Astellas starts a second pivotal degrader trial

Astellas is consolidating its lead in the KRAS G12D degrader race, starting a new pivotal trial of its contender setidegrasib in second-line non-small cell lung cancer. This is the second phase 3 study of the asset, following a first-line pancreatic cancer trial that began in February.However, the Japanese group has ditched the project in another use, second-line-plus colorectal cancer, it disclosed at an R&D day in March. Perhaps early data weren’t convincing.Post-PD-1Meanwhile, it’s all go in NSCLC. The new study has an estimated start date at the end of April, according to a recent listing on clinicaltrials.gov. It will test setidegrasib monotherapy, versus docetaxel, in patients with KRAS G12D-mutated tumours who have previously received an anti-PD-(L)1 antibody plus chemo.The co-primary endpoints are progression-free and overall survival, and the primary analysis is due in Astellas’s fiscal 2028, according to the group’s fourth-quarter presentation.The company will be hoping to replicate results from a phase 1 basket trial; the most recent data drop, published in the NEJM in March, found a 36% ORR among 45 relapsed NSCLC patients receiving a 600mg dose. Median progression-free survival was 8.3 months; 93% of patients had previously received a checkpoint inhibitor plus chemo.Chemo comboIn first-line pancreatic ductal adenocarcinoma Astellas is testing setidegrasib plus mFolfirinox or Nalirifox chemo, versus chemo alone, with a primary endpoint of overall survival. An interim analysis is set for fiscal 2029.That study made setidegrasib the third KRAS G12D-targeting project, and the first degrader, to enter phase 3, behind Verastem/GenFleet’s VS-7375 (GFH375) and Jiangsu HengRui’s HRS-4642. However, both of the last two projects are so far only in phase 3 in China.Since then Incyte has begun the global pivotal Dawn-03 trial of its contender, INCB161734, in first-line PDAC despite a clinical hold in several European countries spurred by a fatal case of pneumonitis. And Revolution Medicines has said its KRAS G12D inhibitor zoldonrasib has started the phase 3 Rasolute-305 trial in first-line PDAC, although this doesn’t yet appear to have been listed on clinicaltrials.gov.There’s less competition in KRAS G12D degraders, with Arvinas’s ARV-806 one to watch; phase 1 data are due this year.Astellas recently discontinued a backup G12D degrader, ASP4396, to focus on setidegrasib. The company also has a pan-KRAS degrader, ASP5834, in phase 1. Pivotal trials of setidegrasibTrialSettingRegimenPrimary endpoint(s)Note3082-CL-03011st-line PDAC+ mFolfirinox or Nalirifox, vs mFolfirinox or NalirifoxOSStarted Feb 2026; results expected 20293082-CL-53012nd-line NSCLC (post-PD-(L)1 + chemo)MonoRx, vs docetaxelPFS, OSEstimated start Apr 2026; results expected 2028Source: OncologyPipeline & clinicaltrials.gov.