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| Gene | EML4 RET |
| Variant | EML4 - RET |
| Impact List | fusion |
| Protein Effect | gain of function - predicted |
| Gene Variant Descriptions | EML4-RET results from the fusion of EML4 and RET (PMID: 33082208), which results in increased Erk phosphorylation in cultured cells (PMID: 33848463), and therefore, is predicted to lead to a gain of protein function. EML4-RET has been identified in lung cancer (PMID: 33082208, PMID: 31485557, PMID: 30487236). |
| Associated Drug Resistance | |
| Category Variants Paths |
EML4 mutant EML4 fusion EML4 - RET RET mutant RET act mut EML4 - RET RET mutant RET rearrange RET fusion EML4 - RET |
| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
|---|---|---|---|---|---|---|---|
| RET act mut | lung non-small cell carcinoma | sensitive | Ponatinib | Preclinical - Cell culture | Actionable | In a preclinical study, Iclusig (ponatinib) inhibited RET phosphorylation and reduced viability of non-small cell lung cancer cells with RET activating mutations (Cancer Res April 15, 2013 73; 2084). | detail... |
| RET mutant | medullary thyroid carcinoma | sensitive | Everolimus | Phase II | Actionable | In a Phase II trial, Afinitor (everolimus) treatment resulted in stable disease in 71% (5/7) of medullary thyroid cancer patients, including patients harboring RET mutations, with median progression-free survival of 33 weeks (PMID: 26294908; NCT01118065). | 26294908 |
| RET mutant | pheochromocytoma | predicted - sensitive | Sunitinib | Case Reports/Case Series | Actionable | In a Phase II trial (SNIPP), a patient with pheochromocytoma harboring a germline RET mutation achieved a partial response to treatment with Sutent (sunitinib), and demonstrated a 64% reduction in tumor volume and remained on treatment for over 7 years (PMID: 31105270). | 31105270 |
| RET mutant | medullary thyroid carcinoma | sensitive | Cabozantinib | Phase III | Actionable | In a Phase III trial, Cometriq (cabozantinib) treatment resulted in improved progression free survival (60 vs 20 weeks) compared to placebo in thyroid medullary carcinoma patients harboring RET mutations (PMID: 27525386). | 27525386 |
| RET mutant | Advanced Solid Tumor | sensitive | Ponatinib | Preclinical - Cell line xenograft | Actionable | In a preclinical study, Iclusig (ponatinib) inhibited proliferation of cancer cell lines harboring RET mutations in cultured and in cell line xenograft models (PMID: 23526464). | 23526464 |
| RET mutant | cancer | sensitive | Sorafenib | Preclinical | Actionable | In a preclinical study, Nexavar (sorafenib) inhibited wild-type RET and RET mutations to prevent cell proliferation in cell culture (PMID: 17664273). | 17664273 |
| RET mutant | medullary thyroid carcinoma | sensitive | Pralsetinib | Phase Ib/II | Actionable | In a Phase I/II trial (ARROW), Gavreto (pralsetinib) treatment was well-tolerated and resulted in an overall response rate (ORR) of 60% (3/55) in patients with advanced or metastatic medullary thyroid cancer harboring RET mutations who received prior treatments, ORR was 60% (32/53) in patients with prior therapies and 71% (15/21) in treatment-naive patients (PMID: 34118198; NCT03037385). | 34118198 |
| RET mutant | medullary thyroid carcinoma | sensitive | Pralsetinib | Guideline | Actionable | Gavreto (pralsetinib) is included in guidelines (category 2B) for patients with medullary thyroid carcinoma harboring RET mutations (NCCN.org). | detail... |
| RET mutant | medullary thyroid carcinoma | sensitive | Pralsetinib | Guideline | Actionable | Gavreto (pralsetinib) is included in guidelines for adult or pediatric patients 12 years or older with advanced or metastatic medullary thyroid gland carcinoma harboring RET mutations (PMID: 31549998, PMID: 35491008; ESMO.org). | 31549998 detail... 35491008 |
| RET mutant | lung non-small cell carcinoma | unknown | unspecified immune checkpoint inhibitor | Clinical Study - Cohort | Actionable | In a retrospective clinical study, patients with non-small cell lung cancer harboring rare targetable drivers (RTD) (BRAF, ERBB2/3, RET, MET, ROS1, NTRK) who received immune checkpoint inhibitors (ICI) achieved longer median overall survival (mOS) (32 vs 13 mo, p=0.01) compared to those who did not receive ICI, mOS was 44.9 mo in a patient harboring RET mutation, although RTD type was not associated with OS in a univariate analysis (PMID: 30268448). | 30268448 |
