This phase II trial tests the impact of biomarkers in predicting initial treatment (first-line) PD1 or PD-L1 (PD\[L\]-1)-based immunotherapy response and in selecting second-line treatment in patients with stage IIIB-IV non-small cell lung cancer (NSCLC). Response and survival rates in advanced stage NSCLC, unlike other cancers, rely on response to first-line therapy. Immunotherapy with PD(L)1-based therapy, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. While immunotherapy has improved survival rate, the prognosis remains poor with most patients receiving chemotherapy after immunotherapy. Many types of tumors tend to lose cells or release different types of cellular products including their deoxyribonucleic acid (DNA) which is referred to as circulating tumor DNA (ctDNA) into the bloodstream before changes can be seen on scans. Health care providers can measure the level of ctDNA in blood or other bodily fluids to determine which patients are at higher risk for disease progression or relapse. The first part of this trial, studying samples of blood and tissue in the laboratory from patients receiving immunotherapy may help doctors learn more about the effects PD(L)1-based therapy on cells. It may also help doctors understand how well patients respond to treatment and may help develop new individualized treatment strategies. The second part of this trial also tests the effect of second-line immunotherapy, such as tremelimumab and durvalumab or adagrasib and bevacizumab, in treating patients with NSCLC with specific genetic mutations that is growing, spreading or getting worse (progressive). Tremelimumab is a monoclonal antibody that may interfere with the ability of tumor cells to grow and spread. A monoclonal antibody is a type of protein that can bind to certain targets in the body, such as molecules that cause the body to make an immune response (antigens). Immunotherapy with monoclonal antibodies, such as durvalumab, may help the body's immune system attack the tumor, and may interfere with the ability of tumor cells to grow and spread. Adagrasib, a type of targeted therapy, may stop the growth of tumor cells by blocking a protein needed for tumor cell growth and may kill them. Bevacizumab is in a class of medications called antiangiogenic agents. It works by stopping the formation of blood vessels that bring oxygen and nutrients to tumor. This may slow the growth and spread of tumor. Giving second-line immunotherapy, tremelimumab and durvalumab or adagrasib with bevacizumab, may be safe, tolerable, and/or effective in treating patients with stage IIIB/IV NSCLC with specific genetic mutations.
Documented informed consent of the participant and/or legally authorized representative. (Adult patients lacking capacity to consent may participate if they have a caretaker that could ensure compliance.)
Participants must have either A) HopeSeq or Tempus molecular testing results reported within 3 months prior to enrollment or currently in process OR B) archival or new biopsy tissue available (to be sent to Tempus). Acceptable sample types include: two formalin-fixed paraffin-embedded (FFPE) tissue core biopsies, or two 25um sections of 5-10mm² tissue, or 15-20 unstained slides at 10um thickness (a minimum of 10 unstained slides must be provided)
Agreement to blood collection for ctDNA research
Age: ≥ 18 years
Surgical intervention within 4 weeks prior to study treatment, except for minor procedures such as port placement
Patients with a condition requiring systemic treatment with corticosteroids (> 10 mg daily prednisone equivalent) within 7 days or another immunosuppressive medication within 30 days of the first dose of study treatment. Inhaled or topical steroids, and adrenal replacement steroid doses ≤ 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease
Radiation therapy within 7 days prior to day 1 of protocol therapy
Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke or myocardial infarction within 6 months of enrollment, unstable angina, congestive heart failure (New York Heart Association [NYHA class] ≥ III), or serious uncontrolled cardiac arrhythmia requiring medication
Sequential
Adagrasib
DrugGiven PO
Anti-PD-L1 Monoclonal Antibody
Biological/VaccineGiven PD-L1-based immunotherapy
Anti-PD1 Monoclonal Antibody
Biological/VaccineGiven PD1-based immunotherapy
Bevacizumab
Biological/VaccineGiven IV
Biopsy Procedure
Procedure/SurgeryUndergo tumor biopsy
Biospecimen Collection
Procedure/SurgeryUndergo blood, CSF, ascites and pleural fluid sample collection
Chemotherapy
DrugGiven chemotherapy
Computed Tomography
Procedure/SurgeryUndergo CT
Durvalumab
Biological/VaccineGiven IV
Magnetic Resonance Imaging
Procedure/SurgeryUndergo PET
Monitoring
Other interventionUndergo monitoring
Positron Emission Tomography
Procedure/SurgeryUndergo PET
Surveillance
BehavioralUndergo close surveillance
Tremelimumab
Biological/VaccineGiven IV
6
Treatment groupsSee each treatment group below.
Progression-free survival (PFS) during first-line treatment (Part I)
Will be estimated using the Kaplan-Meier (KM) method. Comparisons across treatment arms will be performed using stratified log-rank tests and Cox proportional hazards models, with assessment of the proportional-hazards assumption and exploration of time-dependent hazard ratios. Dynamic treatment regimen (DTR)-specific PFS will also be estimated using inverse probability weighting (IPW) to account for multiple randomizations and treatment adaptations.
PFS by arm for second-line treatment (Part II)
Will be estimated using the KM method. Comparisons across treatment arms will be performed using stratified log-rank tests and Cox proportional hazards models, with assessment of the proportional-hazards assumption and exploration of time-dependent hazard ratios. DTR-specific PFS will also be estimated using IPW to account for multiple randomizations and treatment adaptations.
Development and testing of biomarkers predictive of early response to immunotherapy
Will include, but not limited to, blood based, tissue-based and imaging-based biomarkers.
Overall survival (OS)
Will be evaluated by arm. Will be estimated using the KM method. Comparisons across treatment arms will be performed using stratified log-rank tests and Cox proportional hazards models, with assessment of the proportional-hazards assumption and exploration of time-dependent hazard ratios. DTR-specific OS will also be estimated using IPW to account for multiple randomizations and treatment adaptations.
Circulating tumor deoxyribonucleic acid (ctDNA) level
Joint modeling approaches will be applied, combining mixed-effects models for ctDNA trajectories with survival models for PFS or OS. All stratified efficacy analyses will incorporate randomization stratification factors.
ctDNA complete response (CCR) rate
Will be summarized by treatment sequence. Logistic regression models will evaluate associations between CCR and baseline covariates.
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City of Hope Medical Center
Lead sponsor
National Cancer Institute (NCI)
Collaborator
