Lenvatinib Noninferior to Sorafenib in Advanced Hepatocellular Carcinoma: Results from the REFLECT Clinical Trial

Walter Alexander

Liver Cancer

Chicago, IL—Beyond demonstrating noninferiority for overall survival (OS) in advanced, unresectable hepatocellular carcinoma (HCC), lenvatinib (Lenvima) demonstrated superiority over sorafenib (Nexavar) in progression-free survival (PFS), time to progression, and overall response rate in the REFLECT clinical trial, reported lead investigator Ann-Lii Cheng, MD, National Taiwan University Hospital, Taipei, in an oral presentation at the 2017 ASCO annual meeting. With nearly 745,000 deaths attributed to HCC annually, HCC is the second leading cause of death worldwide, noted Dr Cheng.

Over the past 10 years, sorafenib has been the only first-line systemic drug to extend OS in patients with HCC, said Dr Cheng. Global phase 3 clinical trials of sunitinib, brivanib, linifanib, and erlotinib plus sorafenib have failed to meet primary end points of noninferiority or superiority, he added.

The oral multikinase inhibitor lenvatinib targets vascular endothelial growth factor receptors 1, 2, and 3; fibroblast growth factor receptors 1, 2, 3, and 4; platelet-derived growth factor receptor-alpha; and RET and KIT mutations. It has shown promising clinical activity in previous phase 2 research among patients with advanced HCC.

The REFLECT Clinical Trial

The REFLECT clinical trial, a randomized, open-label, noninferiority study, included 954 patients with unresectable HCC (mean age, 61 years; 85% male) with ≥1 measurable target lesions, Barcelona Clinic Liver Cancer stage B or C, Child-Pugh class A, Eastern Cooperative Oncology Group Performance Status ≤1, and no previous systemic therapy. Patients (N = 954) were randomized in a 1:1 ratio to receive lenvatinib (body weight ≥60 kg, 12 mg daily; <60 kg, 8 mg daily) or sorafenib 400 mg twice daily. The primary end point was OS.

The median duration of treatment was 5.7 months in the lenvatinib group versus 3.7 months in the sorafenib group; 87.6% and 83.0% of the planned starting doses were delivered, respectively. Results were not adjusted for the duration of treatment.

The median OS was similar in the 2 groups, with 13.6 months in the lenvatinib group (95% confidence interval [CI], 12.1-14.9) versus 12.3 months in the sorafenib group (95% CI, 10.4-13.9; hazard ratio [HR], 0.92; 95% CI, 0.79-1.06). The noninferiority standard had been set to HR <1.08.

“This is well below the noninferiority margin. Therefore, lenvatinib met its primary end point of noninferiority to sorafenib,” Dr Cheng said. However, OS trends favored lenvatinib across all subgroups, with the exception of neutral findings in the western population (non–Asia-Pacific) and those with macrovascular invasion or extrahepatic spread.

The secondary end point of PFS, as assessed by the modified Response Evaluation Criteria in Solid Tumors, favored lenvatinib at 7.4 months versus 3.7 months for sorafenib (HR, 0.66; P <.00001). All subgroups reflected this advantage for lenvatinib. Similarly, the time to disease progression estimates favored lenvatinib at 8.9 months versus 3.7 months for sorafenib (HR, 0.63; P <.00001).

Among additional secondary end points, the overall response rate (ie, complete response plus partial response) was 24.1% with lenvatinib versus 9.2% with sorafenib (odds ratio, 3.13; 95% CI, 2.15-4.56; P <.00001). Progressive disease rates were 14.9% with lenvatinib versus 30.9% with sorafenib, and the disease control rates (ie, complete response plus partial response plus stable disease) were 75.5% versus 60.5%, respectively.

Investigators also stratified results according to baseline alpha-fetoprotein (AFP; <200 ng/mL or ≥200 ng/mL) levels. Higher AFP levels are associated with poor outcomes, said Dr Cheng. Analysis showed that among patients with higher baseline AFP levels, the median OS was 10.4 months with lenvatinib compared with 8.2 months with sorafenib (HR, 0.78).

Although the need for dose modifications, reductions, or interruptions for treatment-emergent adverse events was similar between lenvatinib and sorafenib, serious adverse events were higher with lenvatinib (18%) than with sorafenib (10%). Grade 3 or 4 hypertension was reported in 23% of patients in the lenvatinib group versus 14% of patients in the sorafenib group. Grade 3 or 4 skin problems (palmar-plantar erythrodysesthesia) were more common in the sorafenib group (11%) than in the lenvatinib group (3%).

Quality of Life

Health-related quality of life, as measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and HCC-specific EORTC QLQ-HCC18 declined similarly (reflecting worsened quality of life) after treatment in both groups. The EORTC QLQ-C30 measures of role functioning, pain, and diarrhea, and a measure of nutrition and body image, worsened significantly sooner in the sorafenib group than in the lenvatinib group (P <.05).

Commenting on the study results at an ASCO “Highlight of the Day” session, Tanios Bekaii-Saab, MD, FACP, Professor, Mayo Clinic College of Medicine and Science, Phoenix, AZ, stated, “It’s clear that lenvatinib may become another first-line option for patients with advanced HCC.”

However, lenvatinib is not yet FDA approved for liver cancer, and the measures showing superiority of lenvatinib over sorafenib (ie, PFS and overall response rate) were secondary end points, limiting the strength of superiority conclusions from the REFLECT clinical trial data, he cautioned.

Lenvatinib is currently FDA approved for use in patients with thyroid cancer or renal-cell carcinoma.