Amivantamab With Tyrosine Kinase Inhibitors (TKIs) for Advanced NSCLC With ALK, ROS1, or RET Alterations

Phase 1 Clinical Trial NCT06225427 sponsored by The University of Colorado, Denver with Janssen Research and Development, LLC

Amivantamab With Tyrosine Kinase Inhibitors (TKIs) for Advanced NSCLC With ALK, ROS1, or RET Alterations

https://clinicaltrials.gov/study/NCT05845671

Principal Investigator: Dr. Tejas Patil

University of Colorado Study Contact: Febin Elias; 303-724-9459; febin.elias@cuanschutz.edu   

University of Michigan Study Contact: Dhaman Bansal; shbansl@med.umich.edu

Who is this trial for: This trial is for patients with one of three forms of non-small cell lung cancer (NSCLC) – ALK, ROS1, or RET - who are progressing on their current TKI under certain conditions, and are willing to try an experimental drug combination in order to extend the life of their current TKI.  Amivantamab is a bi-specific antibody targeting the cell survival pathways MET and EGFR.  The trial may be most appropriate for patients who are progressing without a targetable mutation or clearly identified driver of their cancer growth.

Inclusion criteria: The trial will study the safety, side effects, best dose, and efficacy of amivantamab when paired with TKIs for specific oncogene-driven NSCLC, including ALK.  The target population for this study will be adult patients with currently progressing NSCLC harboring an ALK, ROS1, or RET fusion on an FDA-approved TKI. Patients must have been on their current TKI at the same dose for at least 8 weeks without radiographic progression or clinical intolerance to the TKI prior to enrolling on this study.  In other words, prior to progression, the patient must have been stable on the TKI for at least 8 weeks.  Participants must have at least 1 measurable lesion using computed tomography (CT) scan or magnetic resonance imaging (MRI).  For ALK patients, TKIs included are alectinib, brigatinib, lorlatinib, and others.   Patients are expected to stay on their current TKI with no washout, and receive additional periodic infusions of amivantamab at the trial clinics.  Acceptable ages are 18-90 years.

Exclusion criteria:  The patient cannot have ever received a prior EGFR or MET TKI or any other EGFR or MET-directed treatment in order to participate, however prior crizotinib treatment is allowed if discontinued three months prior to trial screening.   Other prior treatments including chemotherapy, immune checkpoint inhibitors, surgery, and radiotherapy must have been completed by varying time periods up to one month.  Trial exclusion criteria include several pre-existing medical conditions: see  https://clinicaltrials.gov/study/NCT05845671

Some Details:  Estimated enrollment in the lead-in cohort is 10-12 patients, with a total of 16-35 total patients expected to be accrued.   Study duration is estimated to be a total of 4 years, with 3 years of participant enrollment and 1 year for analysis.  A fresh pre-treatment biopsy or equivalent archival material from a tumor biopsy collected prior to study treatment is required.   Blood samples will be routinely collected for lab testing, and CT scans with contrast will be performed periodically.  Infusion frequency at this writing is every three weeks, but may be changed to every two weeks. 

Scientific rationale: Amivantamab (aka Rybrevant) is a bispecific antibody that targets the EGFR and MET pathways.  It was approved by the FDA in 2021 for patients with NSCLC harboring EGFR exon 20 insertion mutations, in combination with carboplatin and pemetrexed.  The trial hypothesis is that EGFR and MET pathways are utilized by cancer cells to circumvent the selective pressure from TKIs as a means of survival.  Continuing the ALK, ROS1, or RET TKI after progression and adding amivantamab represents a rational combination strategy, even when the patient tests negative for EGFR or MET amplification.  It is thought that there may still be EGFR-MET signaling that standard biomarker testing is not discovering, even in the absence of EGFR-MET amplification.  Recent data suggests that these pathways compensate for each other in situations where one pathway is inhibited, leading to "kinase switch" drug resistance. Thus, the expected inhibition of multiple pathways via combination treatment with amivantamab and a TKI may improve overall efficacy by limiting the compensatory pathway activation.  In vitro and in vivo studies showed that amivantamab was able to disrupt EGFR and MET signaling functions through blocking ligand binding and, in exon 20 insertion mutation models, degradation of EGFR and MET. The presence of EGFR and MET on the surface of tumor cells also allows for targeting of these cells for destruction by immune effector cells, such as natural killer cells and macrophages, through antibody-dependent cellular cytotoxicity (ADCC), and by cells ingesting each other (trogocytosis). 

Availability: The trial is open at two locations of the University of Colorado in Denver, where the principal investigator is Dr. Tejas Patil, and a sub-investigator is Dr. Ross Camidge.  It is also open at University of Michigan, where the principal investigator is Dr. Angel Qin.  Janssen Research and Development is a wholly owned subsidiary of Johnson and Johnson, an American pharmaceutical company ranked #2 in the world with revenues of $54.76B in 2023.  

Jeffrey M. Sturm  BS, MA, MBA

ALK Positive, Inc.   www.alkpositive.org

Member Clinical Trials Committee

Member Board of Directors

ALK Positive NSCLC Survivor