| RET mutant | medullary thyroid carcinoma | sensitive | Selpercatinib | FDA approved - Has Companion Diagnostic | Actionable | In a Phase I/II trial (LIBRETTO-121) that supported FDA approval, Retevmo (selpercatinib) treatment was safe in pediatric patients of 2 years or older with solid tumors (8 medullary thyroid cancer, 2 papillary thyroid cancer, 1 osteosarcoma) harboring RET fusion (n=2) or mutations (n=9), and resulted in unconfirmed partial responses in 4 patients, stable disease in 6 patients (two lasting >/=16 weeks) (JCO 39, 10009-10009(2021); NCT03899792). | detail... detail... detail... |
| RET mutant | medullary thyroid carcinoma | sensitive | Selpercatinib | Guideline | Actionable | Retevmo (selpercatinib) is included in guidelines for adult or pediatric patients 12 years or older with advanced medullary thyroid gland carcinoma harboring RET mutations (PMID: 31549998, PMID: 35491008; ESMO.org). | 31549998 detail... 35491008 |
| RET mutant | medullary thyroid carcinoma | sensitive | Selpercatinib | FDA approved - Has Companion Diagnostic | Actionable | In a Phase I/II trial (LIBRETTO-001) that supported FDA approval, Retevmo (selpercatinib) treatment resulted in an objective response rate (ORR) of 69% (38/55), with five complete and 33 partial responses, in adult and pediatric patients of 12 years and older with medullary thyroid cancer harboring RET mutations who were previously treated, while patients who had not been previously treated demonstrated an ORR of 73% (64/88), with ten complete and 54 partial responses (PMID: 32846061; NCT03157128). | detail... detail... 32846061 |
| RET mutant | medullary thyroid carcinoma | sensitive | Selpercatinib | Guideline | Actionable | Retevmo (selpercatinib) is included in guidelines for patients with medullary thyroid carcinoma harboring RET mutations (NCCN.org). | detail... |
| RET mutant | lung non-small cell carcinoma | predicted - sensitive | EP0031 | Phase Ib/II | Actionable | In a Phase I/II trial (KL400-I/II-01), EP0031 treatment was well tolerated in non-small cell lung cancer (NSCLC) patients harboring RET mutations, and resulted in an objective response rate (ORR) of 63% (20/32, 1 complete response (CR)) and disease control rate (DCR) of 91% in pretreated patients, and an ORR of 76% (19/25, 1 CR) and DCR of 92% with median duration of response not reached in treatment-naive patients, and an overall CNS DCR of 100% (J Clin Oncol 41, 2023 (suppl 16; abstr 3007); NCT05265091). | detail... |
| RET mutant | Advanced Solid Tumor | predicted - sensitive | EP0031 | Phase Ib/II | Actionable | In a Phase I/II trial (KL400-I/II-01), EP0031 treatment was well tolerated and demonstrated preliminary activity in patients with advanced solid tumors harboring mutations in RET, resulting in an objective response rate of 64%, with responses being observed in patients with non-small cell lung cancer, medullary thyroid cancer and pancreatic cancer (J Clin Oncol 41, 2023 (suppl 16; abstr 3007); NCT05265091). | detail... |
| RET mutant | colorectal cancer | sensitive | Ponatinib | Preclinical | Actionable | In a preclinical study, Iclusig (ponatinib) demonstrated efficacy in RET mutant positive colorectal cancer cell lines (PMID: 23811235). | 23811235 |
| RET fusion | thyroid cancer | sensitive | Selpercatinib | FDA approved - On Companion Diagnostic | Actionable | In a Phase I/II trial (LIBRETTO-001) that supported FDA approval, Retevmo (selpercatinib) treatment resulted in an objective response rate of 79% (15/19), including one complete and 14 partial responses, with a median response duration of 18.4 months, and median progression-free survival of 20.1 months in adult and pediatric patients 12 years and older with RET fusion-positive thyroid cancer who were previously treated (PMID: 32846061; NCT03157128). | detail... detail... 32846061 |
| RET fusion | thyroid cancer | sensitive | Selpercatinib | FDA approved - On Companion Diagnostic | Actionable | In a Phase I/II trial (LIBRETTO-121) that supported FDA approval, Retevmo (selpercatinib) treatment was safe in pediatric patients of 2 years or older with solid tumors (8 medullary thyroid cancer, 2 papillary thyroid cancer, 1 osteosarcoma) harboring RET fusion (n=2) or mutations (n=9), and resulted in unconfirmed partial responses in 4 patients, stable disease in 6 patients (two lasting >/=16 weeks) (JCO 39, 10009-10009(2021); NCT03899792). | detail... detail... detail... |
