A Study to Compare Setidegrasib (ASP3082) With Docetaxel, in People With Non-small Cell Lung Cancer With a KRAS G12D Mutation

A Randomized, Open-label, Phase 3 Study of Setidegrasib (ASP3082) Versus Docetaxel in Participants With KRAS G12D-mutated Locally Advanced (Unresectable) or Metastatic Non-small Cell Lung Cancer (NSCLC) Who Have Progressed on or After Platinum Based Chemotherapy and Checkpoint Inhibitor Therapy (CPI)

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. The first treatment is usually chemotherapy, given with another treatment that targets specific proteins on cancer cells. If the cancer gets worse, the next main treatment is usually a medicine called docetaxel. This treatment doesn't stop most people's cancer from getting worse for very long. Other treatments are needed to improve outcomes in people with NSCLC.

Genes give your body instructions on how to make proteins. Proteins are needed to keep the body working properly. Many types of cancer are caused by changes in certain genes, making them faulty. Many people with NSCLC have a faulty KRAS gene in their tumor. One such change in the KRAS gene is called a G12D mutation. Researchers are looking for ways to stop the actions of abnormal proteins made from the KRAS G12D mutation.

Setidegrasib (ASP3082) is thought to remove some of the abnormal proteins made from the faulty KRAS gene. Before setidegrasib can become available as a treatment, studies need to be done.

This study is for people with NSCLC with a faulty KRAS gene in their tumor. In this study, some people will be given setidegrasib and some people will be given docetaxel. The main aims are to learn how long people who are given setidegrasib live with cancer without it getting worse, compared to people who are given docetaxel, and if they live for longer. Other aims are to check tumor response, symptoms, how the body processes setidegrasib, and its safety, compared with docetaxel.

The main aims of study are to learn how long people who are given setidegrasib live with cancer without it getting worse, compared to people who are given docetaxel and if people who are given setidegrasib live for longer compared to people who are given docetaxel.

People in this study will be adults with locally advanced, unresectable or metastatic non-small cell lung cancer (NSCLC) with the G12D mutation in their KRAS gene. Locally advanced means the cancer has spread to nearby tissue. Unresectable means the cancer cannot be removed by surgery. Metastatic means the cancer has spread to other parts of the body. They have had no more than 2 previous treatments for their cancer. The key reasons people cannot take part are if they have different faulty genes in their tumor which can be targeted with other treatments, have symptomatic or untreated cancers that have spread from the lung into the brain or nervous system, their cancer has spread to the thin tissue that covers the brain and spinal cord (leptomeningeal disease), or they have recently had other active cancers that required treatment.

In this study, people will either receive setidegrasib or docetaxel. Whether people receive setidegrasib or docetaxel is decided by chance, not by the study doctor. Both study treatments are given slowly through a tube into a vein (infusion). People will continue to receive study treatment until their cancer gets worse, they can't tolerate the study treatment, they start other cancer treatment, they or the doctor decides the person should stop receiving study treatment, or sadly, they pass away. Some people on docetaxel may be able to switch to setidegrasib during the study if their cancer becomes worse. There will be safety checks at each visit, and the doctors will continue to check for medical problems and people's wellbeing throughout the study. People will continue to have scans of their tumor every 6 weeks for the first year, then every 9 weeks until their cancer becomes worse. After people's cancer becomes worse, clinic staff will telephone people every 12 weeks to check on their cancer.

Study Overview

• Status: Not yet recruiting
• Conditions: Non-small Cell Lung Cancer (NSCLC)
• Intervention / Treatment: Drug: Docetaxel; Drug: Setidegrasib

• Study Type: Interventional
• Enrollment (Estimated): 356
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Astellas Pharma Global Development, Inc.; Phone Number: 800-888-7704; Email: Astellas.registration@astellas.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Participant has histologically confirmed locally advanced (unresectable) or metastatic non-small cell lung cancer (NSCLC) with documented Kirsten rat sarcoma viral oncogene homolog (KRAS) G12D mutation result status, based on local or central testing.

  • The participant's positive KRAS G12D mutation result (either in tumor tissue or plasma ctDNA) must be available prior to randomization.
  • If the participant is enrolling based on a local testing result, the result may have been based on tissue or liquid (blood) testing. If the participant is enrolling via central testing, the eligibility sample must be from tissue.

