A phase 1/2, open label study of amivantamab in combination with tyrosine kinase inhibitors among participants with advanced NSCLC harboring ALK, ROS1, and RET gene fusions.

TPS8661 Background: Patients with ALK, ROS1, or RET rearranged NSCLC demonstrate dramatic and sustained responses to tyrosine kinase inhibitors (TKI). Unfortunately, acquired resistance remains a major clinical challenge. The EGFR and MET pathways have been reported as important escape mechanisms for cancer cells treated with highly potent TKIs. Combining amivantamab with ALK, ROS1, or RET TKIs upon radiographic progression represents a rational combination strategy in addressing TKI mediated resistance. Methods: This is an open-label, multicenter, Phase 1b / 2 study of amivantamab in combination with TKIs among participants with advanced NSCLC harboring ALK, ROS1, and RETgene fusions progressing on FDA-approved TKIs for their respective oncogene. Participants must be on their TKI at the same dose for at least 3 months prior to enrolling in the study. A pre-treatment biopsy is required to rule out neuroendocrine transformation and for translational objectives. Local confirmation of an ALK, ROS1, or RET gene fusion through tissue or circulating tumor DNA (ctDNA) assessment is allowed. Plasma collection for ctDNA assessments will occur prior to treatment, on C3D1, and post-treatment. This study will have both a safety lead-in cohort and a dose expansion cohort. A safety lead-in cohort will be treated with amivantamab at the RP2D in combination with their ALK, ROS1, or RET TKI. The primary endpoint will be dose-limiting toxicity (DLT) within the first cycle of dosing at a given dose level. A Bayesian optimal interval (BOIN) design will be employed as a safety lead-in using a dose de-escalation design to find the maximum tolerated dose (MTD) of amivantamab in combination with a standard fixed dose of common ALK, ROS1, and RET TKIs. The RP2D dose for amivantamab was previously set at 1050mg (for patients < 80kg) and 1400mg (for patients ≥ 80kg). Patients will be treated in cohorts of size 3, and the maximum sample size for the dose escalation portion of the trial is 12 patients. The dose expansion cohort will evaluate the safety and efficacy of amivantamab (at the RP2D dose) in combination with standard FDA-approved doses of ALK, ROS1, and RET TKIs. The primary endpoint will be objective response rate (ORR). All patients enrolled at the RP2D level will be included in the phase II efficacy analysis, including patients enrolled in the safety lead-in cohort. A total of 16 to 35 evaluable patients, depending on the safety of the tested treatments in the dose escalation phase, are expected to be accrued to this study. Relevant exclusion criteria include: (1) prior EGFR directed therapy, (2) prior receipt of a MET monoclonal antibody or MET-ADC, (3) crizotinib use as immediate prior line of therapy, (4) small cell transformation, and (5) active, untreated, CNS metastases. The study has initiated enrollment without DLT and is ongoing. Clinical trial information: NCT05845671 .