Expert Discusses Choice Between Immunotherapy and TKIs for HCC

Aiwu Ruth He, MD, PhD

Physicians treating hepatocellular carcinoma (HCC) often have to choose between a tyrosine kinase inhibitor (TKI) and immunotherapy.

The right answer, said Aiwu Ruth He, MD, PhD, associate professor of medicine at Georgetown University, is not always obvious and oncologists need better tools to make an informed choice.

Dr He explored the issue during the Physicians’ Education Resource (PER) 2nd Annual School of Gastrointestinal Oncology.

From 2007 to 2016, there have been 5 phase III, randomized trials assessing novel TKIs or TKI-containing combinations in first line, and 3 others evaluating TKIs in second-line therapy. She used results from the randomized, international, phase 3 RESORCE trial to illustrate the state of TKIs in HCC.

RESORCE evaluated the efficacy and safety of regorafenib (Stivarga) versus placebo in patients with HCC who progressed while taking sorafenib (Nexavar). Patients (N = 573) were treated at 152 medical centers in 21 countries around the world. Nearly 40% of patients lived in Asian countries.

In the study, 379 patients were assigned to 160 mg of once-daily regorafenib on a 3 weeks on/1 week off cycle. Another 194 patients were assigned to placebo. Overall survival (OS) was the primary endpoint.

Median OS was 10.6 months for regorafenib compared with 7.8 months for placebo (HR, 0.63; 95% CI, 0.50-0.79; P <.0001).

“There is an improvement of 3 months in median OS with a 37% reduction in the risk for death,” Dr He said. “In almost [all] groups of patients, they benefit from regorafenib treatment.”

She added that patients in the treatment group had significantly improved progression-free survival (3.1 months vs 1.5 months) and time to progression. Regorafenib patients also had a significantly higher response rate (65.2% vs 36.1%) and a disease control rate nearly double that of placebo.

Patients spent a median of 3.6 months on regorafenib treatment compared with 1.9 months for placebo. Half of patients treated with regorafenib reported grade-3/4 treatment-related adverse events (AEs) compared with just 16.5% of placebo patients.

However, only 10% of regorafenib patients discontinued treatment, compared with 4% in the placebo group, an outcome Dr He declared “pretty good.”

“Adverse events were manageable and consistent with the known regorafenib safety profile,” she said.

Dr He then moved into a review of developments in immunotherapy, which she called “the next very exciting treatment for patients with liver cancer.”

Dr He took her audience through the available results of the Checkmate-040 trial,² a phase I/II study of safety and efficacy of nivolumab (Opdivo) in advanced HCC. The study is still enrolling patients and adding cohorts to further evaluate nivolumab, including a combination arm with ipilimumab (Yervoy).

Based on available data from the study, the FDA recently granted a priority review designation to nivolumab for use as a treatment for patients with HCC following prior sorafenib. The FDA is scheduled to make it its final decision on or before September 24, 2017.

Between November 26, 2012, and August 8, 2016, the phase I/II CheckMate-040 trial accrued 262 patients with advanced HCC with or without hepatitis C virus (HCV) or hepatitis B virus (HBV) infection. There were 48 patients in the dose-escalation phase and 214 patients in the dose-expansion phase. Seventy-seven percent of patients in the dose-escalation phase and 68% of patients in the expansion phase had prior sorafenib.

The median age of patients in the escalation phase was 62 years (range, 55-69), 75% of patients were male, 58% were white, and 40% had an ECOG performance status (PS) of 1. Seventy-five percent had surgical resection and 21% had received radiotherapy.

In the expansion phase the median age was 64 years (range, 56-70), 80% of patients were male, 49% were white, 47% were Asian, and 36% had an ECOG PS of 1. Sixty percent of patients had surgical resection and 19% had received radiotherapy.

In the escalation phase, patients received 0.1 to 10 mg/kg of IV nivolumab every 2 weeks. Patients in the expansion phase received nivolumab at 3 mg/kg every 2 weeks.

The overall objective response rate (ORR) in the escalation phase was 15% (95% CI, 6-28), including 3 complete responses (CRs) and 4 partial responses (PRs). Five of the 7 responses occurred with 3 months of initiating nivolumab. The median duration of response was 17 months (95% CI, 6-24) and the median time to progression was 3.4 months (95% CI, 1.6-6.9). The disease control rate was 58% (95% CI, 43-72).

The 6-month and 9-month OS rates were each 66% (95% CI, 51-78). In the dose escalation phase, the median OS was 15.0 months (95% CI, 9.6-20.2).

The ORR in the expansion group was 20% (42/214; 95% CI, 15-26), including 3 CRs and 39 PRs. Combining these responses with 96 (45%) patients who had stable disease, the disease control rate was 64% (138/214). The 3 CRs occurred in 2 patients without viral hepatitis and 1 patient with HBV infections. All 3 patients had prior sorafenib.

Twenty-nine (69%) of the 42 responses occurred before 3 months. The median duration of response was 9.9 months (95% CI, 8.3 to not estimable) and the median time to progression was 4.1 months (95% CI, 3.7-5.5).

The 6- and 9-month OS rates in the expansion cohort were 83% (95% CI, 78-88) and 74% (95% CI, 67-79), respectively. The 6- and 9-months progression-free survival rates were 37% (95% CI 30-43) and 28% (95% CI 22-35), respectively.

The researchers reported that nivolumab was tolerable with a manageable safety profile during the dose-escalation phase. A maximum-tolerated dose was not reached. Twenty-five percent (12/48) of patients had grade 3/4 treatment-related adverse events (AEs). There were 3 treatment-related serious AEs: pemphigoid, adrenal insufficiency, and liver disorder.

Safety in the expansion cohort was similar to the escalation cohort. Grade 3/4 and serious treatment-related AEs occurred in 19% and 4% of patients, respectively. The incidence of symptomatic treatment-related AEs was comparable in patients, regardless of whether or not they had an HCV or HBV infection. Twenty-four patients discontinued treatment due to AEs, and there were no deaths related to treatment.

Given the continued reporting of positive data with both treatment modalities, determining the optimal sequence of immunotherapy and targeted agents in HCC is a critical challenge.

“The sequence of treating patients with TKIs or immunotherapy needs to be tested in randomized clinical trials,” Dr. He said in summary. “So, in the next few years, there will be a lot of exciting developments in treatment in this field.

References

1. Bruix J, Qin S, Merle P, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;389(10064):56-66. doi: 10.1016/S0140-6736(16)32453-9.
2. El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial [published online April 20, 2017]. doi:10.1016/S0140-6736(17)31046-2.