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 (ASCO) annual meeting. Both drugs were used on top of the AVD regimen of chemotherapy.
The 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.
Adcetris has been the standard of care in first-line Hodgkin lymphoma, 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 Hodgkin lymphoma this year.
Adcetris, used in combination with AVD, got its first-line Hodgkin lymphoma 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.
Opdivo 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 Hodgkin lymphoma. 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.
“Early SWOG data are promising, but longer-term proven outcomes including [overall survival] data are important in a curative setting such as HL,” Seagen said in a statement to Fierce Pharma.
Adcetris may 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.
“Our ultimate goal is to achieve the highest cure rate possible by combining the two most active agents in Adcetris and an anti-PD1 and, as a result, further reduce chemotherapy burden for patients,” Seagen said in a statement.
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.
Originally approved for late-line lymphoma in 2011, Adcetris was Seagen’s first commercial product. But even without the threat from PD-1 inhibitors, Adcetris is expected to lose its top status within the ADC company to Astellas-partnered Nectin-4 ADC Padcev.
A combination of Padcev and Keytruda recently snagged a high-profile approval as a first-line therapy to treat cisplatin-ineligible bladder cancer. SVB Securities’ analysts estimated that first-line bladder cancer could bring Padcev nearly $3.9 billion in peak sales across the U.S. and EU.