| RET fusion | Advanced Solid Tumor | sensitive | Selpercatinib | FDA approved - On Companion Diagnostic | Actionable | In a Phase I/II trial (LIBRETTO-121) that supported FDA approval, Retevmo (selpercatinib) treatment was safe in pediatric patients of 2 years or older with solid tumors harboring RET fusion (n=2) or mutations (n=9), and resulted in unconfirmed partial responses in 4 patients, stable disease in 6 patients (two lasting >/=16 weeks) (JCO 39, 10009-10009(2021); NCT03899792). | detail... detail... detail... |
| RET fusion | Advanced Solid Tumor | sensitive | Selpercatinib | FDA approved - On Companion Diagnostic | Actionable | In a Phase I/II trial (LIBRETTO-001) that supported FDA approval, Retevmo (selpercatinib) treatment resulted in an objective response rate of 44% (18/41, 2 complete responses, 16 partial responses), a clinical benefit rate of 63% (26/41), a median duration of response of 24.5 months, and a median progression-free survival of 13.2 months in patients with RET fusion-positive advanced solid tumors (PMID: 36108661; NCT03157128). | 36108661 detail... |
| RET fusion | Squamous Cell Carcinoma of Unknown Primary | sensitive | Selpercatinib | Guideline | Actionable | Retevmo (selpercatinib) is included in guidelines for patients with squamous cell carcinoma of unknown primary harboring RET fusions (NCCN.org). | detail... |
| RET fusion | ovary epithelial cancer | sensitive | Selpercatinib | Guideline | Actionable | Retevmo (selpercatinib) is included in guidelines as systemic therapy for patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer harboring a RET fusion (NCCN.org). | detail... |
| RET fusion | small intestine adenocarcinoma | sensitive | Selpercatinib | Guideline | Actionable | Retevmo (selpercatinib) is included in guidelines for patients with metastatic small bowel adenocarcinoma with RET fusion (NCCN.org). | detail... |
| RET fusion | intrahepatic cholangiocarcinoma | sensitive | Selpercatinib | Guideline | Actionable | Retevmo (selpercatinib) is included in guidelines as primary (category 2B) and subsequent-line therapy for patients with unresectable or metastatic biliary tract cancer harboring RET fusions, including intrahepatic cholangiocarcinoma (NCCN.org). | detail... |
| RET fusion | gallbladder cancer | sensitive | Pralsetinib | Guideline | Actionable | Gavreto (pralsetinib) is included in guidelines as primary (category 2B) and subsequent-line therapy (category 2B) for patients with unresectable or metastatic biliary tract cancer harboring RET fusions, including gallbladder cancer (NCCN.org). | detail... |
| RET fusion | differentiated high-grade thyroid carcinoma | sensitive | Pralsetinib | Guideline | Actionable | Gavreto (pralsetinib) is included in guidelines for adult or pediatric patients 12 years or older with radioactive iodine-refractory, advanced or metastatic differentiated thyroid gland carcinoma harboring RET fusions (PMID: 31549998, PMID: 35491008; ESMO.org). | 35491008 31549998 detail... |
| RET fusion | pancreatic cancer | predicted - sensitive | Selpercatinib | Case Reports/Case Series | Actionable | In a Phase I/II trial (LIBRETTO-001), Retevmo (selpercatinib) treatment resulted in an objective response rate (ORR) of 43.9% (18/41, 2 complete responses, 16 partial responses) with a median duration of response (mDOR) of 24.5 months in patients with RET fusion-positive advanced or metastatic solid tumors, and ORR and mDOR in patients with pancreatic cancer were 54.5% (6/11) and not reached, respectively (PMID: 36108661; NCT03157128). | 36108661 |
| RET fusion | salivary gland cancer | sensitive | Selpercatinib | Guideline | Actionable | Retevmo (selpercatinib) is included in guidelines for patients with recurrent, unresectable, or metastatic salivary gland tumors harboring RET fusions (NCCN.org). | detail... |
| RET fusion | anaplastic thyroid carcinoma | sensitive | Selpercatinib | Guideline | Actionable | Retevmo (selpercatinib) is included in guidelines for patients with anaplastic thyroid carcinoma harboring RET fusions (NCCN.org). | detail... |
| RET fusion | vaginal carcinoma | sensitive | Selpercatinib | Guideline | Actionable | Retevmo (selpercatinib) is included in guidelines as second-line or subsequent therapy for patients with recurrent or metastatic vaginal squamous cell carcinoma or adenocarcinoma harboring an RET fusion (NCCN.org). | detail... |
| RET fusion | medullary thyroid carcinoma | sensitive | Selpercatinib | Guideline | Actionable | Retevmo (selpercatinib) is included in guidelines for patients with medullary thyroid carcinoma harboring RET fusions (NCCN.org). | detail... |
