The rising antibody-drug conjugate class has hit a setback as Seagen’s
Adcetris, one of the earliest and fast-growing members of the group, was
defeated by immune checkpoint inhibitor.
Compared with Adcetris, Bristol Myers Squibb’s Opdivo significantly
reduced the risk of cancer progression or death by 52% in adults and
children with newly diagnosed stage 3 or 4 classical Hodgkin lymphoma,
according to phase 3 data unveiled at the 2023 American Society of
Clinical Oncology annual meeting. Both drugs were used on top of the AVD
regimen of chemotherapy.
collaborative group-conducted trial, coded SWOG S1826, randomized
nearly 1,000 patients. The results point to Opdivo-AVD as “a new
standard of care that is better tolerated and results in a higher
proportion of patients with durable remissions” than Adcetris-AVD,
Oreofe Odejide, M.D., from the Dana-Farber Cancer Institute and an
invited ASCO expert, said in a statement.
The readout marks a blow to Seagen, which is being acquired
by Pfizer in a $43 billion transaction. Adcetris, a CD30-directed ADC,
is currently Seagen’s best-selling drug with sales up 34% year over year
to reach $243 million in the first quarter. By SVB Securities’ estimate
in an April note before the data readout, front-line Hodgkin lymphoma
means about $780 million in sales for Adcetris at peak. Seagen is
partnered with Takeda on Adcetris outside the U.S. and Canada.
has been the standard of care in first-line HL, with the highest
recommendation from the National Comprehensive Cancer Network (NCCN).
During a conference call in February, Seagen’s U.S. commercial chief
Chip Romp was talking about potentially gaining more shares in
first-line HL this year.
used in combination with AVD, got its first-line HL nod in 2018 and
added a pediatric label in November. Last year, the Echelon-1 trial that
gave Adcetris that first-line nod showed
the ADC regimen could reduce the risk of death by 41% over an old
chemotherapy combo. The overall survival benefit earned Adcetris the
NCCN recommendation as a preferred therapy.
But Adcetris comes with some toxic effects, which can be significant
for a relatively young patient population, Alex Herrera, M.D., from City
of Hope and lead investigator of the SWOG trial, said during a press
briefing. The median age of patients in the SWOG trial was 27 years.
is currently only allowed in HL following Adcetris treatment thanks to
an FDA accelerated approval in 2016. The new SWOG trial will support an
FDA filing for Opdivo in front-line treatment, Herrera told Fierce
Pharma in an interview. It could also help Bristol Myers turn the
original conditional nod into a full approval.
Before the SWOG trial testing Opdivo in the first line, Merck & Co.’s Keytruda in 2020 won a full FDA approval
in previously treated HL. Keytruda demonstrated a 35% progression-free
survival benefit against Adcetris monotherapy in a head-to-head trial,
which helped convert an accelerated approval in the late line.
In the current trial, 94% of patients who received Opdivo were still
alive without progression at one year, versus 86% for Adcetris. The
Opdivo regimen has yet to show a significant patient survival benefit.
By the data cutoff, 11 (2.2%) deaths happened in the Adcetris arm,
compared with four (0.8%) for Opdivo.
It could be a long time
before the SWOG study could show a clear overall survival signal.
Adcetris’ Echelon-1 trial delivered the overall survival readout after a
median six years of follow-up. The current SWOG data are based on a
median follow-up of just one year.
In terms of safety, Opdivo
takers had more neutropenia but fewer bone pain, sensory neuropathy and
liver toxicity. Altogether 22% of patients discontinued Adcetris,
compared with 11% for Opdivo. Although Opdivo was designed to augment
the immune system, immune-related side effects were similar between the
two therapies, Herrera said.
The progression-free survival
advantage, plus a favorable safety profile, should make Opdivo-AVD a
standard of care even without an overall survival showing, Herrera said.
still have a place in newly diagnosed HL. Seagen is testing the
combination of Adcetris and Opdivo, plus reduced chemo, and has shown promising results
from a phase 2 trial. The cocktail triggered complete responses in 88%
of patients with advanced stage HL and in 92% of those with early-stage
HL, according to an update at the American Society of Hematology annual
meeting in December.
Adcetris is still a potent drug, Herrera
said, but the question is how best to incorporate it in the treatment
paradigm. Combining Adcetris with Opdivo while reducing chemo is a
logical approach, he added.