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RET is a kinase altered in thyroid cancer and a small slice of lung cancer, treatable with one selective pill regardless of where the tumour is. This dossier gathers the 10 products (8 approved), 122 trials, 2 pathways and 0 resistance routes in the corpus that involve it, with external identifiers so it can be joined to UniProt, ChEMBL, Open Targets and the rest of biology.
RET is the receptor tyrosine kinase for GDNF-family ligands.
| Cancer | Prevalence | Measure | Note | Source |
|---|---|---|---|---|
| Thyroid cancer | 60-70% | RET mutation in medullary thyroid cancer | ~10-20% RET fusions in papillary | Wikipedia |
| Non-small-cell lung cancer | 1-2% | Fusion | cBioPortal (TCGA) | |
| Non-small-cell lung cancer | 1-2% | Rearrangement, commonly KIF5B-RET or CCDC6-RET | cBioPortal structural variants: 51 of 2,422, 2.1%, in luad_mskcc_2023_met_organotropism (KIF5B in 36 events, CCDC6 in 4); 38 of 2,621, 1.4%, in nsclc_ctdx_msk_2022; 16 of 915, 1.7%, in lung_msk_2017; 3 of 232, 1.3%, in lung_nci_2022. | cBioPortal (TCGA) |
| Colorectal cancer | 0.1% | Gene fusion (NCOA4-RET, CCDC6-RET) | cBioPortal structural variants: 8 of 7,237, 0.11% (NCOA4-RET 4), in crc_msk_2026; 1 of 1,134 in crc_msk_2017; CCDC6-RET in 1 of 594 in coadread_tcga_pan_can_atlas_2018; 1 of 1,516 in crc_eo_2020. | cBioPortal (TCGA) |
Approximate, population-level figures; the measure column says what was counted. Ranges show the midpoint as a bar.
| Residue | Kind | How common | What it does | Addressed by | Defeats | Source |
|---|---|---|---|---|---|---|
| M918T 918 | Activating | not sourced | The MEN2B germline allele and the most common somatic mutation in sporadic medullary thyroid cancer; highly sensitive to selpercatinib. | - | COSMIC: RET | |
| C634R and other cysteine codons 634 | Activating | not sourced | MEN2A germline hotspot in the cysteine-rich domain; forms constitutive dimers. | - | COSMIC: RET | |
| V804M / V804L (gatekeeper) 804 | Resistance | not sourced | Blocks vandetanib and cabozantinib; selpercatinib and pralsetinib were designed to tolerate it. | Solomon et al., J Thorac Oncol 2020 | ||
| G810R/S/C (solvent front) 810 | Resistance | not sourced | Acquired after selpercatinib or pralsetinib; next-generation RET inhibitors are designed around it. | none in corpus | Solomon et al., J Thorac Oncol 2020 |
Frequencies are quoted from the source on each row; a blank means no figure was sourced, not that it is rare. Domain boundaries are approximate. Sources for the map: COSMIC: RET.
| Modality | Approved | Phase 3 | Phase 2 |
|---|---|---|---|
| Small molecule 8 | |||
| Test or device 2 | - | - |
| Trial | Setting | Result | Products | ||
|---|---|---|---|---|---|
| 3 | Active | A Multi-Center, Double-Blind, Randomized, Phase III Study to Investigate the Efficacy and Safety of Nofazinlimab (CS1003) in Combination With Lenvatinib Compared to Placebo in Combination With Lenvatinib as First-Line Therapy in Subjects With Advanced Hepatocellular Carcinoma (HCC) | - | ||
EMERALD-3 NCT05301842 | 3 | Positive | Embolisation-eligible unresectable HCC: STRIDE (durvalumab + tremelimumab) + lenvatinib + TACE vs TACE | PFS HR ~0.70 (interim); OS immature. | |
LITESPARK-011 NCT04586231 | 3 | Positive | Advanced clear-cell renal cell carcinoma that has progressed after anti-PD-1 or anti-PD-L1 therapy: belzutifan 120 mg plus lenvatinib 20 mg versus cabozantinib 60 mg, all oral once daily, open label, randomised 1:1 | Final progression-free survival 14.8 vs 10.7 months (hazard ratio 0.70, 95% CI 0.59 to 0.84; one-sided p<0.0001). Interim overall survival 34.9 vs 27.6 months (hazard ratio 0.85, 0.68 to 1.05; one-sided p 0.061), not statistically significant. Data cutoff 9 April 2025. | |
LITESPARK-012 NCT04736706 | 3 | Negative | Untreated advanced clear-cell RCC: pembrolizumab + lenvatinib ± belzutifan (or ± quavonlimab) | Primary endpoint not met (ASCO GU 2026). | |
| 3 | Active | A Randomized Phase III Trial Assessing a Regorafenib-irinotecan Combination (REGIRI) Versus Regorafenib Alone in Metastatic Colorectal Cancer Patients After Failure of Standard Therapies, According to the A/A Genotype of Cyclin D1 | - | ||
