Lenvatinib OS Noninferior, PFS Improved Versus Sorafenib for Unresectable HCC

Ann-Lii Cheng, MD, PhD, National Taiwan University Hospital

Ann-Lii Cheng, MD, PhD

First-line treatment with lenvatinib (Lenvima) improved progression-free survival (PFS) by 3.7 months and was noninferior for overall survival (OS) compared with sorafenib (Nexavar) for patients with unresectable hepatocellular carcinoma (HCC), according to phase III results presented at the 2017 ASCO Annual Meeting.

In the open-label study, known as REFLECT or Study 304, the median OS with lenvatinib was 13.6 months compared with 12.3 months for sorafenib, the current standard of care (HR, 0.92; 95% CI, 0.79-1.06). The median PFS with lenvatinib was 7.4 versus 3.7 months with sorafenib (HR, 0.66; 95% CI, 0.57-0.77; P <.00001).

"Lenvatinib has demonstrated noninferiority versus sorafenib in OS in patients with unresectable HCC. Lenvatinib has also achieved statistically significant and clinically meaningful improvement in PFS, time to progression, objective response rate,” said lead investigator Ann-Lii Cheng, MD, PhD, National Taiwan University Hospital. "Based on these results, lenvatinib may be a potential treatment option in patients with advanced HCC."

The international, multicenter, open-label, noninferiority Study 304 randomized 954 patients with unresectable HCC to frontline treatment with lenvatinib at either 8 mg or 12 mg once per day based on body weight (n = 478) or sorafenib at 400 mg twice daily (n = 476). The mean age of patients was 61.3 years in the lenvatinib arm and 61.2 years in the sorafenib group. The most common ECOG performance status was 0 (approximately 64%) and two-thirds of patients had macrovascular invasion (MVI), extrahepatic spread (EHS), or both. The most common Child-Pugh class was A (99%) and approximately 80% of patients had BCLC stage C disease.

Nearly a fifth of patients had ≥3 sites of disease involvement, and half of patients had underlying hepatitis B infection. Baseline AFP levels were <200 ng/mL for 53% of patients in the lenvatinib group and for 60% in the sorafenib arm, with the remainder having higher levels. The median baseline AFP level was 133.1 ng/mL in the lenvatinib arm and 71.2 ng/mL in the sorafenib group.

The median time to progression was 8.9 months with lenvatinib (95% CI, 7.4-9.2) and 3.7 months with sorafenib (95% CI, 3.6-5.4), representing a 37% reduction in the risk of progression (HR, 0.63; 95% CI, 0.53-0.73; P <.00001). The objective response rate (ORR) was 24.1% with lenvatinib versus 9.2% with sorafenib (odds ratio, 3.13; 95% CI, 2.15-4.56; P <.00001). The CR rate was 1.3% in the lenvatinib group and 0.4% with sorafenib.

An additional OS analysis was conducted to adjust for differences in baseline AFP between the groups. In those with AFP at baseline <200 ng/mL, the median OS was 19.5 months with lenvatinib versus 16.3 months with sorafenib (HR, 0.91; 95% CI, 0.74-1.12). In those with AFP ≥200 ng/mL, the median OS was 10.4 versus 8.2 months, for lenvatinib and sorafenib, respectively (HR, 0.78; 95% CI, 0.63-0.98).

The median duration of treatment was 5.7 months with lenvatinib and 3.7 months with sorafenib. Dose reductions due to treatment-emergent adverse events (TEAEs) were required for 37% of those in the lenvatinib arm and for 38% of those in the sorafenib group. Drug discontinuations due to TRAEs were needed for 9% and 7% of those in the lenvatinib and sorafenib groups, respectively.

Grade ≥3 TEAEs were more common with lenvatinib versus sorafenib (57% vs 49%, respectively). The most common grade 3/4 TRAEs with lenvatinib and sorafenib, respectively, were hypertension (23% vs 14%), decreased weight (8% vs 3%), decreased platelet count (6% vs 3%), elevated aspartate aminotransferase (5% vs 8%), decreased appetite (5% vs 1%), diarrhea (4% vs 4%), and palmar-plantar erythrodysesthesia (3% vs 11%).

The treatment landscape for patients with unresectable HCC has undergone several changes in the past year, following a decade long drought without new therapies. The multikinase inhibitor regorafenib (Stivarga) gained FDA approval as a second-line therapy following sorafenib, in late April 2017. Additionally, the PD-1 inhibitor nivolumab (Opdivo) has shown promise in the phase II CheckMate-040 study following sorafenib, with an application currently pending with the FDA. A final decision is anticipated on or before September 24, 2017.

Lenvatinib is currently approved as a treatment for patients with recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer and following VEGF therapy in combination with everolimus for patients with advanced renal cell carcinoma. Based on findings from the REFLECT study, Eisai, the developer of lenvatinib, anticipates to complete FDA submission.

Cheng A-L, Finn RS, Qin S, et al. Phase III trial of lenvatinib (LEN) vs sorafenib (SOR) in first-line treatment of patients (pts) with unresectable hepatocellular carcinoma (uHCC). J Clin Oncol. 2017;35 (suppl; abstr 4001).

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"Baseline quality of life questionnaires were similar in both treatment groups and, following treatment, scores declined in both groups," said Cheng. "Role functioning, pain, and diarrhea scores worsened earlier and nutrition and body image deterioration was observed earlier in patients treated with sorafenib versus lenvatinib."