Responsiveness to immune checkpoint inhibitors versus other systemic therapies in RET-aberrant malignancies.

The receptor tyrosine kinase rearranged during transfection (RET) can be oncogenically activated by gene fusions or point mutations. Multikinase inhibitors such as cabozantinib, lenvatinib and vandetanib have demonstrated activity in RET-dependent malignancies, and selective RET inhibitors (Selpercatinib and Pralsetinib) are in clinical trials. However, the responsiveness of RET-dependent malignancies to immune checkpoint inhibitors (ICIs) is unknown. We compared the time to treatment discontinuation (TTD) for ICI versus non-ICI therapy in patients with malignancies harbouring activating RET mutations or fusions (RET+). A retrospective review of all RET+ patients who were referred to the phase I clinical trials programme at the University of Texas MD Anderson Cancer Center was conducted. TTD was estimated using Kaplan-Meier analysis. Multivariate analysis using the Cox proportional hazard model was performed to identify independent risk factors of treatment discontinuation. Of 70 patients who received systemic therapy for RET+ malignancies, 20 (28.6%) received ICI and 50 (71.4%) received non-ICI therapy. Non-ICI therapy was associated with decreased risk for treatment discontinuation compared with ICI in the overall population (HR=0.31; 95% CI 0.16-0.62; p=0.000834) and in patients with RET point mutations (HR=0.13; 95% CI 0.04-0.45; p=0.00134). In patients with RET fusions, non-ICI therapy was associated with a non-statistically significant decreased risk of treatment discontinuation (HR=0.59; 95% CI 0.25-1.4; p=0.24). ICI therapy and a diagnosis other than medullary thyroid cancer (MTC) were independent risk factors for treatment discontinuation. Our study supports the prioritisation of non-ICI over ICI therapy in patients with RET+ tumours.

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© Author (s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.

Déclaration de conflit d'intérêts

Competing interests: VS reports grants and other from Loxo Oncology/ Eli Lilly, grants from Roche/ Genentech, grants and other from Novartis, grants from Bayer, grants from GlaxoSmithKline, grants from Nanocarrier, grants from Vegenics, grants from Celgene, grants from Northwest Biotherapeutics, grants from Berghealth, grants from Incyte, grants from Fujifilm, grants and other from Pharmamar, grants from D3, grants from Pfizer, grants from Multivir, grants from Amgen, grants from Abbvie, grants from Alfa-sigma, grants from Agensys, grants from Boston Biomedical, grants from Idera Pharma, grants from Inhibrx, grants from Exelixis, grants from Blueprint medicines, grants and other from Medimmune, grants from Altum, grants from Dragonfly therapeutics, grants from Takeda, grants from National Comprehensive Cancer Network, grants from NCI-CTEP and UT MD Anderson Cancer Center, grants from Turning point therapeutics, grants from Boston Pharmaceuticals, other from Helsinn, from R-Pharma US, other from INCYTE, other from QED pharma, other from ASCO, other from ESMO, other from Medscape, during the conduct of the study. FM-B reports other from Arduro BioTech, other from DebioPharm, grants and other from eFFECTOR Therapeutics, other from F. Hoffman-La Roche Ltd, grants and other from Genentech, other from IBM Watson, other from Jackson Laboratory, other from Kolon Life Science, other from OrigiMed, other from PACT Pharma, other from Parexel International, other from Pfizer, other from Samsung Bioepis, other from Seattle Genetics, other from Tyra Biosciences, other from Xencor, other from Zymeworks, other from Alkermes, other from Immunomedics, other from Inflection Biosciences, other from Mersana Therapeutics, grants and other from Puma Biotechnology, other from Silverback Therapeutics, other from Spectrum Pharmaceuticals, grants from Aileron Therapeutics, grants from AstraZeneca, grants from Bayer Healthcare Pharmaceutical, grants from Calithera Biosciences, grants from Curis, grants from CytomX Therapeutics, grants from Daiichi Sankyo Co Ltd, grants from Debiopharm International, grants from Novartis, grants from Taiho Pharmaceutical Co, other from Chugai Biopharmaceuticals, other from Mayo Clinic, other from Rutgers Cancer Institute of New Jersey, other from Beth Israel Deaconess Medical Center, outside the submitted work. MIH reports other from Blueprint Medicines, other from Loxo Oncology, other from Eli Lilly and Co, outside the submitted work. JL reports personal fees from Foundation Medicine, during the conduct of the study; personal fees from Foundation Medicine, other from Roche, outside the submitted work.