| RET fusion | extrahepatic bile duct carcinoma | sensitive | Selpercatinib | Guideline | Actionable | Retevmo (selpercatinib) is included in guidelines as primary (category 2B) and subsequent-line therapy for patients with unresectable or metastatic biliary tract cancer harboring RET fusions, including extrahepatic cholangiocarcinoma (NCCN.org). | detail... |
| RET fusion | sarcoma | sensitive | Selpercatinib | Guideline | Actionable | Retevmo (selpercatinib) is included in guidelines as first-line therapy for patients with advanced or metastatic soft tissue sarcoma harboring RET fusions (NCCN.org). | detail... |
| RET fusion | pancreatic adenocarcinoma | sensitive | Selpercatinib | Guideline | Actionable | Retevmo (selpercatinib) is included in guidelines as first-line or subsequent therapy for patients with locally advanced, metastatic, or recurrent pancreatic adenocarcinoma harboring RET fusions (NCCN.org). | detail... |
| RET fusion | papillary thyroid carcinoma | sensitive | Selpercatinib | Guideline | Actionable | Retevmo (selpercatinib) is included in guidelines for patients with papillary thyroid carcinoma harboring RET fusions (NCCN.org). | detail... |
| RET fusion | papillary thyroid carcinoma | sensitive | Selpercatinib | Phase I | Actionable | In a Phase I trial, Retevmo (selpercatinib) treatment resulted in an objective response rate of 83% (5/6) in RET fusion-positive papillary thyroid cancer patients (J Clin Oncol 36, 2018 (suppl; abstr 102); NCT03157128). | detail... |
| RET fusion | lung non-small cell carcinoma | predicted - sensitive | HS-10365 | Phase I | Actionable | In a Phase I trial, HS-10365 treatment demonstrated safety and resulted in a response rate of 70% (21/30) and a disease control rate of 96.7% (29/30) in patients with non-small cell lung cancer harboring RET fusions (Cancer Res (2023) 83 (8_Supplement): CT201; NCT05207787). | detail... |
| RET fusion | pancreatic cancer | predicted - sensitive | Pralsetinib | Case Reports/Case Series | Actionable | In a Phase I/II trial (ARROW), Gavreto (pralsetinib) treatment was well-tolerated, resulted in a partial response in 2 of 2 patients with RET fusion positive pancreatic cancer, with a duration of response of 5.5 and 7.4 months, respectively (J Clin Oncol 38, no. 15_suppl (May 20, 2020) 109-109; NCT03037385). | detail... |
| RET fusion | gastroesophageal junction adenocarcinoma | sensitive | Selpercatinib | Guideline | Actionable | Retevmo (selpercatinib) is included in guidelines as second-line or subsequent therapy for patients with locally advanced, recurrent, or metastatic gastroesophageal junction adenocarcinoma harboring RET fusions (NCCN.org). | detail... |
| RET fusion | esophagus adenocarcinoma | sensitive | Selpercatinib | Guideline | Actionable | Retevmo (selpercatinib) is included in guidelines as second-line or subsequent therapy for patients with locally advanced, recurrent, or metastatic esophageal adenocarcinoma harboring RET fusions (NCCN.org). | detail... |
| RET fusion | neuroendocrine tumor | sensitive | Selpercatinib | Guideline | Actionable | Retevmo (selpercatinib) is included in guidelines for patients with unresectable or metastatic extrapulmonary poorly differentiated neuroendocrine carcinoma, large or small cell carcinoma, or mixed neuroendocrine/non-neuroendocrine neoplasms harboring RET fusions who have progressed on or following prior treatment (NCCN.org). | detail... |
| RET fusion | lung non-small cell carcinoma | unknown | unspecified immune checkpoint inhibitor | Clinical Study - Cohort | Actionable | In a retrospective clinical study, patients with non-small cell lung cancer harboring rare targetable drivers (RTD) (BRAF, ERBB2/3, RET, MET, ROS1, NTRK) who received immune checkpoint inhibitors (ICI) achieved longer median overall survival (mOS) (32 vs 13 mo, p=0.01) compared to those who did not receive ICI, mOS was 25.7 mo in patients harboring RET fusions (n=4), although RTD type was not associated with OS in a univariate analysis (PMID: 30268448). | 30268448 |
| RET fusion | follicular thyroid carcinoma | sensitive | Selpercatinib | Guideline | Actionable | Retevmo (selpercatinib) is included in guidelines for patients with follicular thyroid carcinoma harboring RET fusions (NCCN.org). | detail... |
| RET fusion | hepatocellular carcinoma | sensitive | Selpercatinib | Guideline | Actionable | Retevmo (selpercatinib) is included in guidelines as subsequent-line therapy (category 2B) for patients with hepatocellular carcinoma harboring RET fusions (NCCN.org). | detail... |
| RET fusion | follicular thyroid carcinoma | sensitive | Pralsetinib | Guideline | Actionable | Gavreto (pralsetinib) is included in guidelines for patients with follicular thyroid carcinoma harboring RET fusions (NCCN.org). | detail... |
