Nivolumab Demonstrates Survival and Safety Benefit in Frontline HCC With Longer Follow-Up

Bruno Sangro, MD, PhD

Updated findings from the phase 3 CheckMate-459 trial demonstrate that the continued clinical and safety benefit of nivolumab (Opdivo) monotherapy warrants its consideration as a potential frontline standard of care for patients with advanced hepatocellular carcinoma (HCC), explained Bruno Sangro, MD, PhD.

Results from the primary analysis demonstrated a median overall survival (OS) of 16.4 months with nivolumab versus 14.7 months with sorafenib (Nexavar) in patients with previously untreated advanced HCC (HR, 0.85; 95% CI, 0.72-1.02; P = .0752).¹

A long-term survival update presented at the 2020 ESMO World Congress on Gastrointestinal Cancer revealed that at a minimum follow-up of 33.6 months, nivolumab continued to elicit a clinically meaningful survival benefit compared with sorafenib.² The 33-month OS rates were 29% and 21% with nivolumab and sorafenib, respectively.

Moreover, the prolonged survival benefit was observed regardless of PD-L1 status and viral etiology, said Sangro.

Furthermore, the updated data confirmed that the PD-1 inhibitor has a more favorable safety profile with fewer serious adverse effects (AEs) and liver function preservation compared with sorafenib.

“In this balance between improved survival rates and better tolerability, this new analysis of the CheckMate-459 study provides support of the clinical benefit of nivolumab versus sorafenib,” said Sangro. “This provides [us with] an understanding [that] a good response to nivolumab makes achieving a prolonged survival a possibility.”

In an interview with OncLive, Sangro, director of the Liver Unit at Clínica Universidad de Navarra and a professor of medicine at the Clínica Universidad de Navarra School of Medicine in Pamplona, Spain, discussed the efficacy and safety findings from the long-term analysis of the CheckMate-459 trial in advanced HCC.

OncLive: Could you provide some background on the CheckMate-459 trial and the current unmet need that exists in advanced HCC?

Sangro: The phase 3 CheckMate-459 trial tried to answer the fundamental question of whether nivolumab, a PD-1 inhibitor, was better in terms of OS than sorafenib, which was the standard of care for many years, in advanced HCC.

The study was first reported in June 2019, based on a database lock. The prespecified statistical threshold for superiority and OS was not met. However, there was a clear survival benefit [at the 8-month mark, at which point the curves separated]. We also saw a favorable safety profile.

At that time, a number of patients were censored at 12 months and particularly after 24 months. Now, we’ve run the analysis with an additional 10 months of follow-up and a database log [up to] April 2020.

What did the updated data that were presented at the 2020 ESMO World Congress on GI Cancer show?

With this new information, we now have a clearer picture of the long-term effects of nivolumab versus sorafenib. With a minimum follow-up of 33 months, the OS with nivolumab was 16.7 months compared with more than 14 months with sorafenib.

What is more important is that we are now able to see that the separation of the curves leads to an increased improvement in survival with time. At that minimum follow-up, the rate of survivors was 29% in the nivolumab arm compared with 21% in the sorafenib arm. This means that at this time point, almost 50% more patients are surviving in the nivolumab arm [versus the sorafenib arm].

This adds to a deeper understanding of the long-term benefits of nivolumab versus sorafenib in advanced HCC.

We already know that [nivolumab] comes with a better safety profile with fewer patient experiencing grade 3 or higher AEs. Moreover, fewer patients discontinue treatment due to AEs with nivolumab, and fewer patients have grade 3 or higher symptomatic AEs compared with laboratory AEs.

Was there any element of the updated analysis that surprised you? Was the survival benefit with nivolumab observed across patient subgroups?

The most important data we are presenting are the prolonged survival follow-up. We all know that OS is a meaningful end point for any clinical trial in the advanced stage because it reflects the overall patient population. As time goes on, there is an increase in the separation of the survival curve. Even if the OS remains the same, the rate of long-term survival is better in the nivolumab arm.

[Moreover], this occurs despite the fact that more patients in the sorafenib arm had a second systemic therapy after sorafenib than they did after nivolumab. Indeed, a significant proportion of patients received PD-1 or PD-L1 inhibitors following sorafenib. This could have an impact on the results that we see in the sorafenib arm.

There were 2 other pieces of information that are interesting. One is that there was no clear effect of baseline PD-L1 expression in tumors cells. Patients with higher or lower levels of PD-L1

expression have similar survival outcomes after nivolumab treatment. Differences between nivolumab and sorafenib were more obvious for the PD-L1–low group, but still the survival [rates] in the PD-L1–low and PD-L1–high subgroups were comparable.

The other interesting observation was that the survival benefit was observed across etiologies. Patients with hepatitis B and uninfected patients did as well with nivolumab. Those with viral etiologies showed better survival compared with sorafenib. This difference was absent in patients without viral infection. This is because these patients had a better survival in the sorafenib arm, not because they had worse outcomes in the nivolumab arm.

Altogether, this means that the benefit of nivolumab is maintained, irrespective of PD-L1 status or etiology.

How do the safety profiles of nivolumab and sorafenib compare?

This analysis showed that nivolumab is well tolerated in patients with advanced HCC. In the face of the current approved combination strategies or those being tested in phase 3 clinical trials, toxicities may be a significant issue. The tolerability of single-agent nivolumab deserves some interest.

AEs have an impact on patients’ lives. With nivolumab, symptomatic AEs were low, and the most common grade 3 or higher AEs were observed in less than 5% of patients. This has a strong impact on patients’ quality of life (QOL). QOL was clearly better with nivolumab than it was with sorafenib.

We have also investigated the effect [of these treatments] on liver function and [hepatic] functional reserve. We’ve studied the changes in the Child-Pugh score, or the albumin bilirubin (ALBI) score over time in both arms. We’ve been able to observe that patients [receiving] nivolumab had preserved liver function compared with patients receiving sorafenib where there was an early and sustained decline in liver function as measured by these 2 scores. This provides additional evidence of the benefit of nivolumab’s tolerability compared with sorafenib’s.

References:

1. Yau T, Park JW, Finn RS, 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). Ann Oncol. 2019;30(suppl 5):v851-v934. doi:10.1093/annonc/mdz394
2. Sangro B, Park J, Finn RS, et al. CheckMate 459: long-term survival outcomes with nivolumab versus sorafenib as first-line treatment in patients with advanced hepatocellular carcinoma. Presented at: ESMO World Congress on Gastrointestinal Cancer 2020. July 1-4, 2020; Virtual. Abstract LBA-3.