| 3 | Active | A Phase 3, Randomized, Open-Label, Controlled Study of Cabozantinib (XL184) in Combination With Atezolizumab vs Second Novel Hormonal Therapy (NHT) in Subjects With Metastatic Castration-Resistant Prostate Cancer | - | ||
| 3 | Active | A Randomized, Controlled Phase 3 Study of Cabozantinib (XL184) in Combination With Atezolizumab Versus Sorafenib in Subjects With Advanced Hepatocellular Carcinoma Who Have Not Received Previous Systemic Anticancer Therapy | - | ||
CABINET (Alliance A021602) NCT03375320 | 3 | Positive | Previously treated advanced pancreatic (n=95) and extra-pancreatic (n=203) NETs: cabozantinib vs placebo | PFS HR 0.23 (pNET), 0.38 (epNET). | |
LEAP-012 NCT04246177 | 3 | Mixed | Unresectable non-metastatic HCC: TACE + lenvatinib + pembrolizumab vs TACE + placebo | PFS HR 0.66; final OS HR 0.98. | |
| 3 | Active | A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Cabozantinib (XL184) in Subjects With Radioiodine-Refractory Differentiated Thyroid Cancer Who Have Progressed After Prior Vascular Endothelial Growth Factor Receptor (VEGFR) -Targeted Therapy | - | ||
CONTACT-03 NCT04338269 | 3 | Negative | Advanced RCC progressing on or after a PD-1/PD-L1 inhibitor: atezolizumab + cabozantinib vs cabozantinib | PFS HR 1.03; OS HR 0.94, negative. | |
LIBRETTO-431 NCT04194944 | 3 | Positive | First-line RET-fusion advanced NSCLC: selpercatinib vs platinum-pemetrexed ± pembrolizumab | PFS HR 0.46. | |
LIBRETTO-531 NCT04211337 | 3 | Positive | Untreated progressive RET-mutant medullary thyroid cancer: selpercatinib vs cabozantinib or vandetanib | PFS HR 0.28; 12-month PFS 86.8% vs 65.7%. | |
COSMIC-313 NCT03937219 | 3 | Mixed | Untreated intermediate/poor-risk clear-cell RCC: cabozantinib + nivolumab + ipilimumab vs nivolumab + ipilimumab | PFS HR 0.73; OS HR 1.02 (no benefit). | |
LEAP-002 NCT03713593 | 3 | Negative | First-line unresectable HCC: lenvatinib + pembrolizumab vs lenvatinib | OS HR 0.84, not significant. | |
CLEAR (KEYNOTE-581) NCT02811861 | 3 | Positive | Untreated advanced clear-cell RCC: lenvatinib + pembrolizumab vs sunitinib (and lenvatinib + everolimus arm) | PFS 23.9 vs 9.2 months (HR 0.39); OS HR 0.79. | |
KEYNOTE-775 / Study 309 NCT03517449 | 3 | Positive | Advanced endometrial cancer after platinum: lenvatinib + pembrolizumab vs doxorubicin or weekly paclitaxel | OS 18.3 vs 11.4 months (HR 0.62). | |
CheckMate 9ER NCT03141177 | 3 | Positive | Untreated advanced clear-cell RCC: nivolumab + cabozantinib vs sunitinib | PFS HR 0.51; OS HR 0.77 at ~4 years (46.5 vs 36.0 months). | |
IMblaze370 NCT02788279 | 3 | Negative | Previously treated metastatic colorectal adenocarcinoma, mostly microsatellite-stable: atezolizumab with cobimetinib, or atezolizumab alone, against regorafenib | Median overall survival 8.87 months with atezolizumab and cobimetinib against 8.51 months with regorafenib (hazard ratio 1.00). | |
CELESTIAL NCT01908426 | 3 | Positive | HCC after sorafenib (up to two prior lines): cabozantinib vs placebo | OS 10.2 vs 8.0 months, HR 0.76. | |
REFLECT NCT01761266 | 3 | Positive | First-line unresectable HCC: lenvatinib vs sorafenib (non-inferiority) | OS 13.6 vs 12.3 months, non-inferior (HR 0.92). | |
RESORCE NCT01774344 | 3 | Positive | HCC progressing on sorafenib: regorafenib vs placebo | OS 10.6 vs 7.8 months, HR 0.63. | |
COMET-1 NCT01605227 | 3 | Negative | Metastatic castration-resistant prostate cancer progressing after docetaxel and abiraterone or enzalutamide: cabozantinib 60 mg once daily against prednisone 5 mg twice daily, randomised 2:1, with overall survival as the primary endpoint and bone scan response at week 12 as the secondary endpoint | Median overall survival 11.0 against 9.8 months (hazard ratio 0.90, 95 percent confidence interval 0.76 to 1.06, p=0.213): not met. Bone scan response at 12 weeks 42 against 3 percent and radiographic progression-free survival 5.6 against 2.8 months. | |
CONCUR NCT01584830 | 3 | Positive | Asian patients with refractory metastatic colorectal cancer after at least two previous lines: regorafenib against placebo | Median overall survival 8.8 against 6.3 months (hazard ratio 0.55). | |
