medwireNews: REFLECT study findings indicate that lenvatinib offers non-inferior overall survival (OS) compared with the current standard of care, sorafenib, for the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC).
“Based on these results, lenvatinib may be a potential treatment option in patients with advanced HCC,” lead author Ann-Lii Cheng (National Taiwan University Hospital, Taipei) commented on the findings.
Lenvatinib is an oral multikinase inhibitor of vascular endothelial growth factor receptors 1–3, fibroblast growth factor receptors 1–4, and platelet-derived growth factor receptor α, as well as RET and KIT, he told delegates at the 2017 annual meeting of the American Society of Clinical Oncology, in Chicago, Illinois, USA.
In all, 954 patients with treatment-naïve unresectable HCC were recruited to the phase III open-label trial and randomly assigned to receive daily lenvatinib 8 mg or 12 mg depending on whether their bodyweight was less than 60 kg or at least 60 kg, respectively, or sorafenib 400 mg twice daily.
OS was a median of 13.6 months for the 478 lenvatinib-treated patients versus 12.3 months for the 476 sorafenib-treated patients, giving a hazard ratio (HR) of 0.92. The confidence interval was 0.79–1.06 and the upper limit was below the non-inferiority margin of 1.08 and therefore lenvatinib met the primary endpoint of OS non-inferiority, Cheng said.
Forest plot analysis indicated that OS favored lenvatinib for most patients subgroups, except the Western population (HR=1.08 vs 0.86 for Asia–Pacific region) and patients with macroscopic portal vein invasion and/or extrahepatic spread (HR=0.87 vs 1.05 for those without these features).
Lenvatinib achieves ‘statistically significant and clinically meaningful’ improvements
Lenvatinib was also associated with “statistically significant and clinically meaningful” improvements in other endpoints compared with sorafenib including in progression-free survival (7.4 vs 3.7 months, HR=0.66), time to progression (8.9 vs 3.7 months, HR=0.63), and objective response rate (24.1 vs 9.2%, odds ratio=3.13).
Cheng noted that patients given lenvatinib tended to have a higher baseline level of alpha-fetoprotein (AFP, median 133.1 vs 71.2 ng/mL), a poor prognostic indicator, and adjusting for this gave a HR for OS of 0.856.
In further analysis, the OS for patients with a baseline AFP level of below 200 ng/mL was a comparable median of 19.5 months with lenvatinib and 16.3 months with sorafenib. But the corresponding values for patients with an AFP of 200 ng/mL or above were 10.4 and 8.2 months, denoting a significant difference in favor of lenvatinib.
Lenvatinib was given for a median of 5.7 months versus 3.7 months for sorafenib, with 87.7% and 87.5% of the planned dose given, respectively.
Treatment-related side effects were reported by 94% of the lenvatinib arm and 95% of the sorafenib arm, with grade 3 or more severe events in 57% and 49% respectively. Dose modifications because of side effects occurred in 37% and 38% of the arms, respectively, while treatment was discontinued in 9% and 7%.
The toxicity profile was “comparable” except for “two outstanding differences”, Cheng said.
Specifically, lenvatinib was associated with a higher rate of hypertension events than sorafenib at any grade (42 vs 30%) and at grade 3–4 (23 vs 14%), whereas palmar–plantar erythrodysesthesia was less common with lenvatinib at any grade (27 vs 52%) and grade 3–4 (3 vs 11%).
Health-related quality of life was comparable at baseline and declined in both treatment arms. But patients given lenvatinib had later deterioration of role functioning, pain, and diarrhoea than sorafenib-treated patients, with scores for nutrition and body image also deteriorating faster with sorafenib.
Lenvatinib tumor shrinkage allowed liver transplantation
Discussing the findings with medwireNews , REFLECT author Jeff Evans, from the University of Glasgow in the UK, explained that the only curative treatment for HCC is complete resection with or without transplantation.
A case study from the trial for a 64-year-old male with unresectable HCC was presented at a press conference. The patient had developed new hypervascular lesions after transarterial chemoembolization, before being randomly assigned to lenvatinib in the REFLECT trial.
In 2016–2017, the patient had a “very good sustained radiological response” and, despite progressive disease, became eligible for transplantation. He subsequently underwent the procedure.
“If we could downstage patients and make them more suitable for resection that would be […] worthwhile to do,” Evan said, noting that this has not previously been possible outside of anecdotal cases.
However, he acknowledged that it is yet unknown whether downstaged tumours have as good an outcome or recurrence risk as de novo operative cases.
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