• Participant must have progressed or experienced disease recurrence on or after platinum based chemotherapy (which includes but is not limited to platinum combinations with pemetrexed, paclitaxel, etoposide or gemcitabine) in combination with anti-PD-1/PD-L1 antibody OR platinum-based chemotherapy and anti-PD-1/PD-L1 antibody (in either order) sequentially in the locally advanced (unresectable) or metastatic setting (participant who received anti PD-1/anti-PD-L1 antibody or platinum-based chemotherapy as first-line therapy in the locally advanced [unresectable] or metastatic setting may have received the combination of platinum-based chemotherapy and anti PD1/anti PD L1 antibody in the second line locally advanced [unresectable] or metastatic setting).

  • No additional treatments are allowed in the locally advanced (unresectable) or metastatic setting, with the exception of: Anti-vascular endothelial growth factor (VEGF) therapy (e.g., bevacizumab), when administered in combination with platinum-based chemotherapy and/or anti-PD-1/PD-L1 as part of a first-line standard regimen in the locally advanced (unresectable) or metastatic setting and Anti-CTLA-4 antibodies (e.g., ipilimumab, tremelimumab), when administered in combination with anti-PD-1/PD-L1 (with or without platinum-based chemotherapy) as part of a first-line standard regimen in the locally advanced (unresectable) or metastatic setting.
  • For the purposes of eligibility, for a participant who has received prior neoadjuvant or adjuvant therapy and has had recurrence during or within 6 months of completion of therapy, the neoadjuvant or adjuvant therapy will be counted as a line of systemic therapy in the locally advanced (unresectable) or metastatic setting (for those who received perioperative therapy, the entire course will be counted as a line of systemic therapy in the locally advanced (unresectable) or metastatic setting).
  • For the purposes of eligibility, for a participant with a history of unresectable Stage III disease who has received prior multi-modal therapy and has had recurrence on or within 6 months of completion of therapy, the multi-modal therapy will be counted as a line of systemic therapy in the locally advanced (unresectable) or metastatic setting. If chemoradiation was followed by treatment with checkpoint inhibitor therapy (CPI) without documented progression between chemoradiation and CPI, the entire treatment course will be counted as a line of systemic therapy in the locally advanced (unresectable) or metastatic setting, for the purposes of eligibility.
  • Maintenance therapy following platinum doublet-based chemotherapy is not considered a separate line of therapy.

• Female participant is not pregnant and at least 1 of the following conditions apply:

  • Not a woman of childbearing potential (WOCBP).
  • WOCBP who has a negative urine or serum pregnancy test at screening (Specific to Japan: with a medical interview) and agrees to follow the contraceptive guidance from the time of informed consent through ≥ 6 months after the final setidegrasib administration or ≥ 2 months after the final docetaxel administration, as applicable.
  • Must not be breastfeeding or lactating starting at screening and throughout the investigational period and for ≥ 6 months after the final setidegrasib administration or ≥ 2 months after the final docetaxel administration, as applicable. (Note that this is stricter than some docetaxel product information/labeling documents due to the uncertainty regarding excretion of docetaxel in human milk.)
  • Must not donate ova starting at first administration of study intervention and throughout the investigational period and for ≥ 6 months after the final setidegrasib administration or ≥ 2 months after the final docetaxel administration, as applicable.
• Participant consents to and provides a baseline tumor tissue and plasma specimen during prescreening and/or screening.
• Participant has an ECOG performance status of 0 or 1 within 7 days prior to randomization.

Exclusion Criteria:

