Biopharmaceutical Report II
Eisai’s (TYO:4523) Lenvima (lenvatinib) has a clear path to approval in first-line hepatocellular carcinoma (HCC), with its positive Phase III noninferiority trial versus Bayer’s (ETR:BAYN) Nexavar (sorafenib) displaying unmatched efficacy, experts said. However, even if approved, a noninferiority result -- despite being the first in a decade -- may fall short in persuading clinicians to switch from the established standard-of-care (SOC), they noted on the sidelines of the recently concluded ASCO meeting in Chicago.
Lenvima’s Phase III secondary endpoint data could be a selling point over Nexavar, one expert noted but others said such results including progression-free survival (PFS) have limited clinical value in HCC. And while Lenvima’s sideeffect profile might discourage uptake in some patients, experts noted Lenvima’s and Nexavar’s side-effect profiles are different and the former’s could therefore be a preferable option for certain patients.
The original PDUFA date was in May but was extended to August to allow more time to review the application, a spokesperson said, declining to comment on potential Lenvima uptake barriers. Eisai’s share price barely fluctuated on the PDUFA delay announcement and it did not cause a reaction from interviewed experts.
In March, Eisai announced it made a deal with Merck (NYSE:MRK) for development and commercialization of Lenvima. Analysts have not provided any sales predictions for Lenvima in HCC alone but it is estimated to generate USD 1.83bn worldwide by 2024 in all indications. Eisai’s market cap is JPY 2.4trn (USD 21.9bn).
Lenvima and Nexavar are both oral multikinase inhibitors. Lenvima was FDA approved for advanced renal cell carcinoma in May 2016 and differentiated thyroid cancer in February 2015.
Results approvable but may not be sufficient to drive significant uptake
Lenvima’s noninferior primary endpoint result versus Nexavar is enough for FDA approval, said Dr. Tim Greten, deputy chief, Thoracic and Gastrointestinal Malignancies Branch, National Cancer Institute, Bethesda, Maryland, and Dr. Markus Peck-Radosavljevic, chairman, Department of Gastroenterology and Hepatology, Klinikum Klagenfurt, Austria. In the 1,492-patient Phase III REFLECT trial (NCT01761266), the median overall survival (OS) time in the Lenvima arm was 13.6 months, versus 12.3 months with first-line SOC Nexavar (Kudo, M. et. al. Lancet. 2018 Mar 24;391(10126):1163-1173).
In the past 10 years, there have been about eight trials that have failed in first-line HCC versus Nexavar, and thus Lenvima’s positive Phase III is enough to draw approval, said a Phase III investigator, Greten and Peck-Radosavljevic. Nexavar is also a very high-performing therapy in the real world, which made it hard to match or beat as an established SOC, the investigator added.
Even though the Phase III was a noninferiority trial, Lenvima showed superior data in the secondary endpoints, which would help convince clinicians to prescribe the therapy, noted the investigator. The Phase III trial shows Lenvima was statistically superior to Nexavar in the secondary endpoints of PFS (7.4 months vs 3.7 months), median time to progression (8.9 months vs 3.7 months) and objective response rate (24% vs 9%), according to a September 2017 release.
Lenvima showed superior data in the secondary endpoints, which would help convince clinicians to prescribe the therapy
However, although the secondary endpoints were encouraging, a noninferiority trial would still draw pause in clinicians switching to Lenvima, said Dr. Teresa Macarulla, attending physician, Gastrointestinal Tumors Service, University Hospital of Vall d’Hebron, Barcelona, Spain. Secondary endpoint data have little clinical value in HCC, where patients are after OS and not just stable disease, noted Peck-Radosavljevic. Positive secondary endpoints provide limited guidance if the patient could live long enough to be able to access second-line therapy if the cancer persists, he added.
Lenvima was approved in Japan in March 2018, and the investigator noted that in the first two months, some 1,300 patients were prescribed the therapy, showing its potential for swift uptake. However, since the Phase III is a noninferiority trial, it may come down to on-the-ground marketing to sell Lenvima, noted Peck-Radosavljevic. Eisai is a Japan-based company, so it would have more manpower on the ground to market the therapy, he said.
Different side-effect profile compared to Nexavar could be small upside
Lenvima’s side effects seem to be severe based on available data in other tumors where it is approved, Macarulla said. However, some of Lenvima’s side effects are unique compared to Nexavar, which may make Lenvima worth using in the real world for patients who are sensitive to Nexavar’s side effects, noted Peck-Radosavljevic. In fact, patients can be switched from Nexavar to Lenvima if the former is not tolerable, thus giving patients an option, a hepatologist added.
Phase III Lenvima data in HCC shows the most common adverse events were hypertension (42%), diarrhea (39%), decreased appetite (34%) and decreased weight (31%). In contrast, patients who received Nexavar experienced palmarplantar erythrodysesthesia (52%), diarrhea (46%), hypertension (30%) and decreased appetite (27%), according to the aforementioned Lancet paper.
Lenvima seems to cause less skin toxicity in HCC compared to Nexavar, noted the investigator and Peck-Radosavljevic. According to the Lenvima label, all grades skin and subcutaneous tissue disorders include palmar-plantar erythrodysesthesia (32%), rashes (21%), alopecia (12%) and hyperkeratosis (7%). But skin-related side effects are more of a predominant issue in patients with Asian descent, as observed in Asian countries, said Peck-Radosavljevic. Asian patients experiencing more skin-related side effects may be due to genetic differences from Caucasian patients or Asian patients having a higher dose relative to weight, he explained. However, this could mean that Lenvima may have more success in Asian countries, with Nexavar maintaining as the main choice in Western countries, he said.
Reynald Castaneda, prior to moving to London, was a journalist for healthcare newspaper New Zealand Doctor, covering primary care health politics and medical research. He has a BSc in Biological Sciences from the University of Auckland and a postgraduate diploma in journalism from AUT University. Prior to venturing into journalism, Reynald worked as a laboratory technician for Massey University’s Institute of Molecular Biosciences.