setidegrasib (ASP3082) / Astellas - LARVOL DELTA

…Astellas will also present translational analyses from the Phase 1 study of setidegrasib in patients with KRAS G12D-mutated PDAC at the upcoming AACR Conference on Pancreatic Cancer, September 25-28, 2026 (PRNewswire) - "The analyses will provide further insight into mechanisms of response, resistance and potential rational combination approaches in pancreatic cancer. The findings will be featured in both a proffered oral presentation and a poster presentation."

P1 data • Pancreatic Ductal Adenocarcinoma

Astellas Doses First Patient in Phase 3 Study of setidegrasib in Previously Treated KRAS G12D-Mutated Advanced Non-Small Cell Lung Cancer (PRNewswire) - "The randomized, open-label Phase 3 study is evaluating setidegrasib compared with docetaxel in people with KRAS G12D-mutated locally advanced (unresectable) or metastatic NSCLC whose disease has progressed on or after platinum-based chemotherapy and checkpoint inhibitor therapy (CPI)....Astellas plans to enroll approximately 356 patients across multiple countries into the study."

Trial status • Non Small Cell Lung Cancer

Phase 3, randomized, open-label trial of setidegrasib vs docetaxel in patients with KRAS G12D-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC) that progressed on or after platinum-based chemotherapy and checkpoint inhibitor (CPI) therapy: Trial in progress (ESMO 2026) - No abstract available

Checkpoint inhibition • Clinical • Metastases • P3 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

Efficacy and safety of ASP3082 monotherapy or in combination with mFOLFIRINOX in patients (pts) with pancreatic ductal adenocarcinoma (PDAC). (ASCO-GI 2026) - P1 | "We present results from this first-in-human study in pts with PDAC, including dose escalation and expansion, treated with ASP3082 or ASP3082 with modified folinic acid, fluorouracil, irinotecan hydrochloride, and oxaliplatin (mFOLFIRINOX). ASP3082 showed promising antitumor activity alone or plus mFOLFIRINOX with no new safety signals in pts with PDAC. Findings support further evaluation of ASP3082 including DOR, progression-free survival, and overall survival in pts with KRAS G12D-mutant PDAC in both 1L and later-line settings."

Clinical • Combination therapy • First-in-human • Monotherapy • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • KRAS

Beyond KRASG12C: emerging therapeutic strategies, patent landscape, and clinical progress in targeting KRAS-mutant cancers. (PubMed, Med Oncol) - "For most of its history, KRAS has been regarded as "undruggable." Still, with recent developments in covalent inhibitors targeting KRAS^G12C, specifically sotorasib and adagrasib, it has now been validated as a viable therapeutic target...New classes of KRAS inhibitors have recently emerged, including non-covalent inhibitors (MRTX1133, RMC-9805), pan-RAS (ON) antagonists (RMC-6236), and KRAS-directed degraders (ASP3082), as well as planned rational combinations of these new KRAS inhibitors with agents targeting SHP2, SOS1, MEK, and immune checkpoint inhibitors...The regulatory environment and commercialization efforts present opportunities and challenges for precision oncology in KRAS-driven cancers globally. Overall, the rapid evolution of KRAS-targeted therapeutic agents represents a shift from allele-specific inhibition towards a strategy that is mutation/context-dependent, thereby creating further clinical translation opportunities and increased patient..."

IO biomarker • Journal • Review • Colorectal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS

A Phase 3, double-blind, randomized trial of setidegrasib + mFOLFIRINOX or NALIRIFOX as first-line treatment for patients with metastatic pancreatic ductal adenocarcinoma (PDAC) harboring KRAS G12D mutations: Trial in progress (ESMO 2026) - No abstract available

Clinical • Metastases • P3 data • Oncology • Pancreatic Ductal Adenocarcinoma • KRAS

AI-Driven Multi-Omics Integration of Synthetic Colon Adenocarcinoma for Cluster-Guided PROTAC Candidate Design Targeting KRASG12D. (PubMed, Int J Mol Sci) - "Candidate NOVEL00489 showed a good MM-GBSA estimate, matching the reference ASP3082. Compounds are computational candidates requiring experimental validation. This establishes a transparent benchmark for in silico degrader generation in precision oncology."