• Participant has known untreated or symptomatic central nervous system (CNS) metastases. Participant with previously treated brain metastases may be eligible if they have stable CNS disease for ≥ 2 weeks prior to randomization, all neurologic symptoms have returned to baseline, there is no evidence of new or enlarging brain metastases on brain imaging performed within 28 days prior to randomization and they are receiving ≤ 10 mg/day of prednisone or equivalent.
• Participant has mixed small-cell lung cancer and NSCLC histology.
• Participant has leptomeningeal disease as a manifestation of the current malignancy.
• Participant has another prior malignancy active (i.e., requiring treatment, including hormonal therapies, or intervention) within the previous 2 years different from the primary malignancy for this study, except for local malignancies that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the cervix or breast, which are allowed.
• Participant has known active hepatitis B virus (HBV) (defined as hepatitis B surface antigen [HBsAg]-positive or anti HBV core antibody-positive) or known active hepatitis C virus (HCV) (defined as HCV RNA [qualitative] detected) infection.
• Participant with human immunodeficiency virus (HIV) infection may be eligible if the participant has not had an opportunistic infection within the past 12 months. Participant must be on established antiretroviral therapy for ≥ 4 weeks, have a CD4+ T cell ≥ 200 cells/µL and must have an HIV viral load < 400 copies/mL prior to randomization (HIV testing is not required unless mandated by the local health authority).
• Participant has current grade ≥ 2 peripheral neuropathy.
• Participant has uncontrolled pleural effusion, pericardial effusion or ascites requiring recurrent drainage procedures at a frequency greater than monthly. Participant with PleurX catheters in place may be considered for the study with medical monitor approval.
• Participant has received therapeutic or palliative radiation therapy within 14 days prior to randomization (see first Exclusion Criteria for CNS metastases); participant must have recovered from all radiotherapy related toxicity to ≤ grade 1, with the exception of alopecia (any grade of alopecia allowed).
• Participant has a known actionable mutation for which an approved targeted therapy is locally available, including, but not limited to, KRAS G12C mutation, EGFR mutation (exon 19 deletions, exon 21 L858R point mutation, T790M, exon 20 insertion), ALK or ROS1 rearrangement, NTRK fusion, NRG1 fusion, BRAF V600E mutation, MET exon 14 skipping mutation, RET rearrangement or HER2 activating mutation.
• Participant has received prior treatment with either docetaxel or a KRAS-targeting agent (including KRAS directed inhibitors, degraders, siRNA, vaccines and cellular therapies).
• Participant requires treatment with concomitant drugs that are strong inhibitors or inducers of cytochrome P450 (CYP)3A or CYP2D6.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Setidegrasib; Participants will receive Setidegrasib on days 1, 8 and 15 of every 21-day cycle.	Drug: Setidegrasib; Intravenous infusion; Other Names: ASP3082
Active Comparator: Docetaxel; Participants will receive docetaxel on day 1 of every 21-day cycle.	Drug: Docetaxel; Intravenous infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-Free Survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. as assessed by blinded independent central review (BICR)	PFS is defined as the time from the date of randomization until the date of documented radiographic disease progression per RECIST v1.1, as assessed by BICR or until death due to any cause, whichever comes first.	Up to 2.3 years
Overall Survival (OS)	OS is defined as the time from the date of randomization until the date of death from any cause.	Up to 4.2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to deterioration in NSCLC symptoms (TDLCS): cough evaluated via European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Lung Cancer Module (EORTC QLQ-LC13) items	TDLCS: cough is defined as time between randomization and the first occurrence of a meaningful deterioration in the corresponding EORTC QLQ-LC13 coughing score (item 31) compared with the baseline score. EORTC QLQ-LC13 is a lung-cancer specific module that serves as an additional 13 item questionnaire to the general EORTC cancer questionnaire. It consists of 3 items to assess dyspnea, and 10 single items assessing pain, coughing, sore mouth, dysphagia, peripheral neuropathy, alopecia, and hemoptysis. Scores range from 0 to 100. A high score for a symptom scale/item represents a high level of symptomatology/problems.	Up to 2.3 years
TDLCS: chest pain evaluated via EORTC QLQ-LC13	TDLCS: chest pain is defined as the time between randomization and the first occurrence of a meaningful deterioration in the EORTC QLQ-LC13 chest pain score (item 40) compared with the baseline score. EORTC QLQ-LC13 is a lung-cancer specific module that serves as an additional 13 item questionnaire to the general EORTC cancer questionnaire. It consists of 3 items to assess dyspnea, and 10 single items assessing pain, coughing, sore mouth, dysphagia, peripheral neuropathy, alopecia, and hemoptysis. Scores range from 0 to 100. A high score for a symptom scale/item represents a high level of symptomatology/problems.	Up to 2.3 years
TDLCS: dyspnea evaluated via EORTC QLQ-LC13	TDLCS: dyspnea is defined as the time between randomization and the first occurrence of a meaningful deterioration in the EORTC QLQ-LC13 dyspnea score (composite of items 33 to 35) compared with the baseline score. EORTC QLQ-LC13 is a lung-cancer specific module that serves as an additional 13 item questionnaire to the general EORTC cancer questionnaire. It consists of 3 items (items 33 to 35) to assess dyspnea, and 10 single items assessing pain, coughing, sore mouth, dysphagia, peripheral neuropathy, alopecia, and hemoptysis. Scores range from 0 to 100. A high score for a symptom scale/item represents a high level of symptomatology/problems.	Up to 2.3 years
Time to Worsening of Global Health Status/Quality of Life (GHS/QoL) (TWGQ) measured by European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)	TWGQ is defined as time between randomization and the first occurrence of a meaningful worsening in the composite EORTC QLQ-C30 item scores (19 and 30) compared with the baseline score. EORTC-QLQ-C30 is a 30-item cancer-specific instrument consisting of 5 functional scales (physical, role, emotional, social and cognitive), 9 symptom scales/items (fatigue, nausea/vomiting, general pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties) and a global health status scale. Participants rate items on a four-point scale, with 1 as "not at all" and 4 as "very much." For functional scales, higher scores indicate better functioning, while for symptom scales/items, higher scores indicate worse symptoms.	Up to 2.3 years
Objective Response Rate (ORR) per RECIST v1.1, as assessed by BICR	ORR is defined as the proportion of participants whose best overall response (BOR) is rated as confirmed complete response (CR) or confirmed partial response (PR) per RECIST v1.1. as assessed by BICR.	Up to 2.3 years
