Sorafenib Plus Chemo Combo Shows Benefit in Advanced HCC, But Phase III Trial Not Warranted

May 24, 2019

The combination of sorafenib plus gemcitabine and oxaliplatin demonstrated &ldquo;moderate&rdquo; benefits compared with sorafenib monotherapy in patients with advanced hepatocellular carcinoma, according to findings from an open-label phase II trial recently published in the <em>British Journal of Cancer.</em>

The combination of sorafenib plus gemcitabine and oxaliplatin (GEMOX) demonstrated “moderate” benefits compared with sorafenib monotherapy in patients with advanced hepatocellular carcinoma (HCC), according to findings from an open-label phase II trial recently published in theBritish Journal of Cancer.

The trial met its primary endpoint of 4-month progression-free survival (PFS) rate with 64% in the combination arm and 61% in the sorafenib monotherapy arm. However, the study authors, led by Eric Assenat, MD, PhD, of the Université de Montpellier, Montpellier, France, determined a phase III trial was not warranted.

The authors noted that their study showed the feasibility of the sorafenib and GEMOX combination, but they offered some major caveats. “Although our study is positive for its primary endpoint, we cannot recommend this combination of chemotherapy with sorafenib as standard of treatment, all the more now that new options are available in the landscape of HCC treatments, in first- (lenvatinib) or second-line (cabozantinib and ramucirumab),” they wrote. “The toxicity, moderate benefit on PFS, and the lack of predictive factors of response to the sorafenib and GEMOX combination make a subsequent phase III study not justified in unselected HCC patients.”

The secondary objectives of this trial, which was conducted at 10 centers in France, included evaluating the safety of the experimental regimen. Additional secondary objectives included the objective response to treatment (ORR), disease control rate (DCR), median PFS, and median overall survival (OS).

The trial protocol called for patients in both arms to receive 400 mg of oral sorafenib twice daily. Patients in the combined arm also received gemcitabine (1000 mg/m2) in a 100-minute infusion on day 1 of a 28-day treatment cycle. These patients also received 100 mg/m2oxaliplatin as a 2-hour infusion on day 2, every 2 weeks. Treatment continued for 6 cycles (12 GEMOX courses) or until disease progression or treatment-limiting toxicity. Investigators used computed tomography (± hepatic magnetic resonance imaging) to evaluate tumors every 8 weeks until disease progression.

The authors randomized 94 patients to receive either sorafenib alone (n = 48) or the combined regimen (n = 46). Baseline characteristics such as the Cancer of Liver Italian Progression (CLIP) scores were well-balanced between the 2 arms. Inclusion criteria included World Health Organization (WHO) performance status ≤ 1, life expectancy ≥ 12 months, no known brain metastases, and at least 1 measurable target lesion not previously treated with arterial chemoembolization, radiofrequency, alcohol, or cryoablation. Exclusion criteria included previous systemic chemotherapy or antiangiogenic therapy for HCC and stage B or C cirrhosis.

Patients in both treatment arms received sorafenib for a median of 4 months (range, 1—51 months). A relative dose intensity (RDI) of 80% or more was achieved by 19 patients (43%) in the sorafenib monotherapy arm and 23 patients (59%) in the combination arm. The sorafenib RDI was 75% in the sorafenib arm and 84% in the sorafenib plus GEMOX arm.

Of the 12 planned GEMOX courses in the experimental arm, patients received a median of 7 courses (range, 1—16). The RDI was 78% for gemcitabine and 68% for oxaliplatin. Only 6 patients in this arm (15%) received second-line treatment, compared with just over half the monotherapy arm (n = 24, 55%).

Toxicities were generally comparable in both trial arms. As expected, patients in the combined arm developed more hematological toxicities and neuropathies. For example, nearly one-fourth (23%) of combination patients developed grade 3-4 neutropenia, but no sorafenib-only patients did. Similar disparities occurred with grade 3 fatigue, grade 3 thrombocytopenia, and grade 3 diarrhea. Five percent of the GEMOX patients developed grade 2-3 neuropathy, but no sorafenib-only patients did. In contrast, 18% of monotherapy patients developed hand-foot syndrome while only 5% of GEMOX patients did.

Among the 83 patients who received treatment, 5 were not evaluable for efficacy, 4 in the sorafenib arm and 1 in the GEMOX arm. At the first-stage analysis, 16 of 23 evaluable patients in the experimental arm had not progressed at 4 months. The ORR according to RECIST criteria was 9% in the sorafenib arm (90% confidence interval [CI], 3%—20%) and 15% in the GEMOX arm (90% CI, 6%–28%).

The DCR was 77% in the GEMOX arm (90% CI, 63%—87%) and 70% in the sorafenib arm (90% CI, 57%–81%). No patient experienced a complete response. One control patient required resection after 12 months, while another had not progressed after 50 months. Using modified RECIST criteria, the ORR was 28.2% in the GEMOX arm (90% CI, 15%–45%) and 20.5% in the control arm (90% CI, 9%–35%).

The median follow-up was 36.8 months for patients in the sorafenib arm and 44.4 months for patients in the GEMOX arm. At the time of analysis, 67 patients (81%) had died, 32 (73%) in the sorafenib arm and 35 (90%) in the GEMOX arm. The main cause of death in both arms was disease progression (56 patients, 84%).

The median PFS was 4.6 months in the sorafenib arm (90% CI, 3.9—6.2) and 6.2 months in the combination arm (90% CI, 3.8–6.8). The median time to progression was 4.6 months in the sorafenib alone (95% CI, 3.8–6.2) and 6.2 months in the GEMOX arm (95% CI, 3.7–7.2). For control patients, the median OS was 14.8 months (90% CI, 12.2–22.2), while experimental patients achieved an OS of 13.5 months (90% CI, 7.5–16.2).

The authors also conducted an exploratory analysis of OS in the GEMOX arm for the presence or absence of cirrhosis and serum α-fetoprotein levels. They also analyzed OS according to the tumor location in terms of liver-only disease, extra-hepatic disease only, or both. They found that none of these factors had a significant effect on OS. However, they did note that patients with intrahepatic lesions only, cirrhosis or α-fetoprotein ≥ 200 (μg/L) had a trend to a shorter OS. The median OS was 6.9 months for patients with liver-only disease (n = 9; 95% CI, 3.0—13.7) compared with 14.3 months for patients with extra-hepatic disease (n = 30; 95% CI, 7.8–19.1). Patients with cirrhosis had OS of 8.4 months (n = 23; 95% CI, 6.9–15.5) versus 17.6 months for non-cirrhotic patients (n = 16; 95% CI, 7.2–23.3). Patients with serum α-fetoprotein ≥ 200 μg/L had an OS of 7.8 months (n = 23; 95% CI, 6.3–13.5) compared with 17.6 months for those with serum α-fetoprotein < 200 μg/L (n = 15; 95% CI, 8.4–22.3).


Assenat E, Pageaux G-P, Th&eacute;zenas S, et al. Sorafenib alone vs. sorafenib plus GEMOX as 1st-line treatment for advanced HCC: the phase II randomisedPRODIGE 10 trial. Br J Cancer. 2019;120:896—902.