Lead CheckMate-040 Investigator Discusses Nivolumab in HCC

Bruno Sangro, MD, PhD

Data from the CheckMate-040 trial presented at the 2017 International Liver Congress showed promise for nivolumab (Opdivo) as a second-line therapy for patients with hepatocellular carcinoma (HCC).

The trial is evaluating the PD-1 inhibitor in patients with hepatocellular carcinoma (HCC), HCV- or HBV-infected or uninfected, who have been previously treated with sorafenib (Nexavar).

Overall response rate by blinded independent central review was 14.5% (HCV, 20.0%; HBV, 14.0%; uninfected, 12.5%). The 12-month overall survival (OS) rate was 59.9% and the median OS was 16.7 months.

“I think the main point here is that nivolumab—once available—would certainly be a valuable option for the second-line treatment of patients with HCC, which is a great unmet need. I think that is the conclusion of the study that we have presented, as well as for the global data that we have for nivolumab in HCC,” said lead study author Bruno Sangro, MD, PhD.

OncLive: What are the significant findings from CheckMate-040?

In an interview with OncLive, Sangro, head of Hepatology Unit, Internal Medicine Department, Clinica Universidad de Navarra, discussed the CheckMate-040 data and the future of immuno-oncology agents in HCC.Sangro: The trial we presented was a single-arm phase Ib/II open-label trial in which nivolumab was used for patients with advanced HCC for the first time. The population was mostly patients who had been exposed to sorafenib—the only agent approved for use in this patient population—and had either progressed on or were intolerant of sorafenib.

This was the first time that any PD-1 inhibitor was tested in an HCC population. This is a [difficult] population, because apart from liver cancer, most of these patients have liver cirrhosis. So, safety was 1 of the things that we wanted to observe very carefully from the beginning. In this regard, the results that we have observed is that nivolumab has a very similar, or even slightly better, profile in this population compared to what has been observed in other tumor types. That happened not only in patients without viral infection, but patients with infection due to hepatitis B or hepatitis C. So, it has a very good safety profile with very few adverse events related to the treatment. Particularly, very few intense adverse events, which was quite reassuring to us.

The second thing that we've observed was one of the endpoints of the trial, which was to see if there were signs of efficacy. Usually, in phase Ib/II trials, you only get a hint of the efficacy of a drug. In this case, we were a little surprised to observe that there were real signs of antitumor activity that were clinically relevant. Not only was the response rates between 15% and 20%, which is a high number for HCC, but also these responses were quite durable—the median duration of response was 17 months.

On top of that, a significant portion of those patients who had stable disease as best overall response had indeed, very prolonged stable disease. This is very likely what has driven the observation of median OS that is globally 15 months, which is quite remarkable. But, if we consider only the population of patients that have been exposed to sorafenib—so second-line setting—our median OS is even better at 16 months. This is a survival that is much higher than what had ever been reported for similar clinical trials.

What is the next step with nivolumab in this disease?

In light of these results, how do you predict immuno-oncology agents will progress in this field?

Just to have an idea, the other randomized clinical trials running in the second-line setting of this tumor [have] placebo arms [or] best supportive care arms consistently showing a median OS ranging from 7.5 to 8.5 months. So, observing 16 months is really quite reassuring in terms of antitumor efficacy of the drug.The next step that we have to take is to see if this antitumor effect that we have seen in the second-line can be transferred to the first line as a systemic therapy in advanced cases. This is an objective that is already being pursued, and in fact, a phase III large clinical trial comparing sorafenib versus nivolumab in the first-line setting is ongoing and has already finished recruitment. So, we will learn in the next few months or year if, indeed, nivolumab is also active as a first-line treatment.For checkpoint inhibitors, the wide spectrum of activity across many tumor types, including some of the most dreadful tumor types, indicate that as a class, these agents have a strong potential to transform patient care.

Are there any trials that you find promising in the field of HCC?

Beyond that point, we have a lot of interest in learning if combining immune-oncology agents with locoregional therapy, which is the main treatment worldwide for patients with liver cancer, could be of any benefit. I think it is about time to start testing if patients who are resected or go through ablation can have nivolumab or other checkpoint inhibitors as adjuvant therapies because those are unmet needs. Compared to other tumor types, we lack effective adjuvant therapies, we lack systemic therapies that may improve the outcomes of patients with locoregional therapies. There is a large phase III trial that has compared sorafenib versus a locoregional therapy yttrium-90 radioembolization that is also called selective internal radiation therapy (SIRT). The results were presented [at the 2017 International Liver Congress]. The trial, which was intended to demonstrate the superiority of SIRT versus sorafenib, was negative. But, what we have learned is that SIRT is a safe option for these patients with very advanced tumors, and the patients have a better tolerability with a significantly lower number and intensity of adverse events. So, this means that SIRT could be a tool that we could consider in multidisciplinary discussions in the treatment of patients with advanced HCC.

B. Sangro, T. Yau, C. Hsu, et al. Nivolumab in sorafenib-experienced patients with advanced hepatocellular carcinoma (HCC) with or without chronic viral hepatitis: CheckMate 040 study. Presented at: 2017 International Liver Congress; April 19-23, 2017; Amsterdam, Netherlands. Abstract GS-010.