Time to response (TTR) per RECIST v 1.1 as assessed as assessed by BICR	TTR is defined as the time from the date of randomization to the first documentation of objective response (confirmed CR or confirmed PR) per RECIST v1.1. as assessed by BICR.	Up to 2.3 years
Duration of Response (DOR) per RECIST v 1.1 as assessed by BICR	DOR is defined as the time from the date of first documented response (CR or PR subsequently confirmed) to the date of first documented PD per RECIST v1.1 assessed by BICR, or death due to any cause, whichever occurs first.	Up to 2.3 years
Disease Control Rate (DCR) per RECIST v 1.1 as assessed by BICR	DCR is defined as the proportion of participants whose best overall response is rated as CR, confirmed PR or SD per RECIST v1.1 as assessed by BICR.	Up to 2.3 years
PFS per RECIST v1.1. as assessed by the investigator	PFS is defined as the time from the date of randomization until the date of documented radiographic disease progression per RECIST v1.1 as assessed by the investigator or until death due to any cause, whichever comes first.	Up to 2.3 years
ORR per RECIST v1.1. as assessed by the investigator	ORR is defined as the proportion of participants whose BOR is rated as confirmed CR or confirmed PR per RECIST v1.1. as assessed by the investigator.	Up to 2.3 years
TTR per RECIST v 1.1 as assessed by the investigator	TTR is defined as the time from the date of randomization to the first documentation of objective response (confirmed CR or confirmed PR) per RECIST v1.1. as assessed by the investigator.	Up to 2.3 years
DOR per RECIST v 1.1 as assessed by the investigator	DOR is defined as the time from the date of first documented response (CR or PR subsequently confirmed) to the date of first documented PD per RECIST v1.1 as assessed by the investigator or death due to any cause, whichever occurs first.	Up to 2.3 years
DCR per RECIST v 1.1 as assessed by the investigator	DCR is defined as the proportion of participants whose best overall response is rated as CR, confirmed PR or SD per RECIST v1.1 as assessed by the investigator.	Up to 2.3 years
Number of Participants with Adverse Events (AEs)	An AE is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention.	Up to 4.2 years
Number of Participants with Serious Adverse Events (SAEs)	An SAE is defined as any untoward medical occurrence that, at any dose: Results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, and other medically important events.	Up to 4.2 years
Number of Participants with laboratory value abnormalities and/or AEs	Number of participants with potentially clinically significant laboratory values.	Up to 4.2 years
Number of Participants with electrocardiogram (ECG) abnormalities and/or AEs	Number of participants with potentially clinically significant ECG values.	Up to 4.2 years
Number of Participants with vital sign abnormalities and/or AEs	Number of participants with potentially clinically significant vital sign values.	Up to 4.2 years
Number of Participants with Eastern Cooperative Oncology Group (ECOG) performance status	The ECOG scale will be used to assess performance status. Grades range from 0 (fully active) to 5 (dead). Negative change scores indicate an improvement. Positive scores indicate a decline in performance.	Up to 4.2 years
Pharmacokinetics (PK) of setidegrasib in plasma: End-of-Infusion (EOI) concentration	EOI concentration will be recorded from plasma samples collected.	Up to 23 days
PK of setidegrasib in plasma: concentration immediately prior to dosing at multiple dosing (Ctrough)	Ctrough will be recorded from plasma samples collected.	Up to 197 days
Change from baseline in EORTC QLQ-C30	The EORTC-QLQ-C30 is a 30-item cancer-specific instrument consisting of 5 functional scales (physical, role, emotional, social and cognitive), 9 symptom scales/items (fatigue, nausea/vomiting, general pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties) and a global health status scale. Participants rate items on a four-point scale, with 1 as "not at all" and 4 as "very much." For functional scales, higher scores indicate better functioning, while for symptom scales/items, higher scores indicate worse symptoms.	Baseline and up to 12 weeks
Change from baseline in EORTC QLQ-LC13	EORTC QLQ-LC13 is a lung-cancer specific module that serves as an additional 13 item questionnaire to the general EORTC cancer questionnaire. It consists of 3 items to assess dyspnea, and 10 single items assessing pain, coughing, sore mouth, dysphagia, peripheral neuropathy, alopecia, and hemoptysis. Scores range from 0 to 100. A high score for a symptom scale/item represents a high level of symptomatology/problems.	Baseline and up to 12 weeks
Change from baseline in EuroQol 5-dimensional 5-level version (EQ-5D-5L) Visual Analog Scale	The EQ-5D-5L is a standardized instrument for use as a measure of health outcome consisting of 6 items that cover 5 main domains (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) and a general visual analog scale for health status. Each domain comprises 5 severity levels (no problems, slight problems, moderate problems, severe problems, extreme problems). The general visual analog scale records the respondent's self-rated health status on a vertical graduated (0 = the worst health a participant can imagine to 100 = the best health a participant can imagine) visual analogue scale. Responses to the 5 items will also be converted to a weighted health state index (utility score) based on values derived from general population samples.	Baseline and up to 12 weeks
Change from baseline until week 12 in Patient Global Impression of Change (PGIC)	The PGIC is a single-item questionnaire that asks participants to provide the overall self-assessment of change in their disease on a 7-point scale ranging from "very much worse" to "very much better" as compared to the participant starting the study treatment. Only PGIC questions assessing pain and overall status will be collected.	Baseline and up to 12 weeks
Change from baseline until week 12 in Patient Global Impression of Severity (PGIS)	The PGIS is a single-item questionnaire that asks participants to provide the overall self-assessment of their disease severity on a 4-point scale for the past week, with 1 as "None" and 4 as "Severe". Only PGIS questions assessing pain and overall status will be collected.	Baseline and up to 12 weeks
Patient reported outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) responses over time	Each selected PRO-CTCAE items will be assessed related to one or more attributes that include counts for the frequency, severity, and/or interference with usual or daily activities	Up to 2.3 years
Functional Assessment of Cancer Therapy - General Item 5 (FACT-GP5) responses over time	The FACT-GP5 question assesses overall side effect burden with the following response options "I am bothered by side effects of treatment," is rated on a 5-point scale ranging from "not at all" (0) to "very much" (4) and counts will be presented	Up to 2.3 years

