demonstrated a favorable and manageable safety profile consistent with previous reports,” he added. “Improved quality of life and reduced treatment burden were observed for patients treated with nivolumab.” – by Mark Leiser
Reference: Yau T, et al. Abstract LBA38_PR. Presented at: European Society for Medical Oncology Congress; Sept. 27-Oct. 1, 2019; Barcelona, Spain.
Disclosures: Bristol-Myers Squibb funded this study. Yau reports a consultant/advisory role with and honoraria from Bristol-Myers Squibb. Please see the abstract for all other authors’ relevant financial disclosures.