Defactinib, Avutometinib, and Nivolumab for LKB1-Mutant Lung Cancer
This study is testing a combination of three drugs—defactinib, avutometinib, and nivolumab—for advanced non-small cell lung cancer that has a specific change called an LKB1 mutation and has not responded to previous anti-PD1 treatment. Defactinib and avutometinib are kinase inhibitors, which means they block proteins that cancer cells need to grow. Nivolumab is an immunotherapy that helps your body's immune system fight cancer. Researchers want to see if this combination can stop the cancer from growing for at least 6 months. To join, you must have advanced lung adenocarcinoma with an LKB1 mutation, and for some, a KRAS mutation. The study plans to enroll 50 participants.
- Study design
- This is an interventional study, meaning participants will receive a specific treatment. It aims to enroll 50 participants.
- What's involved
- You would take defactinib and avutometinib by mouth, and receive nivolumab through an IV, in cycles repeating every 28 days. You will also have biopsies, blood draws, and CT scans.
- Compensation
- Not stated in the trial record.
- Follow-up
- After treatment, participants are followed up every 3 months for up to 5 years.
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NCT06495125
Defactinib, Avutometinib and Nivolumab for the Treatment of Anti-PD1 Refractory LKB1-Mutant Advanced Non-Small Cell Lung Cancer
Recruiting
PHASE2Ages 18+InterventionalTreatmentEmory UniversityInvestigator-initiated
~50 participants
Updated 2026-04-06 on ClinicalTrials.gov
What's tested:AvutometinibBiopsyBiospecimen CollectionComputed TomographyDefactinibNivolumab
At a glance
Recruiting sites
2 of 3 listed sites are recruiting right now
RecruitingSuspended, closed, or not yet open
What they're measuring
Progression free survival (PFS)
Measured over At 6 months
Conditions
Where it's being run
3 sites across 1 statesGeorgia3
Study leadership
- Conor E Steuer · PRINCIPAL_INVESTIGATOR · Emory University Hospital/Winship Cancer Institute
Who to contact
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Do you actually qualify for this trial?
Add a private profile and we'll compare every criterion below against your situation — and tell you which ones are met, uncertain, or excluding.
Eligibility criteria
Inclusion
Patients must have been histologically or cytologically diagnosed with non-small cell lung cancer, specifically lung adenocarcinoma
Patients must have advanced stage disease that is not amenable to combined modality therapy or surgical resection
Patients must have known LKB1 mutation
COHORT A ONLY: Patients must have known KRAS mutation
Patients must have progressed on prior therapy with immune checkpoint inhibitor alone and first line chemotherapy, either combined or sequentially, for advanced stage disease. No other lines of chemotherapy in the advanced stage therapy is allowed. The exception is patients with KRAS G12C are also allowed the use of one line of targeted Food and Drug Administration (FDA) approved therapy
Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥ 20 mm with conventional techniques or as ≥ 10 mm with spiral CT scan
Age ≥ 18 years
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
Adequate recovery from toxicities related to prior treatments to at least grade 1 by Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0. Exceptions include alopecia and peripheral neuropathy grade ≤ 2
Absolute neutrophil count ≥ 1,500/mcL
Hemoglobin ≥ 8.0
Platelets ≥ 100,000/mcL
Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for the institution; patients with Gilbert syndrome may enroll if total bilirubin \< 3.0 mg/dL (51 umole/L)
Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase \[SGPT\]) alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN (or \< 5 x ULN in patients with liver metastases)
Creatinine clearance ≥ 60 mL/min/1.73 m\^2 for patients with creatinine levels above institutional normal
Patients must have the ability to ingest oral medications
The effects of defactinib and avutometinib on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry,for the duration of study participation, for 3 months following the last dose of study therapy for male patients, and 1 month following the last dose of study therapy for female patients. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
Patients must be able to understand and be willing to sign a written informed consent document
Baseline corrected QT (QTc) interval \< 460 ms for women and ≤ 450 ms for men (average of triplicate readings) (CTCAE grade 1) using Fredericia's QT correction formula. NOTE: This criterion does not apply to patients with a right or left bundle branch block
Exclusion
Patients who have had systemic therapy within 3 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier
Patients who are receiving any other investigational agents
Patients with unstable or symptomatic brain metastasis or known leptomeningeal disease. Asymptomatic brain metastases are allowed if they meet the following criteria:
Have been treated and have been stable for greater than or equal to 4 weeks as documented by radiologic imaging
Have not required increasing doses of corticosteroids within 2 weeks prior to study treatment
Patients with history of pre-existing auto-immune conditions that would pose a higher risk for toxicity with nivolumab will be excluded
Patients who experienced serious auto-immune toxicity with prior immune checkpoint inhibitor therapy
History of allergic reactions attributed to compounds of similar chemical or biologic composition to avutometinib or defactinib
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
Known hepatitis B, hepatitis C or human immunodeficiency virus (HIV) infection that is active and/or requires therapy
Active skin disorder that has required systemic therapy within the past 1 year. Surgically removed early stage skin cancers are allowed. Topical creams are allowed as well
History of rhabdomyolysis
Concurrent ocular disorders:
Patients with history of glaucoma, history of retinal vein occlusion (RVO), predisposing factors for RVO, including uncontrolled hypertension, uncontrolled diabetes
Patients with history of retinal pathology or evidence of visible retinal pathology that is considered a risk factor for RVO, intraocular pressure \> 21 mm Hg as measured by tonometry, or other significant ocular pathology, such as anatomical abnormalities that increase the risk for RVO
Patients with active or chronic, visually significant corneal disorders, other active ocular conditions requiring ongoing therapy or clinically significant corneal disease that prevents adequate monitoring of drug-induced keratopathy. Examples of visually significant corneal disorders include corneal degeneration, active or recurrent keratitis, and other forms of serious ocular surface inflammatory conditions. Visually significant corneal disorders do NOT include dry eyes, blepharitis, and uncomplicated corneal erosions
Patients with the inability to swallow oral medications or impaired gastrointestinal absorption due to gastrectomy or active inflammatory bowel disease
Treatment with warfarin. Patients on warfarin for deep vein thrombosis/pulmonary embolism should be converted to low-molecular-weight heparin (LMWH) or direct oral anticoagulants (DOACs). Exposure to medications (with or without prescriptions), supplements, herbal remedies, or foods with potential for drug-drug interactions with defactinib within 14 days prior to the first dose of avutometinib or defactinib and during the course of therapy, including:
Strong CYP3A4 inhibitors or inducers, strong CYP2C9 inhibitors or inducers, strong P-glycoprotein (P-gp) inhibitors or inducers
Patients with a known "treatable driver mutation" with FDA approved targeted therapy (such as EGFR, ALK, ROS1, NTRK, BRAF, RET, MET exon 14, HER2). The exception is KRAS as listed in the inclusion section
History of prior malignancy within past 2 years prior to study entry, with the exception of curatively treated malignancies or malignancies with very low potential for recurrence or progression
Female patients who are pregnant or breastfeeding
What this trial measures
- Progression free survival (PFS)At 6 months
PFS will be defined as the time from the date of first protocol therapy to the date of first documentation of disease progression or death due to any cause, whichever occurs first. PFS will be evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1. PFS will be calculated with a 95% confidence interval using Kaplan-Meier method based on the efficacy evaluable population.