New data have shown a trend toward clinically meaningful improvements in survival and response rates and a favorable safety profile with first-line immunotherapy compared to current standard treatment for advanced hepatocellular carcinoma (HCC).

The data, reported by Yau et al at the European Society for Medical Oncology (ESMO) 2019 Congress, demonstrated that despite not reaching its prespecified primary endpoint for improved overall survival, the CheckMate 459 study showed improvements in overall survival and response rates and a favorable safety profile in patients with advanced HCC treated with first-line nivolumab compared to sorafenib, a current standard of care (LBA38_PR).

CheckMate 459 Study

The phase III CheckMate 459 study randomized 743 patients with advanced hepatocellular carcinoma to nivolumab or sorafenib as first-line treatment.

Median overall survival was 16.4 months for nivolumab and 14.7 months for sorafenib (hazard ratio [HR] = 0.85; 95% confidence interval [CI] = 0.72–1.02; P = .0752). This did not meet the predefined threshold of statistical significance. However, clinical benefit was observed across predefined subgroups of patients, including those with hepatitis infection and those with vascular invasion and/or extrahepatic spread.

The overall response rate was 15% for nivolumab (including 14 patients with complete response) and 7% for sorafenib (5 patients with complete response).

Grade 3/4 treatment-related adverse were reported in 22% of patients in the nivolumab arm (81 patients) and in 49% of those given sorafenib (179 patients). These led to discontinuation in 4% (16) and 8% (29) patients, respectively.

“These results are important in the treatment of hepatocellular carcinoma, as there have been no significant advances over sorafenib in the first-line setting in more than a decade,” said study author Thomas Yau, MD, of University of Hong Kong, China. He added, “HCC is often diagnosed in the advanced stage, where effective treatment options are limited. 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.”

Dr. Yau acknowledged that the study did not meet the predefined threshold for statistically significant improvement in overall survival. “However,” he said, “the primary analysis demonstrated a clinically meaningful overall survival benefit, which is particularly impactful considering the high frequency of subsequent use of systemic therapy, including immunotherapy in the sorafenib arm. Importantly, there was also a higher complete response rate with nivolumab compared to sorafenib.” He added that the patient-reported findings suggested that patients in the nivolumab arm experienced better quality of life and further supported clinical data that demonstrated a treatment benefit for nivolumab versus sorafenib in advanced HCC.

Expert Perspective

Commenting on the relevance of the new data, Angela Lamarca, MD, PhD, Christie NHS Foundation Trust, Manchester, UK, said, “In view of the fact that the CheckMate 459 study did not meet the predefined threshold of statistical significance for its primary endpoint (overall survival), these results are unlikely to change the current standard of care. However, it is becoming more apparent that immunotherapy could have a role for the first-line treatment of advanced HCC and the differences in response rates are clinically meaningful.” She was disappointed that the higher response rate with nivolumab did not translate to improved progression-free survival or overall survival.

“The favorable safety profile with nivolumab is of relevance…[and] becomes apparent in the form of less toxicity-related treatment discontinuation with nivolumab,” said Dr. Lamarca. The potential impact on patients’ quality of life is also important, she added. “In a hypothetical scenario in which both options (sorafenib and immunotherapy) were available and reimbursed, and if quality of life was shown to be better with nivolumab (because of the better safety profile compared to sorafenib suggested in this study), clinicians and patients may favor the option with a more tolerable safety profile.” She concluded by highlighting that this study did not meet its primary endpoint and therefore conclusions were to be made cautiously and also that the high cost of immunotherapy could not be ignored.

Study Limitations

Dr. Lamarca noted that the well-designed study had two possible limitations, namely the unselected population and the predefined threshold of statistical significance. Results suggested patients with high programmed cell death ligand 1 (PD-L1) had an increased response rate only in the nivolumab arm, suggesting its potential role as a predictor biomarker. However, she said, “More research is needed to better understand how to select patients for immunotherapy. PD-L1 looks promising in this study but we need a more reliable marker to select patients who will derive benefit.…The lack of a reliable biomarker may have contributed to the study’s failure to show improved overall survival with immunotherapy.”

“In addition, the study design with a ‘high’ predefined threshold of statistical significance is generating confusion in the community with potentially beneficial therapies generating statistically negative studies,” Dr. Lamarca said. ■

Disclosure: CheckMate 459 was funded by Bristol-Myers Squibb. For full disclosures of the study authors, visit esmo.org.