Phase I/II CheckMate 040 Study Suggests Nivolumab Is Active and Well Tolerated As First- or Second-Line HCC Monotherapy; Phase III Analyses Underway

Phase I/II CheckMate 040 Study Suggests Nivolumab Is Active and Well Tolerated As First- or Second-Line HCC Monotherapy; Phase III Analyses Underway

Dr. Ignacio Melero
Dr. Milind M. Javle
Interim results of the large phase I/II CheckMate 040 study of nivolumab indicate that the anti–PD-1 antibody is both active and well tolerated when given as monotherapy to patients with advanced hepatocellular carcinoma (HCC; Abstract 226). The study included 262 patients with unselected PD-L1 tumors—182 of whom had received sorafenib and 80 of whom were treatment naive. Confirmed objective response rate (ORR) in the dose-expansion group reached 18.6% or better, and upwards of 70% of these patients survived to 9 months.

Ignacio Melero, MD, of the Clinica Universidad de Navarra, in Spain, presented the findings on behalf of his co-investigators.

Many patients with HCC present with advanced disease, leading to a poor prognosis. The current standard of care for these individuals is the multikinase inhibitor sorafenib. However, no standard exists for those whose disease progresses on this agent.

The current findings suggest that nivolumab immunotherapy holds the potential to enhance the therapeutic armamentarium for HCC as it has already done for melanoma, non–small cell lung cancer, renal cell carcinoma, head and neck squamous cell carcinoma, and Hodgkin lymphoma.  

CheckMate 040 was a dose-escalation and -expansion study conducted in 262 patients with advanced HCC who were not suitable for surgical resection. Hepatitis B virus or hepatitis C virus infection was allowed, as was one prior line of treatment, typically sorafenib. Patients were evaluated based on treatment-naive or sorafenib-experienced status to inform future analyses.

Following confirmation of safety and tolerability in the dose-escalation phase, all patients in the dose-expansion phase received intravenous nivolumab 3 mg/kg every 2 weeks until progressive disease or intractable toxicity set in.  

The ORR among 145 sorafenib-experienced patients in the dose-expansion phase of the trial reached 18.6%, largely consisting of partial responses (16.6%). The addition of another 45.5% of patients with stable disease bumped the disease control rate to 64.1%. Notably, responses were observed regardless of whether patients had hepatitis B virus infection, hepatitis C virus infection, or no viral hepatitis infection, and regardless of PD-L1 expression on tumor cells.

Of the patients who demonstrated an objective response to nivolumab in the dose-expansion phase, the median time to response was 2.7 months, and the median duration of response has not yet been reached.

Median overall survival (OS) in the sorafenib-experienced group has also not yet been reached for those in the dose-expansion phase, but it extended to 15.0 months for the 37 individuals in the dose-escalation phase. Dr. Melero remarked that “stabilization of disease is a driver of survival,” as illustrated by the data showing that 82% of patients receiving nivolumab 3 mg/kg survived to 6 months and 71% survived to 9 months.

Findings similar to those in the treatment-experienced cohort were observed in the smaller cohort of 69 patients who were treatment naive. In the dose-expansion phase, the ORR reached 21.7%, the disease control rate reached 65.2%, 6-month OS reached 87%, and 9-month OS reached 77%.

Dr. Melero said that the toxicity profile of nivolumab in patients with HCC appeared similar to that observed in other tumor types, with no new concerning safety signals. Among patients in the dose-expansion phase, treatment-related adverse events occurred in 74% of patients. However, only 19% of these events reached grade 3 or 4 severity, and no grade 5 events occurred. The most common grade 3/4 treatment-related adverse events that arose consisted of increased levels of aspartate aminotransferase (4%) and alanine aminotransferase (2%), with no evidence of clinical repercussions.

Rounding out the efficacy and safety findings, Dr. Melero also presented data showing that measures of patient-reported quality of life held steady throughout 25 weeks of assessment. No clinically meaningful differences were observed from baseline to any time point or between the first- and second-line cohorts.

“One can say from this study that checkpoint inhibitors may offer major clinical benefit but for a minority of patients,” discussant Milind M. Javle, MD, of The University of Texas MD Anderson Cancer Center, said in his critique of the CheckMate 040 findings. “Clearly, predictive biomarkers for immuno-oncology are critical.”

Although PD-L1 expression was not predictive in the current study, Dr. Javle suggested several other biomarkers that may hold value for enriching the population of patients who stand to gain from nivolumab.

Still, Dr. Javle acknowledged that immunotherapies represent the latest and greatest advance in the changing HCC landscape. “Immuno-oncology in HCC has come of age,” he said. “Better predictors, immuno-oncology combinations, and application to other HCC settings are needed.”

One that note, Dr. Melero did indicate that the phase III CheckMate 459 trial is currently underway and aims to compare nivolumab and sorafenib as first-line therapy in patients with advanced HCC.

–Kara Nyberg, PhD