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BARCELONA -- First-line treatment with nivolumab (Opdivo) for advanced hepatocellular carcinoma (HCC) did not lead to a statistically significant improvement in overall survival (OS) compared with sorafenib (Nexavar), but there were clinically meaningful improvements in response rates, a researcher reported here.

Although OS in the CheckMate 459 trial failed to meet the predefined threshold of statistical significance (hazard ratio 0.85, 95% CI 0.72-1.02, P=0.07), median OS in both arms of the study was actually the longest seen in a first-line, phase III study in advanced HCC at 16.4 months (95% CI 13.9-18.4 months) in the nivolumab arm versus 14.7 months (95% CI 11.9-17.2 months) in the sorafenib arm, according to Thomas Yau, MD, of the University of Hong Kong.

Only 22% of patients on nivolumab experienced grade 3 to 4 treatment-related adverse events (TRAEs) compared with 49% treated with the sorafenib, a tyrosine kinase inhibitor. There were also clinically meaningful differences between treatments arms in the FACT-HEP quality of life score in favor of nivolumab through to week 113 of the trial, Yau reported at the European Society for Medical Oncology (ESMO) annual meeting.

"CheckMate 429 is formally another negative phase III immunotherapy trial," observed ESMO discussant Arndt Vogel, MD, PhD, of Hannover Medical School in Germany. "But with clinically meaningful safety and efficacy data in line with the previous report of CheckMate 040, the 'package' in terms of efficacy, safety and quality of life is in favor of nivolumab."

In , nivolumab led to durable responses, a manageable safety profile, and promising long-term survival in patients with advanced HCC regardless of etiology or prior sorafenib therapy, pointed out Yau, MD, who was also involved in CheckMate 040.

CheckMate 459 randomized 371 patients to nivolumab (240 mg) given intravenously every second week, while another 372 patients received oral sorafenib (400 mg) twice a day until disease progression or unacceptable toxicity.

The median age in both groups was 65 and over 85% of both arms had advanced HCC from hepatitis C infection.

The median duration of therapy was 4.2 months for those receiving nivolumab and 3.7 months for those receiving sorafenib. At a median follow-up of 15.2 months in the nivolumab arm and a median of 13.3 months in the sorafenib arm, almost two-thirds of patients in both groups had discontinued treatment due to disease progression, Yau noted. Some 9% of nivolumab patients and 11% of those on sorafenib discontinued treatment because of treatment-related toxicity.

On the other hand, 37% of patients treated with immunotherapy and one-third of those treated with sorafenib were still alive at 24 months post-randomization, he added, and the small survival advantage seen among nivolumab patients persisted out to 36 months. Some 4% of patients on nivolumab achieved a complete response and 12% achieved a partial response versus 1% and 6%, respectively, of patients on sorafenib.

Improvement in the overall response rate (ORR) was over two-fold higher with nivolumab compared with sorafenib (odds ratio 2.41, 95% CI 1.48-3.92), Yau noted. Progression-free survival (PFS) rates were similar in both arms, at a median PFS of 3.7 months (95% CI 3.1-3.9 months) for nivolumab and 3.8 months (95% CI, 3.7-4.5 months) for sorafenib.

However, numerically more patients were free of progression at 12 months in the nivolumab arm at 22% compared with 14% of those on sorafenib, and the same was true at 24 months where 14% and 6% of patients were free of disease progression in the nivolumab versus sorafenib arms, respectively.

Looking at median OS in different subgroups, Yau noted that there was a "consistent effect" with nivolumab regardless of baseline PD-L1 expression although there was a trend toward better OS in patients with PD-L1 expression ≥1%. In this group of patients, median OS was 16.1 months (95% CI 8.4-22.3 months) whereas median OS was lower at 8.6 months (95% CI 5.7-16.3 months) in the same group of patients treated with sorafenib.

For patients with <1% of PD-L1 tumor expression, median OS was not significantly different with nivolumab at 16.7 months (95% CI 13.9-18.6 months) but it was significantly better for those on the sorafenib at a median of 15.2 months (95% CI 12.6-18.1 months), Yau reported.

For overall patient outcomes, 38% who progressed on nivolumab received subsequent systemic therapy as did 46% of patients who had failed on sorafenib.

"HCC is often diagnosed in the advanced stage, where effective treatment options are limited," Yau said in a statement. "The encouraging efficacy and favorable safety profile seen with nivolumab demonstrates the potential benefit of immunotherapy as a first-line treatment for patients with this aggressive cancer," he concluded.

Vogel noted that response assessment is increasingly relevant in advanced HCC, and that the ORR seen in CheckMate 459 is in line with previous studies.

He also emphasized that median OS in first-line, phase III studies in advanced HCC has been steadily increasing over time, possibly a reflection of the better quality -- and quantity -- of systemic therapies that patients often receive after failing first-line treatment.

Angela Lamarca, MD, of the Christie NHS Foundation Trust Manchester in England, also noted that it is becoming more apparent that immunotherapy could serve patients well as first-line treatment for advanced HCC.

"The favorable safety profile with nivolumab is of relevance," Lamarca added in a statement. "In a hypothetical scenario in which both options were available and reimbursed -- and if quality of life was shown to be better with nivolumab -- clinicians and patients may favor the option with a more tolerable safety profile."

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