Journal • Colon Adenocarcinoma • Colon Cancer • Colorectal Adenocarcinoma • Colorectal Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • KRAS

Characterization of KRAS-G12D ubiquitination and degradation by setidegrasib (ASP3082) and its combination potential in preclinical models (EORTC-NCI-AACR 2026) - "Abstract will be available as of 4 November (with consent of the author)"

Preclinical • Oncology • KRAS

Preliminary safety and clinical activity of ASP3082, a first-in-class, KRAS G12D selective protein degrader in adults with advanced pancreatic (PC), colorectal (CRC), and non-small cell lung cancer (NSCLC) (ESMO 2024) - P1 | "The ongoing study suggests that ASP3082, a novel KRAS G12D degrader, has an acceptable safety profile and promising antitumor activity, especially in pts with heavily pretreated PC. Based on these results, further studies are needed."

Clinical • Metastases • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

Efficacy and safety of ASP3082, a novel protein degrader, as monotherapy in patients (pts) with non-small cell lung cancer (NSCLC) with KRAS G12D mutation (AACR-NCI-EORTC 2025) - P1 | "Conclusions Consistent with findings from the dose escalation study, ASP3082 monotherapy showed promising antitumor activity in a heavily pretreated patient population with NSCLC; safety events were generally manageable. These findings support further evaluation of ASP3082 as a new first-in-class treatment option for pts with KRAS G12D-mutant solid tumors."

Clinical • Monotherapy • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS • PD-L1

Phase 1 evaluation of ASP3082, a first-in-class selective protein degrader, in patients (pts) with KRAS G12D-mutant pancreatic ductal adenocarcinoma (PDAC): Pharmacokinetics (PK) and biomarker insights. (ASCO-GI 2026) - P1 | "ASP3082 induced robust KRAS G12D mutant protein degradation and inhibition of RAS-MAPK signaling in tumors. Findings indicate ctDNA KRAS G12D VAF is a prognostic and pharmacodynamic biomarker, supporting continued clinical development of ASP3082."

Biomarker • Clinical • P1 data • PK/PD data • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • CA 19-9 • CEACAM5 • KRAS

Efficacy and safety of setidegrasib in patients (pts) with advanced NSCLC with KRAS G12D mutation (ELCC 2026) - P1 | "Legal entity responsible for the study Astellas Pharma Inc. Funding Astellas Pharma Inc."

Clinical • First-in-human • IO biomarker • Metastases • Lung Cancer • Non Small Cell Lung Cancer • KRAS • PD-L1

Progress and challenges in the design and development of selective KRAS G12D-targeted drug discovery: inhibitors, degraders and emerging therapeutic strategies. (PubMed, Future Med Chem) - "Building on this breakthrough, advances have been made in KRAS G12D-targeted drug development, including potent non-covalent inhibitors such as MRTX1133, HRS-4642, LY3962673, and INCB161734, as well as RAS(ON) tri-complex inhibitors such as RMC-9805...Among the developed pan-RAS inhibitors, RMC-6236 is the most advanced candidate in clinical development. In parallel, targeted protein degradation strategies, particularly PROTAC-based degraders such as ASP3082 and RP03707, have emerged as promising alternatives to overcome resistance and improve therapeutic durability. Combination strategies involving EGFR inhibitors, chemotherapy, and immunotherapy are also expanding clinical potential. This review summarizes recent progress in KRAS G12D-targeted inhibitors and degraders, highlighting current challenges and future opportunities for improving KRAS-directed cancer treatment."

IO biomarker • Journal • Review • Colorectal Cancer • Lung Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • Targeted Protein Degradation • KRAS

The ongoing first-line treatment race for metastatic pancreatic ductal adenocarcinomas: will a tough disease lose its horror? (PubMed, Future Oncol) - "PDACs are K-RAS addicted (incidence >90%), however, RAS oncogenes have been regarded to be "undruggable." Several highly specific inhibitors have been developed with atebimetinib (MEK inhibitor), daraxonrasib (tri-complex pan-K-RAS inhibitor), zoldonrasib (tri-complex K-RAS G12D inhibitor), INCB161734 (non-covalent ON/OFF inhibitor specific for K-RAS G12D), HRS-4642 (liposomal G12D inhibitor), and setidegrasib (G12D degrader) currently undergoing phase III evaluation in first-line PDACs. Since the benefits provided by chemotherapy regimens are limited, it is conceivable that the novel targeted approaches may have the potential to overcome these limitations. Of note, outcomes for some of these compounds numerically exceeded the historical benchmarks with standard chemotherapy suggesting that a chemotherapy backbone might no longer be needed in the future."

