Necitumumab and Trastuzumab in Combination With Osimertinib for the Treatment of Refractory Epidermal Growth Factor Receptor (EGFR)-Mutated Stage IV Non-small Cell Lung Cancer

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PRIMARY OBJECTIVES: I. Determine the recommended phase II dose (RP2D) of osimertinib and necitumumab in combination with trastuzumab. (Phase Ib) II. Evaluate the efficacy of osimertinib, necitumumab, and trastuzumab (ONT) as measured by objective response rate (ORR), which is defined as complete res...

PRIMARY OBJECTIVES: I. Determine the recommended phase II dose (RP2D) of osimertinib and necitumumab in combination with trastuzumab. (Phase Ib) II. Evaluate the efficacy of osimertinib, necitumumab, and trastuzumab (ONT) as measured by objective response rate (ORR), which is defined as complete response (CR) or partial response (PR) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. (Phase II) SECONDARY OBJECTIVES: I. To evaluate the efficacy of ONT as measured progression free survival (PFS), duration of response (DoR), and overall survival (OS). II. To evaluate the safety and tolerability of ONT as measured by adverse events (AEs) defined by Common Terminology Criteria for Adverse Events version 5.0 (CTCAE V 5.0). EXPLORATORY OBJECTIVES: I. To assess patient-reported outcomes on health-related quality of life and adverse events. II. Assess potential biomarkers associated with response from liquid biopsies and optional but recommended baseline tissue biopsy. IIa. Correlate pre-and post-treatment biopsies molecular changes with response. III. Correlate mutant allele fraction in circulating tumor deoxyribonucleic acid (DNA) (ctDNA) via liquid biopsy with response. OUTLINE: This is a phase Ib, dose-escalation study of osimertinib and necitumumab followed by a phase II study. Patients receive necitumumab intravenously (IV) over 60 minutes and trastuzumab IV over 30-90 minutes on days 1 and 15. Patients also receive osimertinib orally (PO) once daily (QD) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. After the completion of study treatment, patients are followed up at 30 days, every 8 weeks through week 24, then every 12 weeks up to 1 year.

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