Clinically meaningful improvements in survival and response rates and a favorable safety profile have been shown with first-line immunotherapy compared to current standard treatment for advanced hepatocellular carcinoma (aHCC).
Advanced hepatocellular carcinoma is a complex condition generally associated with a poor prognosis which accounts for 6% of all cancers worldwide. It is the fifth most common malignancy, with an estimated half million new cases diagnosed per year globally, and a mortality rate equivalent to its incidence. 
New data Reported during the annual meeting of the European Society for Medical Oncology, being held in Barcelona, Spain, September 27 – October 1, 2019, shows that despite not reaching its pre-specified primary endpoint for improved overall survival, the CheckMate 459 study (NCT02576509) , a randomized, multi-center phase III trial of nivolumab vs sorafenib as first-line treatment in patients with advanced hepatocellular carcinoma, did showed improvements in overall survival and response rates as well as a favorable safety profile in patients with advanced HCC treated with first-line nivolumab (Opdivo®; Bristol-Myers Squibb Company) compared to the current standard of care sorafenib (Nexavar®; Bayer).
However, while sorafenib is the first-line treatment for advanced hepatocellular carcinoma, there is still an unmet need to prolong survival and improve tolerability.
“These results [from CheckMate 459] 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,” noted study author Thomas Yau, MD, University of Hong Kong, China.
“HCC is often diagnosed in the advanced stage, where effective treatment options are limited. The encouraging efficacy and favourable safety profile seen with nivolumab demonstrates the potential benefit of immunotherapy as a first-line treatment for patients with this aggressive cancer,” Yau added.
Although the study did not meet the predefined threshold for statistically significant improvement in overall survival, the study did show clinically beneficial results.
“However,” Yau noted, “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.”
According to Yau, the patient-reported findings suggested that patients in the nivolumab arm experienced better health related Quality of Life and further supported clinical data that demonstrated a treatment benefit for nivolumab vs. sorafenib in the treatment of patients with advanced HCC.
“In view of the fact that the CheckMate 459 study did not meet the predefined threshold of statistical significance for its primary end-point (overall survival), these results are unlikely to change the current standard of care,” said Angela Lamarca, MD, Ph.D, MSc, a medical oncologist, at the Christie NHS Foundation Trust, Manchester, UK, specialized in gastrointestinal malignancies, including hepato-pancreato-biliary (HPB) and neuroendocrine tumours (NETs).
“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,” Lamarca added.
She was disappointed that the higher response rate with nivolumab did not translate to improved progression-free survival or overall survival.
“The favourable safety profile with nivolumab is of relevance,” Lamarca said.
“The favourable safety profile becomes apparent in the form of less toxicity-related treatment discontinuation with nivolumab.” 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 favour the option with a more tolerable safety profile”. She concluded highlighting that this study did not meet its primary end-point and therefore conclusions were to be made cautiously and also that the high cost of immunotherapy could not be ignored.
Lamarca noted that the well-designed study had two possible limitations, including an unselected population and the predefined threshold of statistical significance.
The results suggested that patients with high PD-L1 had an increased response rate only in the nivolumab arm suggesting its potential role as a predictor biomarker. However, Lamarca noted that more research is needed to, in her words, “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”, she suggested.
“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,” Lamarca concluded.
Study design and results
The phase III CheckMate 459 study randomised 743 patients with advanced hepatocellular carcinoma to nivolumab or sorafenib as first-line treatment systemic therapy–naive pts aged ≥18 years with advanced hepatocellular carcinoma. These patients were randomized 1:1 to nivolumab (n=371; 240 mg IV Q2W) or sorafenib (400 mg oral BID).
The 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.
The 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=0.0752).
This did not meet the predefined threshold of statistical significance (HR 0.84, P=0.0419). However, the researchers observed a clinical benefit across predefined subgroups of patients, including those with hepatitis infection and those with vascular invasion and/or extrahepatic spread and region (Asia vs non-Asia).
The overall response rate was 15% for nivolumab (including 14 patients with complete response [CR]) and 7% for sorafenib (5 patients with complete response or [CR]).
Grade 3 / 4 treatment-related adverse were reported in 81 patients (22%) in the nivolumab arm and 179 patients (49%) treated with sorafenib. These led to discontinuation in 4% (16) and 8% (29) patients, respectively. No new safety signals were observed with nivolumab. 140 pts (38%) in the nivolumab arm and 170 pts (46%) in the sorafenib arm received subsequent therapy. Additional OS analyses and patient-reported outcomes will be presented to support the benefit of nivolumab.
The researchers concluded that, based on the outcome the primary endpoint of OS did not achieve statistical significance vs sorafenib, nivolumab, the data demonstrated clinically meaningful improvements in OS, ORR, and CR rate as firts-line treatment for patients with advanced hepatocellular carcinoma. Nivolumab demonstrated a favorable safety profile consistent with previous reports.
The CheckMate 459 study was funded by Bristol-Myers Squibb.
An Investigational Immuno-therapy Study of Nivolumab Compared to Sorafenib as a First Treatment in Patients With Advanced Hepatocellular Carcinoma – NCT02576509
 Yau T, J.W. Park JW, R.S. Finn RS, Cheng AL, Mathurin P, Edeline J, Kudo M, Han KH, 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) | LBA38_PR. To be presented by Thomas Yau during the proffered paper session on Friday, 27 September 2019, 14:00-15:30 CEST in Madrid Auditorium (Hall 2). Annals of Oncology, Volume 30, Supplement 5, October 2019
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