— Adding durvalumab and bevacizumab to transarterial chemoembolization nearly doubles PFS
Charles Bankhead, Senior Editor, MedPage This day
January 21, 2024
SAN FRANCISCO — After extra than 20 years of making an are attempting, systemic therapy for unresectable liver cancer has improved outcomes with transarterial chemoembolization (TACE), a randomized trial showed.
Patients who got durvalumab (Imfinzi) plus bevacizumab (Avastin) besides to TACE had a median development-free survival (PFS) of 15.0 months as when put next with 8.2 months for TACE plus placebo. The arrive used to be driven basically by bevacizumab, as sufferers who got fully durvalumab had a median PFS of 10.0 months, a nonsignificant distinction from the placebo arm.
Damaging events (AEs) befell in a the same percentage of sufferers in all three medication teams. Grade 3/4 AEs presumably connected to appear medication befell extra steadily within the durvalumab-bevacizumab arm (25.5%) versus about 6% with TACE and placebo or single-agent durvalumab. Rates of fatal AEs did now not differ all over medication teams, reported Riccardo Lencioni, MD, of the College of Pisa in Italy, on the Gastrointestinal Cancers Symposium.
“The EMERALD-1 trial met the fundamental endpoint and is the first, worldwide section III look to point out a statistically principal and clinically meaningful enchancment in PFS with an immunotherapy and TACE-based fully mostly regimen in unresectable HCC [hepatocellular carcinoma] eligible for embolization,” said Lencioni. “The abet used to be consistent all over all scientific subgroups, and the safety profile used to be manageable.”
The trial did now not contend with the question of whether PFS is an passable surrogate for overall survival (OS), a mission that has been debated for extra than a decade, said invited discussant Josep M. Llovet, MD, PhD, of the Icahn College of Pills at Mount Sinai in New York City and the College of Barcelona in Spain. A most modern diagnosis of 27 section III randomized trials in superior HCC showed that the minimum threshold for surrogacy with PFS is a hazard ratio (HR) <0.6. Absolutely the PFS distinction in EMERALD-1 translated into an HR 0.77.
“For sure, all of the trials with a hazard ratio beneath 0.6 own resulted in determined leads to overall survival,” said Llovet. “Conversely, if the hazard ratio is above that, it’s miles perilous if the trial might be determined or negative in phrases of survival.”
The outcomes moreover raised a matter about the role of bevacizumab in superior HCC, he persisted. Every other most modern look showed that atezolizumab (Tecentriq) plus bevacizumab is superior to single-agent sorafenib, but monotherapy with an immune checkpoint inhibitor is now not.
Llovet participated in a but-to-be-printed look of 320 sufferers with superior HCC. Investigators stumbled on that a third of the tumors had been immunocompetent, and nearly all responded to immunotherapy. The final two-thirds had been immunologically “frosty” tumors. If the frosty tumors had activation of notch signaling, a marker of resistance to bevacizumab, they had been now not prone to reply, whereas absence of the signaling cascade reflects downregulation of NRP1, which is a marker of response to bevacizumab.
Despite the boundaries of PFS as a surrogate for survival, EMERALD-1 is the first look in extra than 20 years to show cloak an enchancment previous the activity of TACE on my own, Llovet acknowledged. The outcomes further emphasize the importance of bevacizumab in combination with immunotherapy.
“The implication is that durvalumab plus bevacizumab plus TACE can develop to be the customary-or-backyard of care in intermediate HCC,” he concluded. “Upper GI endoscopy might be most principal in these cases.”
EMERALD-1 fervent 616 sufferers with unresectable HCC, no extrahepatic disease, and Child-Pugh stage A-B7. They had been randomized to 3 teams: durvalumab plus TACE adopted by durvalumab and placebo; durvalumab plus TACE adopted by durvalumab and bevacizumab; or placebo plus TACE adopted by placebo.
The fundamental endpoint used to be PFS for the comparability of the durvalumab-bevacizumab-TACE arm versus TACE-placebo. A key secondary used to be comparability of PFS for durvalumab with TACE adopted by durvalumab-placebo.
The fundamental diagnosis showed a 6.8-month absolute distinction in PFS in desire of durvalumab-bevacizumab versus TACE on my own (P=0.032), Lencioni reported. Landmark PFS analyses preferred durvalumab-bevacizumab at 12 (55.9% vs 39.8%) and 18 months (43.1% vs 28.3%). The comparability of durvalumab-TACE versus TACE-placebo yielded a nonsignificant HR 0.94.
Median time to development (TTP) extra than doubled with durvalumab plus bevacizumab versus TACE-placebo (22.0 vs 10.0 months), a 37% reduction within the HR. In distinction durvalumab-TACE ended in a median TTP of 11.5 months, now not tremendously completely different from TACE-placebo. Overall response fee used to be 41.0% with durvalumab-TACE, 43.6% with durvalumab-bevacizumab-TACE, and 29.6% with TACE-placebo.
The EMERALD-1 trial used to be backed by AstraZeneca.
Lencioni disclosed relationships with AstraZeneca.
Llovet disclosed relationships with Eisai, Merck, Roche, Genentech, AstraZeneca, Bayer, Bristol Myers Squibb, Eli Lilly, Moderna, Glycotest, Exelixis, Sagimet, Boston Scientific, and Omega Therapeutics.
Gastrointestinal Cancers Symposium
Source Reference: Lencioni R, et al “EMERALD-1: A section III randomized, placebo-managed look of transarterial chemoembolization blended with durvalumab with or with out bevaizumab in participants with unresecetable hepatocellular carcinoma eligible for embolization” GiCS 2024; Summary LBA432.