Collaborators and Investigators

• Sponsor: Astellas Pharma Global Development, Inc.
• Investigators: Study Director: Medical Director, Astellas Pharma Inc

Study record dates

Study Major Dates

• Study Start (Estimated): April 30, 2026
• Primary Completion (Estimated): June 30, 2030
• Study Completion (Estimated): June 30, 2030

Study Registration Dates

• First Submitted: April 27, 2026
• First Submitted That Met QC Criteria: April 27, 2026
• First Posted (Actual): May 4, 2026

Study Record Updates

• Last Update Posted (Actual): May 4, 2026
• Last Update Submitted That Met QC Criteria: April 27, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Docetaxel; Non-small cell lung cancer (NSCLC); ASP3082; KRAS G12D; setidegrasib
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Carcinoma, Non-Small-Cell Lung; Organic Chemicals; Hydrocarbons; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Terpenes; Taxoids; Cyclodecanes; Diterpenes; Docetaxel
• Other Study ID Numbers: 3082-CL-5301

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Access to anonymized individual participant level data collected during the study, in addition to study-related supporting documentation, is planned for studies conducted with approved product indications and formulations, as well as products terminated during development. Studies conducted with product indications or formulations that remain active in development are assessed after study completion to determine if Individual Participant Data can be shared. Further details on Astellas' data sharing policy can be found at https://www.clinicaltrials.astellas.com/transparency/.
• IPD Sharing Time Frame: Access to participant level data is offered to researchers after publication of the primary manuscript (if applicable) and is available as long as Astellas has legal authority to provide the data.
• IPD Sharing Access Criteria: Researchers must submit a proposal to conduct a scientifically relevant analysis of the study data. The research proposal is reviewed by an Independent Research Panel. If the proposal is approved, access to the study data is provided in a secure data sharing environment after receipt of a signed Data Sharing Agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No