Eisai’s (TYO:4523) Lenvima (lenvitanib) for
first-line unresectable hepatocellular carcinoma (HCC) has a convincing FDA
approval rationale based on positive Phase III results versus Bayer’s
(ETR:BAYN) Nexavar (sorafenib), a high efficacy bar, experts agreed. Although
some experts raised reservations about the Phase III trial only showing Lenvima
as non-inferior to Nexavar in an open-label trial, this shouldn’t be an
approval barrier, other experts noted.
Analyst reports have not commented on
Lenvima’s approval prospects. But experts noted their confidence in the data,
highlighting the outperforming Nexavar which did not prevent Lenvima’s
non-inferiority. Lenvima’s potent antiangiogenic mechanism is ideal for HCC
since its tumors are highly vascular and dependent on liver vessels to
proliferate, further supporting approval justification, they added.
Although one analyst report states Lenvima’s
side effect profile is within the known scope, experts noted its hypertension
rates are higher than Nexavar. This could potentially be a differentiating
factor between the two drugs considering efficacy data puts them neck-and-neck,
some noted.
Based on data presented at this month’s
American Society of Clinical Oncology (ASCO) in Chicago, Eisai plans to submit
regulatory applications for unresectable HCC to the FDA and other territories,
a June 2017 media release shows. Data was collected from the randomized Phase
III REFLECT trial, which compared Lenvima and Nexavar in 954 subjects
(NCT01761266), ClinicalTrials.gov shows.
Some analysts predict Nexavar has potential to
reach USD 1bn in all indications. Lenvima was FDA approved for the treatment
thyroid cancer in February 2015 and advanced renal cell carcinoma in May 2016.
Eisai did not respond to a request for comment.
Healthy FDA approval prospects
All experts agreed Lenvima’s Phase III results
should secure FDA approval, particularly its primary endpoint of Overall
Survival (OS) highlighting Lenvima as non-inferior to Nexavar. The median OS in
the Lenvima group was 13.6 months compared to 12.3 months for Nexavar
(p<0.00001) [Cheng, A. et. al. J Clin Oncol 35, 2017 (suppl; abstr 4001)].
Showing non-inferiority in first-line HCC is a
high bar considering many drugs have failed in Phase III when pitted against
Nexavar, said Dr Richard Finn, Phase III investigator and assistant professor
of medicine, David Geffen School of Medicine, UCLA, and Dr Emmanuel Thomas,
assistant professor, Sylvester Comprehensive Cancer Center, Schiff Center for
Liver Diseases, Miami, Florida. Bristol-Myers Squibb’s (NYSE:BMY) Phase III
trial investigating brivanib (BMS-582664) versus Nexavar failed to demonstrate
non-inferiority [Johnson, PJ et. al. J Clin Oncol. 2013 Oct 1;31(28):3517-24].
Pfizer’s (NYSE:PFE) Phase III trial investigating Sutent (sunitinib) versus
Nexavar was stopped for futility after first interim analysis [Cheng, A. et.
al. J Clin Oncol. 2013 Nov 10;31(32):4067-7].
Finn noted Nexavar’s 12.6 months OS in the
Lenvima trial is unusually high in contrast to other Phase III trials featuring
Nexavar, which makes Lenvima’s non-inferiority success encouraging for
approval. In the Phase III brivanib trial, Nexavar’s OS was 9.9 months. A
possible reason to Nexavar’s high OS in the Lenvima trial is that investigators
were very experienced with Nexavar and therefore subjects could have been
treated earlier than real world patients leading to better outcomes, Finn said.
In the unlikely event Lenvima is not approved
it could be due to the trial being a non-inferiority trial which is not very well-established
design in HCC, said Dr Jorg Trojan, head of gastrointestinal oncology,
University Hospital Frankfurt, Goethe University, Frankfurt, Germany. It would
have been ideal if the Phase III open-label trial was blinded as allowing
investigators to know which drug the subject received may have reduced result
subjectivity, added Dr Marcus Peck Radosavljevic, associate professor of
medicine, department of gastroenterology and hepatology, Medical University of
Vienna, Austria.
But drug approvals based on non-inferiority
studies are not unusual and the FDA are unlikely to consider it an approval
roadblock, Peck and Finn said. Trojan added Phase III’s head-to-head trial
design is welcome as it spells out how Lenvima compares with Nexavar without
having to compare two different trials.
Trojan said Lenvima’s mechanism is also
logical for HCC, further supporting its approval prospects. Peck said, like
Nexavar, Lenvima is a tyrosine-kinase inhibitor (TKI) which seems to be ideal
for patients who have failed chemotherapy.
But Lenvima theoretically should be more
potent than Nexavar in HCC, since Lenvima has a more specific target, Trojan
said. Lenvima is a potent anti-angiogenic drug, meaning it blocks blood vessel
growth in cancer, Trojan and Finn said. This is ideal for HCC because its tumors
are highly vascular and dependent on liver vessels to spread, Trojan said. In contrast,
Nexavar is dubbed as a “dirty TKI” as it targets many pathways, he explained.
Differentiated but reasonable toxicity profile
Trojan said Lenvima’s side effect profile also
supports approval, with Finn noting there are no new Lenvima safety signals in
the Phase III trial. The most common side effects were hypertension (42%),
diarrhea (39%), weight loss (31%) and fatigue (30%), Phase III data shows.
Hypertension seems to be more frequent with Lenvima, and it could be due to the
drug’s antiVEGF effect, Peck said. This shouldn’t be an approval barrier as it
could be an indicator that the drug is reaching the right target, Peck added.
Trojan said this difference in side effects
between Lenvima and Nexavar could be a critical differentiation point between
the two drugs since Lenvima is only non-inferior. If Lenvima is approved, a
likely real-world scenario would be patients who may be susceptible to
hypertension would not be given Lenvima, Peck said. In patients who are
sensitive to Nexavar’s side effects like diarrhea and hand-foot skin reaction
could then be given Lenvima, Trojan said. Finn said there’s a lower frequency
of skin reactions with Lenvima due to target profile nuances between the two
drugs.
There have been concerns Lenvima could lead to
severe bleeding events, but this has so far not surfaced, Trojan said. Lenvima
has been linked to bleeding events in thyroid cancer and bleeding events can
happen with HCC as demonstrated when Roche’s (VTX:ROG) Avastin (bevacizumab) --
a drug which similarly targets VEGF -- was investigated for the indication,
Trojan added.
Reynald Castaneda
Reporter, London