NIVOLUMAB FOR HCC

SAN FRANCISCO ― Immunotherapy is making inroads as a potential treatment for a number of cancer types, and the latest to add to the list is advanced hepatocellular carcinoma (HCC).

Early responses have been reported from the Checkmate 040 study, in which nivolumab (Opdivo, Bristol-Myers Squibb) was used as a single agent in advanced HCC. Its use resulted in objective responses and long-term survival in patients who had previously been treated with sorafenib (Nexavar, Onyx/Bayer), and "very importantly, also in sorafenib-naive patients," said lead study author Ignacio Melero, MD, of the Clinica Universidad de Navarra, Pamplona, Spain.

Dr Melero presented his findings here at the Gastrointestinal Cancers Symposium (GICS) 2017.

For patients with advanced HCC, the prognosis is poor. The multitargeted tyrosine kinase inhibitor sorafenib is currently the only approved systemic treatment for the disease, Dr Melero commented.

Patients who experience disease progression while taking sorafenib have few options, noted Dr Melero.

"Nivolumab provided early, stable, and durable responses," he said. "And these responses were observed irrespective of PD-L1 [programmed death ligand 1] expression on tumor cells."

Nine months after starting treatment, 71% of patients remain alive.

The overall response rate in patients who received nivolumab as second-line treatment was 18.6% (n = 27); three patients achieved a complete response.

The response rate was a little lower when nivolumab was used in the first-line setting. There were no complete responses, but 15 patients (21.7%) achieved a partial response.

Efficacy was not dependent on hepatitis infection status, and responses occurred in both infected and uninfected patients.

Escalation Leads to Expansion

The Checkmate 040 study was conducted in two phases.

"Because of the inflammation that often affects the liver, we were very afraid of precipitating hyperacute or fulminant hepatitis in these patients, and that was the reason that we undertook a very careful dose escalation," Dr Melero explained.

The dose escalation phase was conducted in 48 patients, who received primary pretreatment with sorafenib. These patients included those infected with hepatitis B virus (HBV) and hepatitis C virus (HCV), as well as patients who were uninfected.

Findings from the dose escalation phase in pretreated HCC patients were presented at the 2015 annual meeting of the American Society of Clinical Oncology and were reported by Medscape Medical News at that time.

Those early data showed an "unprecedented" overall response rate for a systemic therapy in advanced HCC. Eight of 42 (19%) evaluable patients responded to nivolumab (tumor reduction beyond 30%), including two with complete responses, the investigators reported at that time. The results compare favorably with those seen with sorafenib, which has a response rate in this setting of only 2%.

Owing to the efficacy and safety seen in the escalation phase, the study was extended into an expansion phase, with 214 patients being treated with nivolumab at the now standard dose of 3 mg/kg

About half of patients were uninfected (n = 113). About 25% (n = 51) were infected with HBV, and 25% (n = 50) were infected with HCV.

The majority of patients (n = 145) had received prior sorafenib treatment and so were receiving nivolumab in the second-line setting; 69 patients were treatment naive.

The primary endpoint in the dose-expansion phase was objective response rate by RECIST v1.1. Secondary endpoints included duration of response and overall survival.

Among pretreated patients, stable disease was achieved in 45.5% (n = 66); 31.7% (n = 45) experienced disease progression. Similar results were seen for patients in the first-line setting; stable disease was achieved in 43.5% (n = 30) of patients, and 31.9% (n = 22) experienced disease progression on treatment.

When responses occurred, they tended to be very durable, Dr Melero pointed out. The time to response was 2.7 months. The duration of response, which was 17.1 months in the dose escalation phase, has not yet been reached in the current study.

"In regards to PD-L1, we found that there were responses regardless of PD-L1 status," he said. "There were compatible response rates in PD-L1-positive and PD-L1-negative tumors."

Safety was manageable and consistent across patient cohorts and was very similar to what has been observed in studies involving patients with other solid tumors. There were no new safety signals.

"Most of the grade 3 and 4 toxicities were lab abnormalities without clinical repercussions in the patients," Dr Melero said.

He added that a phase 3 study that is evaluating the use of nivolumab in treatment-naive patients with advanced HCC is ongoing.

Future Belongs to Immuno-Oncology

In a discussion of the paper, Milind Javle, MD, from the University of Texas MD Anderson Cancer Center, Houston, noted that the "study was impressive in the sense that the response rate was 19%, and the response was pretty brisk.

"There was similar efficacy whether it was given first- or second-line, and what is most impressive is that 71% of patients are still alive at 9 months," said Dr Javle. "This indicates that even if patients do progress, they survive for a reasonably long time."

From this study, one can say that checkpoint inhibitors may offer major clinical benefit, but only for a minority of patients, he noted.

Dr Javle emphasized that predictive markers for response in immuno-oncology are critical.

"Some are available in the clinic today, with the most popular one being PD-L1, although it was not predictive in the current study," he said.

Now the question is, where to go next?

There are ongoing first-line studies of nivolumab vs sorafenib and pembrolizumab vs sorafenib, but perhaps one can conceive a second-line study vs regorafenib (Stivarga, Bayer), Dr Javle commented.

Studies of combination strategies, such as with anti-PD-1/PD-L1 plus CTLA4 or with small molecule tyrosine kinase inhibitors, are also being considered, he explained. The role of immune-oncology in the adjuvant setting is also being explored.

The landscape of HCC has changed dramatically during the past 2 decades, with the advent of the HBV vaccine, sorafenib coming on the marketplace, and new effective therapies for HCV. "A second-line study for regorafenib was positive, but the future clearly belongs to immune-oncology," Dr Javle concluded.

"So clearly immune-oncology in HCC has come of age. Better predictors, immuno-oncology combinations, and application to other HCC settings are needed," he added.

The study was supported by Bristol-Meyers Squibb. Dr Melero has received honoraria from AstraZeneca, Bayer, Bristol-Myers Squibb, Incyte, Merck Serono, MSD, and Roche; has served in a consulting/advisory role with AstraZeneca, Bayer, Bristol-Myers Squibb, Incyte, Merck Serono, MSD, and Roche; and has received research funding from Alligator Bioscience (Inst), Pfizer (Inst), and Tusk Therapeutics (Inst). Other coauthors also report relationships with industry. Dr Javle has disclosed no relevant financial relationships.