Journal • Oncology • Palliative care • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • KRAS

A Study to Learn How Fluconazole, Carbamazepine and Itraconazole Affect How the Body Processes ASP3082 in Healthy Adults (clinicaltrials.gov) - P1 | N=54 | Active, not recruiting | Sponsor: Astellas Pharma Global Development, Inc. | Recruiting ➔ Active, not recruiting | Trial completion date: Jul 2026 ➔ May 2027 | Trial primary completion date: Jul 2026 ➔ May 2027

Enrollment closed • Trial completion date • Trial primary completion date • KRAS

Safety and efficacy of setidegrasib monotherapy in patients (pts) with advanced biliary tract (BTC) and gynecologic (GYN) cancers (ESMO-GI 2026) - P1 | "Conclusions Setidegrasib 600 mg had a favorable safety profile in heavily pretreated pts with advanced BTC or GYN, with no new safety signals compared with pts with lung or pancreatic cancers. Early clinical activity supports further evaluation in these pts."

Clinical • Metastases • Monotherapy • Ampulla of Vater Carcinoma • Biliary Tract Cancer • Cholangiocarcinoma • Colorectal Cancer • Gallbladder Cancer • Gastrointestinal Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • KRAS

A Study to Learn How ASP3082 is Processed in Healthy Men (clinicaltrials.gov) - P1 | N=8 | Not yet recruiting | Sponsor: Astellas Pharma Global Development, Inc.

New P1 trial

Discovery of a KRAS(G12D) degrader ASP3082 (setidegrasib): Ternary complex structure model-based rational optimization of bifunctional degrader (ACS-Fall 2026) - P3 | "Structure-based optimization guided by a ternary complex model constructed with the hit degrader efficiently culminated in the identification of ASP3082. Here we disclose the MedChem story and pharmacological profile of ASP3082, which is currently being evaluated in a phase 3 clinical trial (NCT07409272)."

Targeted Protein Degradation • KRAS

Development of Therapies Targeting Non-G12C KRAS Mutations (Focusing on G12D and Pan-RAS) (PubMed, Gan To Kagaku Ryoho) - "Sotorasib and adagrasib, which are KRAS G12C inhibitors, have shown favorable clinical results mainly in non-small cell lung cancer (NSCLC) and have already been introduced into clinical practice...Setidegrasib (ASP3082) is a first-in-class proteolysis-targeting chimera molecule (PROTAC) that targets the KRAS G12D mutation...Currently, multiple international collaborative phase Ⅲ trials on RMC-6236, mainly focusing on PDAC and NSCLC, are underway. The development of new drugs targeting molecules other than KRAS G12C is progressing rapidly, and in KRAS mutation-positive solid cancers where prognosis was difficult to improve with conventional chemotherapy, there is a high possibility that the existing standard treatments will be significantly revised."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • HRAS • KRAS • NRAS • RAS

3082-CL-0101: A Study of ASP3082 in Adults With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=681 | Recruiting | Sponsor: Astellas Pharma Inc | Trial completion date: Oct 2026 ➔ Dec 2027 | Trial primary completion date: Oct 2026 ➔ Dec 2027

Trial completion date • Trial primary completion date • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

A Study of ASP3082 in Adults With Previously Treated Solid Tumors (clinicaltrials.gov) - P1 | N=356 | Recruiting | Sponsor: Astellas Pharma Inc | N=260 ➔ 356

Enrollment change • Metastases • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • KRAS

A Study of ASP3082 in Adults With Previously Treated Solid Tumors (clinicaltrials.gov) - P1 | N=240 | Recruiting | Sponsor: Astellas Pharma Inc | N=136 ➔ 240

Enrollment change • Colorectal Cancer • Oncology • Solid Tumor • KRAS

A Study of ASP3082 in Adults With Previously Treated Solid Tumors (clinicaltrials.gov) - P1 | N=356 | Recruiting | Sponsor: Astellas Pharma Inc | Trial completion date: Jun 2026 ➔ Oct 2026 | Trial primary completion date: Jun 2026 ➔ Oct 2026

Metastases • Trial completion date • Trial primary completion date • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • KRAS

A Study of ASP3082 in Adults With Previously Treated Solid Tumors (clinicaltrials.gov) - P1 | N=541 | Recruiting | Sponsor: Astellas Pharma Inc | N=356 ➔ 541

Enrollment change • Metastases • Oncology • Solid Tumor • KRAS

3082-CL-0101: A Study of ASP3082 in Adults With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=681 | Recruiting | Sponsor: Astellas Pharma Inc | Trial completion date: Dec 2027 ➔ Dec 2028 | Trial primary completion date: Dec 2027 ➔ Dec 2028

Trial completion date • Trial primary completion date • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS