This phase II trial tests how well defactinib and avutometinib in combination with nivolumab works in treating patients with LKB1-mutant non-small cell lung cancer that has not responded (refractory) to an anti-PD1 treatment and may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced). Defactinib and avutometinib belong to a class of drugs called kinase inhibitors. These drugs target kinase proteins found in tumor cells. Tumor cells need these proteins to survive and grow. By blocking these proteins, defactinib and avutometinib may cause tumors to stop growing or grow more slowly. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the tumor and may interfere with the ability of tumor cells to grow and spread. Giving defactinib and avutometinib in combination with nivolumab may kill more tumor cells in patients with anti-PD1 refractory LKB1-mutant advanced non-small cell lung cancer.
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 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
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
Single group
Avutometinib
DrugGiven PO
Biopsy
Procedure/SurgeryUndergo biopsy
Biospecimen Collection
Procedure/SurgeryUndergo blood sample collection
Computed Tomography
Procedure/SurgeryUndergo CT
Defactinib
DrugGiven PO
Nivolumab
Biological/VaccineGiven IV
Positron Emission Tomography
Procedure/SurgeryUndergo PET
Progression free survival (PFS)
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.
PFS
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 RECIST v1.1. The Kaplan-Meier method will be used to estimate the median PFS with 95% confidence interval.
Overall survival (OS)
OS will be measured from the date of first protocol treatment to the date of death. The Kaplan-Meier method will be used to estimate OS with 95% confidence interval.
Duration of response (DOR)
DOR will be measured from the time measurement criteria are met for complete response or partial response (whichever is first recorded) until the first date that recurrent or progressive disease is documented. Summary statistics will be used to describe the mean and median DOR.
Incidence of adverse events (AEs)
AEs will be graded using National Cancer Institute Common Toxicity Criteria for Adverse Events v5.0. All AEs will be summarized and described within each cohort. The incidence of severe events or toxicities will be described as well as the proportion of patients with grade 3 or higher toxicity.
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Emory University
Lead sponsor
National Cancer Institute (NCI)
Collaborator