| RET fusion | gallbladder cancer | sensitive | Selpercatinib | Guideline | Actionable | Retevmo (selpercatinib) is included in guidelines as primary (category 2B) and subsequent-line therapy for patients with unresectable or metastatic biliary tract cancer harboring RET fusions, including gallbladder cancer (NCCN.org). | detail... |
| RET fusion | ampulla of Vater adenocarcinoma | sensitive | Selpercatinib | Guideline | Actionable | Retevmo (selpercatinib) is included in guidelines as first-line or subsequent therapy for patients with metastatic ampullary adenocarcinoma harboring RET fusions (NCCN.org). | detail... |
| RET fusion | esophagus squamous cell carcinoma | sensitive | Selpercatinib | Guideline | Actionable | Retevmo (selpercatinib) is included in guidelines as second-line or subsequent therapy for patients with locally advanced, recurrent, or metastatic esophageal squamous cell carcinoma harboring RET fusions (NCCN.org). | detail... |
| RET fusion | extrahepatic bile duct carcinoma | sensitive | Pralsetinib | Guideline | Actionable | Gavreto (pralsetinib) is included in guidelines as primary (category 2B) and subsequent-line therapy (category 2B) for patients with unresectable or metastatic biliary tract cancer harboring RET fusions, including extrahepatic cholangiocarcinoma (NCCN.org). | detail... |
| RET fusion | rectum cancer | sensitive | Selpercatinib | Guideline | Actionable | Retevmo (selpercatinib) is included in guidelines for patients with metastatic rectum cancer harboring RET fusion (NCCN.org). | detail... |
| RET fusion | cholangiocarcinoma | sensitive | Selpercatinib | Guideline | Actionable | Retevmo (selpercatinib) is included in guidelines as primary (category 2B) or subsequent-line therapy (category 2A) for patients with unresectable or metastatic cholangiocarcinoma harboring RET fusions (NCCN.org). | detail... |
| RET fusion | differentiated high-grade thyroid carcinoma | sensitive | Selpercatinib | Guideline | Actionable | Retevmo (selpercatinib) is included in guidelines for patients with advanced or metastatic differentiated thyroid gland carcinoma harboring RET fusions (PMID: 31549998, PMID: 35491008; ESMO.org). | 35491008 31549998 detail... |
| RET fusion | intrahepatic cholangiocarcinoma | sensitive | Pralsetinib | Case Reports/Case Series | Actionable | In a Phase I/II trial (ARROW), Gavreto (pralsetinib) treatment was well-tolerated, resulted in a partial response in a patient with RET fusion-positive intrahepatic cholangiocarcinoma, with a duration of response of 7.5 months (J Clin Oncol 38, no. 15_suppl (May 20, 2020) 109-109; NCT03037385). | detail... |
| RET fusion | intrahepatic cholangiocarcinoma | sensitive | Pralsetinib | Guideline | Actionable | Gavreto (pralsetinib) is included in guidelines as primary (category 2B) and subsequent-line therapy (category 2B) for patients with unresectable or metastatic biliary tract cancer harboring RET fusions, including intrahepatic cholangiocarcinoma (NCCN.org). | detail... |
| RET fusion | cervical cancer | sensitive | Selpercatinib | Guideline | Actionable | Retevmo (selpercatinib) is included in guidelines as second-line or subsequent therapy for patients with cervical cancer harboring RET fusions (NCCN.org). | detail... |
| RET fusion | lung non-small cell carcinoma | sensitive | Selpercatinib | Guideline | Actionable | Retevmo (selpercatinib) is included in guidelines as a first-line therapy for patients with metastatic non-small cell lung cancer harboring RET fusions (PMID: 36872130; ESMO.org). | 36872130 detail... |
| RET fusion | lung non-small cell carcinoma | sensitive | Selpercatinib | Phase III | Actionable | In a Phase III trial (LIBRETTO-431), first-line Retevmo (selpercatinib) treatment resulted in superior median progression-free survival (PFS) compared to platinum-based chemotherapy with (24.8 vs 11.2 mo, HR=0.46, p<0.001) or without ((24.8 vs 11.2 mo, HR=0.48, p<0.001) Keytruda (pembrolizumab) in advanced non-small cell lung cancer patients harboring a RET fusion, and improved intracranial (IC) response rate (82.4% vs 58.3%) and median IC PFS (16.1 vs 10.4 mo) (PMID: 38807655; NCT04194944). | 38807655 |
| RET fusion | lung non-small cell carcinoma | sensitive | Selpercatinib | FDA approved - On Companion Diagnostic | Actionable | In a Phase I/II trial (LIBRETTO-001) that supported FDA approval, Retevmo (selpercatinib) treatment resulted in an objective response rate (ORR) of 64% (64/105) in patients with RET fusion-positive non-small cell lung cancer, with a median duration of response of 17.5 months, ORR was 85% (33/39) and 91% (10/11) in previously treated patients and patients with measurable CNS metastasis, respectively (PMID: 32846060; NCT03157128). | detail... 32846060 detail... |
