Frontline Nivolumab Demonstrates Survival Benefit Over Sorafenib in Advanced HCC

The phase III CheckMate 459 trial (NCT02576509) demonstrated a clear trend towards improvement in overall survival (OS) with the treatment of nivolumab (Opdivo) versus sorafenib (Nexavar) in treatment-naïve patients with unresectable hepatocellular carcinoma (HCC). However, the study failed to meet its primary endpoint of improved OS, according to topline results.

The median OS was 16.4 months versus 14.7 months with nivolumab versus sorafenib, respectively (HR 0.85 [95% CI: 0.72—1.02];P = 0.0752). The predefined threshold of statistical significance was not met (HR 0.84,P= 0.0419), but clinical benefit was observed across subgroups that were stratified prior to randomization, including hepatitis infection status, presence of vascular invasion and/or extrahepatic spread, and Asian or non-Asian.

The multicenter, randomized, phase III clinical trial evaluated nivolumab in comparison with sorafenib as frontline treatment of patients with unresectable HCC. Overall, 743 patients with advanced HCC were randomized to receive either nivolumab (n = 371) or sorafenib (n = 372) with a minimum follow-up of 22.8 months at follow-up.

Secondary endpoints in CheckMate 459 included progression-free survival (PFS), objective response rate (ORR), and the relationship between the PD-L1 status and efficacy. The ORR in the nivolumab arm was 15% versus 7% in the sorafenib arm. Median PFS in the nivolumab arm was 3.7 months versus 3.8 months in the sorafenib arm. The ORR in patients who were PD-L1-positive with PD-L1 expression of 1% or greater was 28% in the nivolumab arm versus 9% in the sorafenib arm. In patients with less than 1% PD-L1 expression who were PD-L1-negative, the ORR was 12% versus 7%, respectively.

No new safety signals were observed in the CheckMate 459 trial. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 22% of patients in the nivolumab arm and 49% in the sorafenib arm. TRAEs led to discontinuation in 4% of patients receiving nivolumab and 8% receiving sorafenib.

Additionally, 38% of patients in the nivolumab arm and 46% in the sorafenib arm received subsequent therapy. Investigators believe the subsequent therapy may have had an impact on the median OS data that was observed in this analysis.

“We think subsequent therapy may have a significant impact on the OS,” said ThomasYau, MD. “If you look at the median duration of sorafenib, it was 3.7 months, which is consistent with all phase III sorafenib trials. However, the OS suddenly increased by several months, which is about 3 to 4 months better.”

In an interview withTargeted Oncology, Yau, associate professor at the University of Hong Kong, discussed the findings from the phase III CheckMate trial evaluating nivolumab in patients with advanced HCC compared with standard-of-care sorafenib. He highlighted the next steps for the trial following these data, which were presented at the 2019 European Society of Medical Oncology (ESMO) Congress.

TARGETED ONCOLOGY: What was the rationale for evaluating nivolumab in the frontline versus sorafenib in this patient population?

Yau:In CheckMate 040, we tested the efficacy and safety of single-agent nivolumab in the patients who are refractory to sorafenib. We observed a promising activity in that trial. We also see the use of nivolumab in patients with HCC, and most of them are effective and safe. This gave us a hint that we may be able to use nivolumab earlier as a first-line therapy, which may be a better treatment than sorafenib.

Another important rationale is that in the HCC, we have used tyrosine kinase inhibitors (TKIs) for more than 12 years. However, the OS is not  impressive. There are also many patients complaining of TRAEs associated with the TKIs. We need better treatments to improve survival but more importantly, to improve the tolerability and the quality of life (QoL). QoL in patients with HCC is important.

TARGETED ONCOLOGY: How was the trial designed?

Yau:The trial is a global, randomized, open-label phase III study to assess the efficacy, tolerability and health-related QoL of the patients with HCC. [To be enrolled in the trial,] patient had to have a histologically proven HCC, and they should have good liver functions. The majority of patients belong to Child-Pugh Class A with an ECOG performance status of 0 or 1. Most importantly, patients should be systemic therapy-naïve.

We randomized the patients in a 1:1 ratio to receive either just nivolumab or the standard dose of sorafenib until unacceptable toxicity. Before randomization, we stratified the patients. First, [patients were stratified by] the etiology of HCC. The second subgroup was the [presence of] vascular invasion and/or extrahepatic spread, and the third subgroup was geographic, meaning Asia or non-Asia. The primaryendpointof this study was OS. The secondary endpoints were PFS, response rate, and the relationship between the PD-L1 status and the efficacy. We also have another end point assessing how the QoL in the patient is related to either nivolumab or sorafenib.

In this study, we randomized the patients between January 2016 to May 2017. At the 2019 ESMO Congress, our presentation was based on our data done in June 2019.

