This phase Ib/II trial studies the side effects and best dose of trastuzumab and necitumumab together with osimertinib, and to see how well they work for the treatment of stage IV non-small cell lung cancer that is EGFR-mutated, resistant to osimertinib, and has not responded to previous treatment (refractory). Immunotherapy with monoclonal antibodies, such as trastuzumab and necitumumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Osimertinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving trastuzumab and necitumumab together with osimertinib may work better than osimertinib alone in treating patients with stage IV EGFR-mutated non-small cell lung cancer.
Name: Necitumumab
Name: Osimertinib
Name: Quality-of-Life Assessment
Name: Questionnaire Administration
Name: Trastuzumab
Description: Will be defined by the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE V5.0).
Measure: Incidence of adverse events (Phase Ib) Time: Up to 1 yearDescription: Will be based on the Full Analysis Set (FAS) of the phase II portion of the trial and the phase Ib patients treated at the recommended phase II dose (RP2D). ORR is defined as defined as complete response (CR) or partial response (PR) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Will be determined by the investigator. A Cox proportional hazards model will be used to estimate the hazard ratio and its 95% confidence interval (CI).
Measure: Objective response rate (ORR) (Phase II) Time: Up to 1 yearDescription: PFS is defined as the time from trial initiation to cancer progression per RECIST 1.1 based on investigator assessment or death due to any cause.
Measure: Progression free survival (PFS) (Phase II) Time: Up to 1 yearDescription: DoR is time from documentation of tumor response to disease progression.
Measure: Duration of response (DoR) (Phase II) Time: Up to 1 yearDescription: OS is defined as time from randomization to death by any cause.
Measure: Overall survival (OS) (Phase II) Time: Up to 1 yearDescription: Will be assessed using Patient Reported Outcomes-Common Terminology Criteria for Adverse Events (PRO-CTCAE).
Measure: Patient reported outcomes (PROs) Time: Up to 1 yearDescription: Will be obtained from the Functional Assessment of Cancer Therapy - Lung (FACT-L) questionnaire. Will be analyzed by the clinical biostatisticians in the University of California, Los Angeles (UCLA) Department of Medicine Medical Statistics Core.
Measure: Quality of life data questionnaire Time: Up to 1 yearDescription: Will be assessed using response from liquid biopsies and optional but recommended baseline tissue biopsy. Will correlate pre-and post-treatment biopsies molecular changes (i.e. expression of HER2, HER3, AXL, MET) with response.
Measure: Potential biomarkers associated with response from liquid biopsies Time: Up to 1 yearDescription: Will be assessed using liquid biopsy with response.
Measure: Mutant allele fraction in circulating tumor deoxyribonucleic acid (DNA) (ctDNA) Time: Up to 1 yearAllocation: N/A
Single Group Assignment
There is one SNP
Enrollment of patients with mutations other than exon 19 deletion and the L858R point mutation require literature supporting sensitivity to EGFR tyrosine kinase inhibitors - Progressed on osimertinib. --- L858R ---