| RET fusion | Adenocarcinoma of Unknown Primary | sensitive | Selpercatinib | Guideline | Actionable | Retevmo (selpercatinib) is included in guidelines for patients with adenocarcinoma of unknown primary harboring RET fusions (NCCN.org). | detail... |
| RET fusion | medullary thyroid carcinoma | sensitive | Pralsetinib | Guideline | Actionable | Gavreto (pralsetinib) is included in guidelines as systemic therapy for patients with medullary thyroid carcinoma harboring RET fusions (NCCN.org). | detail... |
| RET fusion | Advanced Solid Tumor | predicted - sensitive | Pralsetinib | Phase Ib/II | Actionable | In a Phase I/II trial (ARROW), Gavreto (pralsetinib) treatment was well tolerated in patients with advanced solid tumors harboring RET fusions, and led to an overall response rate of 57% (13/23, 3 complete and 10 partial responses), a clinical benefit rate of 70% (16/23), a disease control rate of 83% (19/23), a median duration of response of 11.7 months, a median progression-free survival of 7.4 months, and a median overall survival of 13.6 months (PMID: 35962206; NCT03037385). | 35962206 |
| RET fusion | lung non-small cell carcinoma | sensitive | SY-5007 | Phase I | Actionable | In a Phase I trial, SY-5007 therapy was tolerable and led to an objective response rate (ORR) of 57.8% (67/116, 67 partial responses), disease control rate (DCR) of 95.7% (111/116), and median progression-free survival of 21.1 mo in advanced solid tumor patients with RET fusions or alterations, and an ORR of 64.1% (41/64) and DCR of 96.9% (62/64) at the phase II dose in non-small cell lung cancer patients with KIF5B (n=51), CCDC6 (n=12), NCOA4 (n=1), or other RET fusions (n=4) (PMID: 39489747; NCT05278364). | 39489747 |
| RET fusion | anaplastic thyroid carcinoma | sensitive | Pralsetinib | Guideline | Actionable | Gavreto (pralsetinib) is included in guidelines as systemic therapy for patients with anaplastic thyroid carcinoma harboring RET fusions (NCCN.org). | detail... |
| RET fusion | oncocytic carcinoma of the thyroid | sensitive | Selpercatinib | Guideline | Actionable | Retevmo (selpercatinib) is included in guidelines for patients with thyroid Hurthle cell carcinoma harboring RET fusions (NCCN.org). | detail... |
| RET fusion | lung non-small cell carcinoma | sensitive | Pralsetinib | FDA approved - On Companion Diagnostic | Actionable | In a Phase I/II trial (ARROW) that supported FDA approval, Gavreto (pralsetinib) treatment was well-tolerated, resulting in an objective response rate of 61% (53/87) and 70% (19/27) in previously treated and treatment-naive patients with RET fusion-positive non-small cell lung cancer, respectively (PMID: 34118197; NCT03037385). | detail... 34118197 detail... |
| RET fusion | lung non-small cell carcinoma | sensitive | Pralsetinib | Clinical Study | Actionable | In a retrospective study, Gavreto (pralsetinib) treatment resulted in an overall response rate of 55.6%, a disease control rate of 72.2%, a median progression-free survival of 10.7 months, and overall survival of 21.2 months in patients with metastatic non-small cell lung cancer harboring a RET fusion (n=36) including KIF5B-RET (n=13) and CCDC6-RET (n=2) (PMID: 39241296). | 39241296 |
| RET fusion | lung non-small cell carcinoma | sensitive | Pralsetinib | Clinical Study | Actionable | In a retrospective study, Gavreto (pralsetinib) treatment resulted in an objective response rate (ORR) of 61% (39/59, 2 complete responses (CR), 37 partial responses (PR)) and a disease control rate (DCR) of 79.7% in non-small cell lung cancer patients harboring RET fusions, and an intracranial ORR of 66.7% (4/6, 3 CR and 1 PR), an intracranial DCR of 100% in patients with measurable brain metastases (PMID: 36379124). | 36379124 |
| RET fusion | lung non-small cell carcinoma | sensitive | Pralsetinib | Guideline | Actionable | Gavreto (pralsetinib) is included in guidelines as a first-line therapy for patients with metastatic non-small cell lung cancer harboring RET fusions (PMID: 36872130; ESMO.org). | detail... 36872130 |
| RET fusion | thyroid cancer | sensitive | Pralsetinib | FDA approved | Actionable | In a Phase I/II trial (ARROW) that supported FDA approval, Gavreto (pralsetinib) treatment was well-tolerated, and resulted in an overall response rate (ORR) of 89% (8/9) in patients with advanced or metastatic RET fusion-positive thyroid cancer, with a median duration of response of 14.5 months, and 67% of responding patients continuing treatment (PMID: 34118198; NCT03037385). | 34118198 detail... |
