Seattle Genetics (NASDAQ:SGEN) and Takeda
Pharmaceutical’s (TYO:4502) Adcetris (brentuximab vedotin) will likely get a
Hodgkin’s lymphoma (HL) label expansion from the FDA based on results of the
AETHERA study, experts said.
The Phase III trial’s (NCT01100502) positive
results on the primary endpoint of progression free survival (PFS) in patients
who are at high risk of relapse following autologous stem cell transplant
(autoSCT) make approval likely, they said. The current practice is not to treat
high-risk patients and to wait for them to relapse before receiving allogeneic
SCT (alloSCT), some experts said, noting that alloSCT is a difficult procedure
to undergo. As such, an expert added, forestalling relapse is valuable for
those patients.
Topline results of the study were presented at
the American Society of Hematology’s (ASH’s) 2014 annual meeting in December,
and this news service reported 11 September 2014 that AETHERA had potential to
expand the Adcetris label in the US and EU.
Seattle Genetics did not respond to requests
for comment.
Label expansion likely
The AETHERA data will likely drive an
expansion of Adcetris’ label in HL to include use in the consolidative setting
post-autoSCT and result in widespread use of the drug, said Dr David Peace,
professor, medicine, University of Illinois College of Medicine, Chicago; Dr
Nam Dang, deputy chief, Division of Hematology and Oncology, University of
Florida College of Medicine, Gainesville; and Dr Elizabeth Budde, assistant
professor, Department of Hematology and Hematopoietic Cell Transplantation,
City of Hope, Duarte, California. Median PFS by independent review was 43
months for the Adcetris group and 24 months for the placebo group, according to
an 18 February Seattle Genetics press release.
The data looks compelling and is likely to
lead to FDA approval, said Dr David Aboulafia, section head, Department of
Hematology/Oncology, Virginia Mason Clinic, Seattle, Washington. On the other
hand, he said, it raises the question of how to sequence the drug because a lot
of the patients get Adcetris before transplant, but for high-risk patients who
have not received it pre-transplant, it will likely become a post-transplant
maintenance standard of care. This news service reported 11 September 2014 that
even if AETHERA was positive for PFS and OS, the results may not apply to
patients getting Adcetris in first- or second-line therapy, and while the drug
is not routinely used in those settings, that could change going forward. The
study excluded patients previously treated with Adcetris, according to
ClinicalTrials.gov.
The FDA has accepted Seattle Genetics’ sBLA
based on the AETHERA data, the company said in a 20 April press release.
Currently, the drug has accelerated approval for HL patients after failure of
autoSCT or patients who are not autoSCT candidates and have failed at least two
prior multi-agent chemotherapy regimens, as well as for systemic anaplastic
large-cell lymphoma (ALCL) after failure of at least one multi-agent
chemotherapy regimen.
AETHERA enrolled high-risk patients with a
high-risk disease, noted Dr Nishitha Reddy, associate professor, medicine,
Vanderbilt-Ingram Cancer Center, Nashville, Tennessee. With HL curable in
80-85% of patients, those being taken to transplant represent a small
percentage, while those meeting the criteria for high-risk are an even small
percentage, maybe 7-8%.
The study included patients considered at
high-risk of residual HL post-autoSCT, including 196 refractories to frontline
therapy, 107 who had relapsed less than 12 months after frontline therapy and
26 who had relapsed at least 12 months after frontline therapy with extranidal
disease, according to published results (Moskowitz, et al. Lancet. 2015 May
9;385(9980):1853-62). The current practice is not to do anything for those
patients, and to simply wait until they relapse before giving them allogeneic
stem cell transplant (alloSCT), noted Reddy and Budde. Yet, alloSCT after
autoSCT is not a trivial procedure and is very hard on patients, they added. Frontline
HL treatments include radiation and chemotherapy-combination regimens like
doxorubicin/bleomycin/vinblastine/dacarbazine (ABVD) and
bleomycin/etoposide/doxorubicin/ cyclophosphamide/vincristine/procarbazine
(BEACOPP), according to the American Society of Clinical Oncology.
It would be very helpful to be able to delay
alloSCT by a couple of years, Reddy said. Watching and waiting after autoSCT
without maintenance can be nerve-wracking for patients, so Adcetris maintenance
therapy will definitely benefit them, Budde said.
Given Adcetris’ extensive use in HL and ALCL
and her center’s ample experience with the administration and side-effect
profile of the drug, Budde said she saw herself giving it widely in the
post-autoSCT high-risk setting. Approval in that setting will also likely
change practice in the sense that community oncologists will be more
comfortable giving the drug, Dang said, explaining that academic oncologists
such as he tends to be more liberal in their usage of drugs like Adcetris.
In AETHERA, the most frequent adverse events
included peripheral sensory neuropathy and neutropenia, according to the
results.
Yet, usage in the community setting may not be
so likely because most oncologists who deal with post-transplant relapses are more
or less in the academic setting, Reddy said, adding that she did not foresee a
huge increase in Adcetris’ usage following FDA approval of the label expansion.
AETHERA’s lack of OS difference between the
arms, could be due to patients in the placebo arm crossing over to receive
Adcetris, Dang noted. This news service reported 11 September 2014 that OS
improvement may be needed for doctors to use Adcetris in post-transplant
maintenance or for the drug to change practice, though HL is a difficult disease
in which to show OS benefit. However, commenting on the most recent data, Budde
said the goal of post-transplant maintenance is to keep patients in remission,
making PFS a more important endpoint.
A pre-specified analysis showed no
statistically significant difference in OS between the two arms, according to a
29 September 2014 Seattle Genetics and Takeda press release, but a further
analysis for OS is expected in 2016. For the pooled study population at 24
months, the Kaplan-Meier estimate for OS was 88%, according to the ASH abstract
(abstract no. 673).
Seattle Genetics’ market cap is USD 5.8bn.
Alaric DeArment
Reporter, New York
Alaric DeArment covers cancer drugs and
vaccines for BioPharm Insight. Previously, he was associate editor at Drug Store
News, covering retail and specialty pharmacy, pharmaceuticals, biologics and
regulatory affairs. A native of Seattle, he graduated with honors with a
bachelor’s degree in journalism from Ball State University and also lived in
China from 2001-2004.