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 side effect 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.
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 palmar-plantar 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
Reporter, London
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.