TARGETED ONCOLOGY: What were the findings?

Yau:We found that with the use of nivolumab, the median OS was 16.4 months. This is the high-risk first-line OS we observed in the patients with HCC so far in all the clinical trials. In the patients put on sorafenib, they demonstrated a median OS of 14.7 months. We were a bit surprised by this high OS as it is almost the highest [OS] of all phase III trials of sorafenib. Taken in all together, it translates to a hazard ratio of 0.85 withPvalue of .0752.

Statistically, it just marginally missed the statistically significant [primary endpoint of OS]. However, if you look at the Kaplan-Myer OS curve between nivolumab and sorafenib, it was the first time in the frontline treatment of advanced HCC that we saw a separation of the OS curve. If you look at the nivolumab OS curve, there was no evidence of any early detriment. With a longer follow-up, we saw a very nice separation of the curve and the long tail in the patients that received nivolumab.

Regarding the secondary endpoint PFS, we saw that initially, the 2 survival curves overlap together in the initial 6 months. The median PFS in the nivolumab and sorafenib arms were pretty similar, around 3.8 months. However, the PFS curves after 6 months separate very nicely. If you look at the median PFS at 1-year and 2-years, the nivolumab arm did much better.

If you look at the response rate, our patients on nivolumab almost doubled the response rate compared with the sorafenib arm. More importantly, we had 4% of the patients achieve a complete response in contrast to only 1% of the patients in the sorafenib arm. Also, we have more patients (12%) achieve partial response (PR) in the nivolumab arm compared with 6% of patients that achieved a PR in the sorafenib arm. If you look at our data carefully, the median duration of disease control is significantly higher in the nivolumab arm, which was about 7.5 months compared with 5.6 months in the sorafenib arm.

TARGETED ONCOLOGY: Did you discover any new safety signals with nivolumab in this trial?

Yau:The patients receiving nivolumab tolerated treatment much better than sorafenib. Many patients on sorafenib complain of an increase in diarrhea, painful skin reactions, and fatigue. More importantly, if you look at the grade 3/4 treatment-related toxicities, there was a trend toward 22% in nivolumab arm compared to around 50% in the sorafenib arm.

If you look at the health-related QoL, in this trial, it was very interesting because 80% of the patients completed a health-related QoL questionnaire. If you are at base-line, they are pretty similar between the 2 arms. However, when we go through treatment, we can see all the patients on nivolumab report a much better health-related QoL than the patients on sorafenib. This is clinically meaningful, especially when we ask the patient an item, such as how much they are burdened by the burden of treatment, and patients on nivolumab haven’t gotten much change in health-related QoL. However, the majority of patients on sorafenib report problems with health-related QoL.

Taken together, we think the first-line use of nivolumab translates into a better survival and better response rate, much better tolerability and health-related QoL, although it just statistically, marginally missed the statistical significance.

TARGETED ONCOLOGY: Were patients in the sorafenib arm allowed to cross over to the nivolumab arm?

Yau:Yes. If you look at the subsequent treatment for the patients in the sorafenib group, nearly half of the patients received subsequent treatment, especially those patients who were randomized to the sorafenib arm. They received more subsequent treatment than the nivolumab arm. Around 50% of the patients in the sorafenib arm received subsequent systemic therapy, while 20% of them received immunotherapy and another 10% received an investigational treatment. The majority of the investigational treatments were immunotherapies. Although majority of these patients were refractory, we still have around 23% of patients that received a subsequent TKI after they developed refractory disease to sorafenib.

We think subsequent therapy may have a significant impact on the OS. If you look at the median duration of sorafenib, it was 3.7 months, which is very consistent with all phase III sorafenib trials. However, the OS suddenly increased by several months, which is about 3 to 4 months better. We think the main reason is due to the impact of subsequent treatment.

TARGETED ONCOLOGY: What did the PD-L1 analysis show?

Yau:This showed that the patients were either PD-L1-positive or -negative benefit from nivolumab treatment. However, we can only observe a response rate and OS in a [small number of patients]. We can only assess 18 of the enrolled patients that are PD-L1-positive. It is a small subset of patients.

TARGETED ONCOLOGY: What are the next steps for this research?

Yau:The CheckMate-459 demonstrates a strong clinical activity of nivolumab as first-line treatment for patients with advanced HCC based on the survival, the response rate, the tolerability, and more importantly, the health-related QoL. Although statistically, we have to say it did not meet the primary endpoint. However, it did show a very clinically meaningful activity. It should be considered 1 of the options for patients as a first-line treatment of advanced HCC.

Reference:

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). Presented at 2019 ESMO Congress; September 27-October 1, 2019; Bareclona, Spain.