| RET fusion | Erdheim-Chester disease | sensitive | Selpercatinib | Guideline | Actionable | Retevmo (selpercatinib) is included in guidelines as first-line or subsequent-line therapy for patients with Erdheim-Chester disease harboring RET fusions (NCCN.org). | detail... |
| RET fusion | stomach cancer | sensitive | Selpercatinib | Guideline | Actionable | Retevmo (selpercatinib) is included in guidelines as second-line or subsequent therapy for patients with unresectable locally advanced, recurrent, or metastatic gastric cancer harboring RET fusion (NCCN.org). (NCCN.org). | detail... |
| RET fusion | lung non-small cell carcinoma | sensitive | Vandetanib | Phase II | Actionable | In a Phase II trial, Caprelsa (vandetanib) treatment resulted in partial remission in 17% (3/18) and stable disease in 44% (8/18) of non-small cell lung adenocarcinoma patients harboring RET fusions (J Clin Oncol 34, 2016 (suppl; abstr 9013)). | detail... |
| RET fusion | lung non-small cell carcinoma | sensitive | Vandetanib | Phase II | Actionable | In a Phase II trial, Caprelsa (vandetanib) treatment resulted in a disease control rate of 88% (15/17), median progression-free survival (PFS) of 4.7 months, and partial response in 53% (9/17) of non-small cell lung adenocarcinoma patients harboring RET fusions (J Clin Oncol 34, 2016 (suppl; abstr 9012)). | detail... |
| RET fusion | oncocytic carcinoma of the thyroid | sensitive | Pralsetinib | Guideline | Actionable | Gavreto (pralsetinib) is included in guidelines for patients with thyroid Hurthle cell carcinoma harboring RET fusions (NCCN.org). | detail... |
| RET fusion | colon cancer | predicted - sensitive | Pralsetinib | Case Reports/Case Series | Actionable | In a Phase I/II trial (ARROW), Gavreto (pralsetinib) treatment was well-tolerated, resulted in stable disease in 2 patients with RET fusion-positive colon cancer, with a duration of response of 7.3 and 9.3 months, respectively (J Clin Oncol 38, no. 15_suppl (May 20, 2020) 109-109; NCT03037385). | detail... |
| RET fusion | colon cancer | sensitive | Selpercatinib | Guideline | Actionable | Retevmo (selpercatinib) is included in guidelines for patients with metastatic colon cancer harboring RET fusions (NCCN.org). | detail... |
| RET fusion | colon cancer | sensitive | Selpercatinib | Case Reports/Case Series | Actionable | In a Phase I/II trial (LIBRETTO-001), Retevmo (selpercatinib) treatment resulted in an objective response rate (ORR) of 43.9% (18/41, 2 complete responses, 16 partial responses) with a median duration of response (mDOR) of 24.5 months in patients with RET fusion-positive advanced or metastatic solid tumors, and ORR and mDOR in patients with colon cancer were 20.0% (2/10) and 9.4 months, respectively (PMID: 36108661; NCT03157128). | 36108661 |
| RET fusion | papillary thyroid carcinoma | sensitive | Pralsetinib | Phase Ib/II | Actionable | In a Phase I/II trial (ARROW), Gavreto (pralsetinib) treatment was well-tolerated, resulted in an objective response rate of 75% (9/12) and a median duration of response of 14.5 months in patients with RET fusion positive papillary thyroid cancer (J Clin Oncol 38, no. 15_suppl (May 20, 2020) 109-109; NCT03037385). | detail... |
| RET fusion | papillary thyroid carcinoma | sensitive | Pralsetinib | Guideline | Actionable | Gavreto (pralsetinib) is included in guidelines as systemic therapy for patients with papillary thyroid carcinoma harboring RET fusions (NCCN.org). | detail... |
| RET rearrange | lung non-small cell carcinoma | predicted - sensitive | Alectinib | Case Reports/Case Series | Actionable | In a clinical study, Alecensa (alectinib) treatment resulted in objective radiographic response in 50% (2/4) and stable disease in 25% (1/4) of non-small cell lung carcinoma patients harboring RET rearrangement (PMID: 27544060). | 27544060 |
| RET rearrange | lung non-small cell carcinoma | predicted - sensitive | Alectinib | Case Reports/Case Series | Actionable | In a retrospective analysis, Alecensa (alectinib) treatment resulted an intracranial response in 1 of 2 patients with RET-rearranged non-small cell lung cancer (PMID: 30017832). | 30017832 |