SELECT NCT01321554 | 3 | Positive | Radioiodine-refractory differentiated thyroid cancer with progression: lenvatinib vs placebo | PFS 18.3 vs 3.6 months; HR 0.21. | - |
CORRECT NCT01103323 | 3 | Positive | Metastatic colorectal cancer progressing after all approved standard therapies: regorafenib 160 mg daily, three weeks on and one off, with best supportive care, against placebo | Median overall survival 6.4 against 5.0 months (hazard ratio 0.77); grade 3 or worse hand-foot skin reaction in 17 percent. | |
GRID NCT01271712 | 3 | Positive | Metastatic or unresectable gastrointestinal stromal tumour after failure of imatinib and sunitinib: regorafenib against placebo | Regorafenib lengthened progression-free survival compared with placebo in GIST after imatinib and sunitinib; approved in February 2013. | |
EXAM NCT00704730 | 3 | Positive | Progressive metastatic medullary thyroid cancer: cabozantinib against placebo | Cabozantinib lengthened progression-free survival compared with placebo in progressive medullary thyroid cancer; approved in November 2012. | |
ZETA NCT00410761 | 3 | Positive | Unresectable locally advanced or metastatic medullary thyroid cancer: vandetanib against placebo, with open-label vandetanib allowed at progression | Vandetanib prolonged progression-free survival over placebo in advanced medullary thyroid cancer; approved in April 2011 as the first drug for the disease. | |
| 3 | Planned | A Phase III Randomized Controlled Clinical Study Comparing BL-M07D1 With Physician's Choice Therapy in Patients With HER2 IHC3+ Advanced Colorectal Cancer Who Failed Prior Treatment With Oxaliplatin, Fluorouracil and Irinotecan | - |
No recorded escape route names this target.
KEGG's non-small cell lung cancer map shows a set of alternative on-switches (EGFR mutation, KRAS mutation, EML4-ALK, RET and MET alterations) that all feed the same RAS/ERK, PI3K/AKT and STAT relays, plus loss of the p16 and p53 brakes. Each on-switch now has its own targeted pill, which is why molecular testing comes before treatment.
Which nodes have drugs →This KEGG map shows thyroid cancers driven by one relay, the MAPK pathway: RET or NTRK fusions and BRAF mutations in papillary tumours, RAS mutations or PAX8-PPARG fusion in follicular tumours, and TP53 loss marking anaplastic cancer. It matters because RET, NTRK and BRAF alterations each have their own drug, and MAPK blockade can restore iodine uptake.
Which nodes have drugs →| Assay | Platform | Cut-off | Gates |
|---|---|---|---|
| FoundationOne CDx Foundation Medicine (Roche) · FDA CDx 2017 | NGS tissue | Per companion claim: EGFR, ALK, BRAF V600, ERBB2 amplification, KRAS wild-type, BRCA1/2 and HRR genes, PIK3CA, MET exon 14, RET, FGFR2 fusions, IDH1, NTRK fusions; MSI-high; TMB at least 10 mutations per megabase | |
| FoundationOne Liquid CDx Foundation Medicine (Roche) · FDA CDx 2020 | NGS plasma | Per companion claim: EGFR (osimertinib, erlotinib, gefitinib), ALK (alectinib), BRCA1/2 and ATM (olaparib, rucaparib), PIK3CA (alpelisib), FGFR3 (erdafitinib), NTRK and RET; negative plasma results reflex to tissue | |
| Oncomine Dx Target Test Thermo Fisher Scientific · FDA CDx 2017 | NGS tissue | Per companion claim: BRAF V600E (dabrafenib plus trametinib), ROS1 fusions (crizotinib), EGFR (gefitinib), RET fusions (pralsetinib), MET exon 14 (tepotinib), EGFR exon 20 insertions |
No model entry for this target yet; check the cancer entries on the models page.
No open questions recorded for this target yet. Suggest one.
Query for this target: (TITLE:"RET" OR ABSTRACT:"RET") AND (cancer OR tumor OR tumour OR oncology OR carcinoma OR lymphoma OR leukemia OR leukaemia OR myeloma OR sarcoma OR melanoma OR glioma). Results are unfiltered search hits about RET, not a curated reading list.
The dossier as machine-readable JSON, at /api/v1/dossiers/ret.json: identifiers from HGNC, Ensembl, UniProt and ChEMBL, products with status, trials, pathways, hotspots, open questions and assays. The full entity record is in the open API at /api/v1/entities/ret.json. Licence CC BY-NC 4.0.