Introduction
Amivantamab (AMI) is a bispecific antibody (bsAb) that binds to EGFR and cMET receptors and inhibits tumor growth in non-small cell lung cancer (NSCLC). AMI was FDA-approved in 2021 for the treatment of patients with metastatic NSCLC who harbor exon-20 mutations in EGFR. AMI is a promising therapy but not all patients respond to it. Immunohistochemical and mutation analysis of biopsies are used to select candidates likely to respond to bsAb treatment. These methods are highly invasive. However, PET imaging is noninvasive and may serve as an equal or superior means of patient selection. First, we must overcome biological and technological challenges. Namely, EGFR- and cMET- expression are both expected to change after AMI treatment, but PET cannot discriminate between radionuclides if two tracers are injected simultaneously. In this proof of concept study, we designed a novel imaging paradigm to image both receptors on the same day by sequential administration of a long-lived tracer [89Zr]Zr-DFO-anti-cMET (89Zr t1/2 = 78.4 hr) that binds to cMET and a short-lived tracer [11C]erlotinib (11C t1/2 = 20.4 min) that binds to EGFR mutants. Here, we evaluate changes in receptor expression in vivo over the course of treatment while overcoming limitations of the standard diagnostic techniques.
Materials and Methods
We used HCC827 NSCLC xenografts in nude mice. [89Zr]Zr-DFO-anti-cMET (41. 3 ± 3.9 µCi) was injected via tail vein (n=2), followed by acquisition of static 10-min PET scans at 2 hr, 1, 2, and 3 days post injection. On day 3, to subtract the contribution of 89Zr activity from the subsequent [11C]erlotinib scan, a 5-min static (“pre-injection”) scan was done using 11C acquisition parameters. Following this scan, 130 ± 28 µCi of [11C]erlotinib was injected and 120 min dynamic scan was acquired. The 89Zr activity contribution was subtracted from the 11C scan based on the activity in the 5-min “pre-injection scan,” and[11C]erlotinib scan was decay corrected. Starting on day 5, animals were treated with AMI (10 mg/kg 2x per week) for 25 days. Following a 7-day washout period, dual-tracer imaging was repeated. Binding potential (BP) for the 89Zr-anti-cMET was calculated by Logan Plot; and the tumor uptake rate constant (Ki) was calculated for [11C]erlotinib using Patlak Plot. Analyses were performed before and after treatment with AMI.
Results
In both animals, standard uptake values for each tumor decreased (Figure). BP of [89Zr]Zr-DFO-anti-cMET was reduced by >66% in animal-1(pre- = 14.1, and post-therapy = 4.7, respectively) and >42% in animal-2 (7.5, and 4.3, respectively). Ki of 11C-erlotinib was reduced by >30% in animal-1 (pre- = 0.0129, and post-therapy = 0.0088 min-1, respectively) and >42% in animal-2 (0.0129, and 0.0122, respectively).
Conclusion
Preliminary analysis suggests that same-day dual-tracer PET studies are feasible and that after proper correction for the presence of multiple isotopes, the images offer quantitative measures of receptors targeted by bsAb, which could be used to determine response to treatment. Further imaging with full cohorts of tumor-bearing and control animals will be necessary to confirm a response of tumors to AMI therapy with dual-tracer PET.