The Choice Between Immunotherapy and TKIs for Liver Cancer

Aiwu Ruth He, MD, PhD

Options for treating patients with hepatocellular carcinoma (HCC) may currently be limited, with most physicians turning to a tyrosine kinase inhibitor (TKI) for advanced disease, but physicians may soon be able to choose between a TKI and immunotherapy. In the future, oncologists will need to make an informed choice between these 2 modalities as more information on immunotherapy treatment in HCC comes to light, according to Aiwu Ruth He, MD, PhD.

Dr He, associate professor of medicine at Georgetown University School of Medicine, explored this issue during the 2nd Annual School of Gastrointestinal Oncology hosted by Physicians’ Education Resource (PER) on April 29 in New York City. She used results from the randomized, international, phase III 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. In the study, 379 patients were assigned to 160 mg of 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).¹&ldquo;There is an improvement of 3 months in median OS with a 37% reduction in the risk for death,&rdquo; Dr He said. &ldquo;In almost [all] groups of patients, they benefit from regorafenib treatment.&rdquo;

She added that patients in the treatment group had significantly improved progression-free survival (PFS; 3.1 vs 1.5 months) and time to progression rates. 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 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 &ldquo;pretty good.&rdquo;

&ldquo;AEs were manageable and consistent with the known regorafenib safety profile,&rdquo; she said.

Dr He then moved into a review of developments in immunotherapy, which she called &ldquo;the next very exciting treatment for patients with liver cancer,&rdquo; in a review of the available results of the ongoing Checkmate-040 trial,²a phase I/II study of nivolumab (Opdivo) in advanced HCC. The study is planning to add cohorts to further evaluate nivolumab, including in a combi- nation arm with ipilimumab (Yervoy).

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

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, including 48 patients in the dose-escalation phase and 214 in the dose-expansion phase. Seventy-seven percent of patients in the dose-escalation phase and 68% of patients in the expansion phase had received 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 intravenous 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 within 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- 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 of 214 patients; 95% CI, 15%-26%), including 3 CRs and 39 PRs. Combining these responses with 96 patients (45%) who had stable disease, the disease control rate was 64% (138 of 214). The 3 CRs occurred in 2 patients without viral hepatitis and in 1 patient with HBV infection. All 3 of those patients had prior sorafenib.

Twenty-nine (69%) of the 42 responses occurred before 3 months. The median duration of response was 9.9 months 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-month PFS 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 of 48) of patients had grade 3/4 treatment-related AEs. There were 3 treatment-related serious AEs: pemphigoid, adrenal insuficiency, and liver disorder.

Safety in the expansion cohort was similar to that of 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, regard- less of whether patients had HCV or HBV. 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 immuno- therapy and targeted agents in HCC is a critical challenge.

&ldquo;The sequence of treating patients with TKIs or immunotherapy needs to be tested in randomized clinical trials,&rdquo; Dr He said in summary.

References:

1. Bruix J, Qin S, Merle P, et al; RESORCE Investigators. Regorafenib for patients with hepatocellular car- cinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-con- trolled, 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 carci- noma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial [published online April 20, 2017]. Lancet. 2017. doi: 10.1016/S0140-6736(17)31046-2.