SNMMI 2023: PET Evaluation of Changes in c-MET Expression in Metastatic Renal Cell Carcinoma Under Therapy with Cabozantinib

(UroToday.com) The 2023 Society of Nuclear Medicine and Molecular Imaging (SNMMI) Annual Meeting held in Chicago, IL between June 24th and 27th, 2023 was host to a session on urologic malignancies. Dr. Lena Unterrainer presented the results of an analysis evaluating changes in c-MET expression in metastatic renal cell carcinoma (RCC) patients using c-MET-targeted PET imaging.

 
C-MET is an epithelial cell membrane receptor protein that functions as a tyrosine-protein kinase. This cell surface protein is involved in cancer progression and tumorigenesis across various malignancies. Significantly, c-MET upregulation has been associated with poor clinical outcomes and drug resistance.

C-MET expression has been demonstrated to be higher in RCC tissue, compared to adjacent normal renal tissue. Furthermore, higher c-MET expression correlates with worse disease-specific survival. As such, c-MET acts as a potential adverse prognostic biomarker in the RCC disease space.

Cabozantinib is a vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) that has demonstrated efficacy in the first line treatment setting for locally advanced/metastatic RCC either as a single agent (CABOSUN)¹ or in combination with nivolumab (CheckMate 9ER),² and in the second line setting, when compared to everolimus (METEOR).³ 

Given the proven efficacy of cabozantinib in this disease space, along with other numerous treatment options with varying mechanisms of action, can we use imaging tools to help select appropriate candidates for systemic therapy and to predict treatment responses? To this end, several questions remain unanswered:

1. Can we use PET imaging to assess the pre-treatment whole-body c-MET expression?
2. Can we use PET imaging to evaluate lesion-based c-MET expression?
3. Can we use PET parameters to predict treatment responses?

Over the past few year several c-MET-targeting radioligands have been developed, as summarized in the table below:

Of these agents, ⁶⁸Ga-EMP-100 is the only radioligand to have been evaluated in human subjects⁴ and has the potential to be labelled with a beta emitter. This radioligand has the highest uptake in the bladder and kidney, followed by the liver and spleen, as illustrated graphically below:

Dr. Unterrainer highlighted that there is significant intra-individual heterogeneity in tracer uptake as demonstrated in the patient below (hilar lesion uptake, but no pulmonary lesion uptake), which may reflect differences in c-MET expression between tumor sites in the same individual. 

Overall, 21% of metastatic RCC lesions are ⁶⁸Ga-EMP-100 PET-negative. Of these 21%, 50% are present in the lung and 28% in the liver.

In this study, Dr. Unterrainer and colleagues performed ⁶⁸Ga-EMP-100 PET/CT both prior to (median: 19 days) and following the initiation of cabozantinib (median: 60 days). They evaluated the % changes of SUV_max in PET-positive whole-body total tumor volume. Response was assessed as follows:

1. Stable disease: SUV_max remained within a 30% range (+/- 30%)
2. Partial response: SUV_max decrease of >30%
3. Complete response: no detectable c-MET expressing lesions
4. Progressive disease: SUV_max increase of >30% or appearance of new lesions 

To date, eight patients with metastatic RCC have been included. Overall, the SUV_max following initiation of cabozantinib is lower compared to the SUV_max at baseline (4.5 versus 8.0; p=0.028). Disease responses were as follows:

• Stable disease: 3/8
• Partial response: 3/8
• Complete response: 1/8 (low c-MET expression at baseline, followed by no detectable c-MET expression on follow up PET)
• Progressive disease: 1/8 (multiple new c-MET expressing lesions).

Dr. Unterrainer concluded that ⁶⁸Ga-EMP-100 PET/CT can visualize changes of c-MET expression in patients undergoing cabozantinib therapy, earlier than can be detected with morphologic changes on CT. Numerous questions are yet to be answered in this disease space:

• Are changes in c-MET expression associated with clinical responses?
• Is ⁶⁸Ga-EMP-100 PET/CT a predictive biomarker?
• Can ⁶⁸Ga-EMP-100 PET/CT lead to early changes in systemic therapy?
• What is the impact of c-MET negative lesions?
• Can ⁶⁸Ga-EMP-100 PET/CT lead to lesion-based therapeutic approaches in metastatic RCC?
• Are theranostic approaches possible in this disease space?

Presented by: Lena Unterrainer, MD, Ahmanson Translational Theranostics Division, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, UCLA, Los Angeles, CA

Written by: Rashid K. Sayyid, MD, MSc – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the 2023 Society of Nuclear Medicine and Molecular Imaging (SNMMI) Annual Meeting, Chicago, IL, Sat, June 24 – Tues, June 27, 2023.

1. Choueiri TK, Halabi S, Sanford BL, et al. Cabozantinib versus Sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: The Alliance A031203 CABOSUN Trial. J Clin Oncol 2017;35(6):591-597.
2. Choueiri TK, Powles T, Burotto M, et al. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2021 Mar 4;384(9):829-841.
3. Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med 2015;373(19):1814-1823.
4. Mittlmeier LM, Todica A, Gildehaus FJ, et al. ⁶⁸Ga-EMP-100 PET/CT – a novel ligand for visualizing c-MET expression in metastatic renal cell carcinoma – first in-human biodistribution and imaging results. Eur J Nucl Med 2022;49:1711-1720.