By Connie Tat, Ph.D. and Arnold DuBell, Ph.D., MBA
Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide, and is responsible for nearly 745,000 deaths per year1. In 2007, Nexavar, a multi-targeted tyrosine kinase inhibitor (TKI), was established as the first FDA-approved agent for first-line HCC, based on a 2.8-month improvement in overall survival (OS) relative to placebo in the Phase III SHARP trial2. Use of Nexavar came at a high price however, as 80% of the Nexavar-recipient patients in the SHARP trial experienced adverse events including diarrhea, hand-foot skin reaction and others.
Despite the low bar, novel therapeutic contenders have historically struggled to unseat Nexavar as the standard of care in front-line. For example, four global Phase III trials [evaluating Sutent® (sunitinib, Pfizer), brivanib (Bristol-Myers Squibb), linifanib (AbbVie), and Tarceva® (erlotinib, Genentech / Roche)] failed to meet their primary endpoints. This is due in part to liver dysfunction (cirrhosis) present in many HCC patients as well as other comorbidities resulting from infection with hepatitis B or hepatitis C, and/or occurrence of non-alcoholic fatty liver disease. In practice, systemic therapies such as Nexavar are limited to patients with the least degree of cirrhosis (Child-Pugh A). Those with greatly impaired liver function (Child-Pugh C) are often unable to tolerate current therapeutic options and generally receive best supportive care. Even those with reasonable liver function may struggle to tolerate combination therapies that include Nexavar as a backbone.
As the high unmet needs in hepatocellular carcinoma (HCC) have historically been insurmountable, a novel agent is greatly needed that improves both efficacy and tolerability to encompass more patients in the treatable population. Eisai entered the competitive landscape in front-line HCC with Lenvima® (lenvatinib) in 2009. Lenvima is another multitargeted TKI which is approved for use as a monotherapy in differentiated thyroid cancer and in combination with Afinitor® (everolimus, Novartis) for the treatment of advanced RCC following one prior anti-angiogenic therapy. (Note that for the latter indication, Lenvima is branded in Europe as Kisplyx®). To evaluate Lenvima in HCC patients in the first-line setting, Eisai initiated a global, randomized, open-label Phase III non-inferiority study (“REFLECT”) in 2013. REFLECT randomized 954 patients with unresectable HCC to Lenvima (12 mg or 8 mg q.d., based on body weight) or Nexavar (400 mg b.i.d.) to support regulatory filings in the U.S., Europe and Japan. The primary endpoint is non-inferiority in overall survival, and secondary endpoints include PFS, ORR, health-related quality of life, and pharmacokinetics. Data from this trial were presented at ASCO 20173. Lenvima met its non-inferiority primary endpoint in OS (13.6 months versus 12.3 months, HR 0.92). The agent also demonstrated to be statistically superior to Nexavar in terms of PFS (7.4 months versus 3.7 months, HR 0.66, p<0.00001), TTP (8.9 months versus 3.7 months, HR 0.63, p<0.00001) and ORR (24% versus 9%, p<0.00001).
The toxicity profiles for the two agents were roughly similar, with comparable incidence of grade ≥3 treatment-related adverse events (57% versus 49%), dose reductions (37% versus 38%) and drug discontinuations (9% versus 7%). The two grade 3-4 toxicities of note were hypertension (23% versus 14%) and palmar-plantar erythrodysesthsia (3% versus 11%). Other common grade 3-4 toxicities included decreased weight (8% versus 3%), elevated aspartate aminotransferase (5% versus 8%) and thrombocytopenia (6% versus 3%). Based on this data, Eisai announced plans to submit for regulatory approval later this year.
Overall, HCC seems to be at a hopefully positive point, as Stivarga® (regorafenib, Bayer) was recently approved for use in Nexavar-refractory HCC patients. Moreover, Opdivo® (nivolumab, Bristol Myers Squibb / Ono Pharmaceuticals) was recently filed for US accelerated approval in Nexavar-refractory patients based on Phase I/II data, and is currently being evaluated in the Phase III CheckMate 459 trial for use in the first-line setting. REFLECT is one of the few positive trials in the last ten years, and although the results were not groundbreaking, it does suggest that Lenvima may be a potential first-line treatment option in advanced HCC. Does the REFLECT data suggest that Lenvima will be used over Nexavar in first-line? The discussant, Katie Kelley, implied that non-inferiority trials are typically used for agents that are less toxic, less costly, or easier to administer. Kantar Health therefore “seats” Lenvima next to Nexavar, as it only showed non-inferiority with regard to overall survival but did not show a reduced toxicity profile. Further, Nexavar is entrenched in this setting, with 50-60% utilization in first-line based on Child-Pugh status, and 15% utilization in second and third-lines4.
Another concern for Lenvima is drug sequencing. As noted above, Stivarga is indicated for Nexavar-refractory patients, and Opdivo could soon have a similar label. This begs the question that if Lenvima is used in the first-line, will physicians need to wait to use Stivarga in the third-line setting after Nexavar is offered in the second-line? Could physicians’ preference to use first-line Nexavar and second-line Stivarga impact where Lenvima might be offered? We will have to see who else earns their “seat at the table” to determine how this shuffling is to occur.