NIVOLUMAB FOR HCC

The lifespan of patients with advanced hepatocellular carcinoma and class B Child–Pugh status can be extended with the checkpoint inhibitor nivolumab (Opdivo/Bristol-Myers Squibb), new results from the CheckMate 040 trial (NCT01658878) show.

Patients lived a median of 7.6 months after treatment with the PD-1 receptor blocking antibody, reported Masatoshi Kudo, MD, PhD, from Kindai University in Osaka, Japan.

In contrast, historic data show that patients with class B Child–Pugh status who are treated with sorafenib (Nexavar, Bayer) — the first-line therapy for advanced hepatocellular carcinoma — live about 4 months, he said here at The Liver Meeting 2018.

This might not seem like much of a difference, but it's enough that the company will likely apply for approval for this indication from the US Food and Drug Administration (FDA), he told Medscape Medical News.

"I think there is a benefit" to using nivolumab, he added.

Many patients with hepatocellular carcinoma have class B Child–Pugh liver function, but these patients are often excluded from trials of advanced hepatocellular carcinoma. The benefits of sorafenib are unclear in these patients, leaving them with few options for treatment, said Kudo.

Nivolumab was approved for sorafenib-treated patients with class A Child–Pugh status and advanced hepatocellular carcinoma in Canada, the United States, and elsewhere on the basis of results from the dose-escalation and expansion phases of CheckMate 040 (Lancet. 2017;389:2492-2502).

The CheckMate 040 cohort involved patients with class B Child–Pugh status, and was the first prospective study of immunotherapy in these patients.

Of the 49 patients in the class B cohort assessed by Kudo and his colleagues, 37 had class B7 status, 11 had class B8 status, and one had class A6 status. Twenty-four of the patients had previously been treated with sorafenib and 25 had not. Median age was 67 years.

Eight had hepatitis B infection, 21 had hepatitis C infection, and 19 had an alpha-fetoprotein level of at least 400 μg/L.

These patients were less likely than the 262 CheckMate 040 patients with class A Child–Pugh status to develop extrahepatic metastases (73.5% vs 89.3%), but more likely to experience vascular invasion (40.8% vs 31.3%).

The patients received intravenous nivolumab 240 mg for 30 minutes every 2 weeks until toxicity became unacceptable or the disease progressed.

 About 45% of patients had stable disease, defined as tumors neither shrinking nor growing significantly, but the range was wide; in a few of these patients, the tumors shrank almost completely, whereas in a few others, they nearly doubled in size.

At data cutoff, two patients had ongoing responses.

During the 6- to 18-month follow-up period, the investigator-assessed overall response rate was 10.2% and the disease control rate was 55.1%.

The safety profile of nivolumab in these patients was similar to that of the CheckMate 040 patients with class A Child–Pugh status, and the rate of discontinuation because of toxic effects was similar in the class B and class A cohorts (4.1% vs 5.7%).

One of the two patients in the class B cohort who discontinued nivolumab had grade 3 hepatic function disorder; the other had grade 2 hyperbilirubinemia plus grade 3 hypertransaminasemia.

There were fewer treatment-related adverse events in the class B cohort than in the class A cohort (51.0% vs 78.6%). These included skin and subcutaneous tissue disorders, asthenia, increased levels of aspartate aminotransferase and alanine aminotransferase, increased liver function, hypertransaminasemia, abnormal hepatic function and hyperbilirubinemia, blood and lymphatic system disorders, gastrointestinal disorders, metabolism and nutrition disorders, nervous system disorders, infections and infestations, musculoskeletal and connective tissue disorders, and eye disorders.

After his presentation, Kudo was asked if the treatment worsened viral hepatitis infections. There were no flare ups, he reported, but there were not enough patients to analyze response rates on the basis of viral subgroups.

Nivolumab, which sells for about $29/mg in the United States, has been cited as an example of the costliness of checkpoint inhibitors (Am Health Drug Benefits. 2015;8[spec issue]:9).

"It's not like we're curing these patients, but it sounds like some patients are getting a survival benefit from it," said Sidney Barritt IV, MD, from the University of North Carolina at Chapel Hill.

And "this sicker population did not have any worse adverse events than the Child A population," he told Medscape Medical News. But "whether that median survival is clinically significant for the patient or the family, or gives them a benefit over doing nothing, is not entirely clear."

Still, he said, the data seem likely to lead to an FDA extension of nivolumab for patients with class B Child–Pugh status.

Kudo has disclosed no relevant financial relationships. Barritt is a consultant for Target PharmaSolutions and Dova Pharmaceuticals, and has participated in phase 3 trials of NASH drugs.

The Liver Meeting 2018: American Association for the Study of Liver Diseases (AASLD): Abstract LB-2. Presented November 12, 2018.

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