| RET rearrange | lung non-small cell carcinoma | no benefit | Ponatinib | Case Reports/Case Series | Actionable | In a retrospective analysis, multikinase inhibitor treatment demonstrated suboptimal clinical efficacy in RET-rearranged non-small cell lung cancer patients with measurable baseline brain metastasis, with a confirmed intracranial response rate of 18% (2/11); Iclusig (ponatinib) treatment resulted in no intracranial response in 4 patients with evaluable brain metastasis (PMID: 30017832). | 30017832 |
| RET rearrange | lung non-small cell carcinoma | sensitive | Selpercatinib | Guideline | Actionable | Retevmo (selpercatinib) is in guidelines as a first-line and subsequent therapy for patients with advanced or metastatic non-small cell lung cancer harboring RET rearrangements (NCCN.org). | detail... |
| RET rearrange | papillary thyroid carcinoma | sensitive | Sorafenib | Preclinical | Actionable | In a preclinical study, Nexavar (sorafenib) inhibited RET phosphorylation and activation of downstream signaling, and decreased growth of papillary thyroid carcinoma cells harboring the RET/PTC1 oncogene in culture (PMID: 17664273). | 17664273 |
| RET rearrange | lung non-small cell carcinoma | sensitive | Pralsetinib | Guideline | Actionable | Gavreto (pralsetinib) is included in guidelines as a first-line and subsequent therapy for patients with advanced or metastatic non-small cell lung cancer harboring RET rearrangements (NCCN.org). | detail... |
| RET rearrange | Advanced Solid Tumor | sensitive | RXDX-105 | Preclinical - Pdx | Actionable | In a preclinical study, CEP-32496 (RXDX-105) induced tumor regression in patient-derived xenograft models of several advanced solid tumor type with RET rearrangements (2015 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; Abstract A174). | detail... |
| RET rearrange | lung non-small cell carcinoma | predicted - sensitive | Sunitinib | Clinical Study | Actionable | In a clinical study, analysis of patients with RET-rearranged non-small cell lung cancer treated with RET inhibitors demonstrated a response rate of 18% (2/9, all partial responses), and stable disease in 33% (3/9) of patients following Sutent (sunitinib) treatment (PMID: 28447912). | 28447912 |
| RET rearrange | lung non-small cell carcinoma | predicted - sensitive | RXDX-105 | Phase I | Actionable | In a Phase Ib trial, treatment with RXDX-105 (CEP-32496) resulted in an overall response rate of 19% (6/31) and stable disease in 39% (12/31) of patients with treatment-naive non-small cell lung cancer harboring a RET fusion (PMID: 30487236; NCT01877811) | 30487236 |
| RET rearrange | lung non-small cell carcinoma | predicted - sensitive | RXDX-105 | Case Reports/Case Series | Actionable | In a clinical case study, a patient with non-small cell lung cancer harboring a RET rearrangement demonstrated a sustained partial response following treatment with RXDX-105 (CEP-32496) on a Phase Ib clinical trial (PMID: 28011461; NCT01877811). | 28011461 |
| RET rearrange | lung adenocarcinoma | no benefit | Sunitinib | Clinical Study - Cohort | Actionable | In a Phase II trial, Sutent (sunitinib) treatment demonstrated limited clinical efficacy, with no objective responses and stable disease in 71% (5/7) of lung adenocarcinoma patients harboring RET rearrangements (PMID: 32312893; NCT01829217). | 32312893 |
| RET rearrange | papillary thyroid carcinoma | sensitive | Ponatinib | Preclinical | Actionable | In a preclinical study, Iclusig (ponatinib) decreased proliferation of papillary thyroid carcinoma cells harboring the RET/PTC1 rearrangement in culture (PMID: 23526464). | 23526464 |
| RET rearrange | lung non-small cell carcinoma | sensitive | Cabozantinib | Guideline | Actionable | Cometriq (cabozantinib) is in guidelines as a first-line and subsequent therapy for patients with advanced or metastatic non-small cell lung cancer harboring RET rearrangements (NCCN.org). | detail... |
| RET rearrange | lung non-small cell carcinoma | sensitive | Cabozantinib | Clinical Study | Actionable | In a clinical study, analysis of patients with RET-rearranged non-small cell lung cancer treated with RET inhibitors demonstrated a response rate of 37% (7/19), with complete response in 5% (1/19) and partial response in 32% (6/19) of patients, and stable disease in 26% (5/19) of patients following Cometriq (cabozantinib) treatment (PMID: 28447912). | 28447912 |
| RET rearrange | lung adenocarcinoma | predicted - sensitive | Cabozantinib | Phase II | Actionable | In a Phase II trial, treatment with Cometriq (cabozantinib) resulted in an overall response rate of 28% (7/25) in patients with RET-rearranged lung adenocarcinoma, with a median duration of response of 7.0 months (PMID: 27825636; NCT01639508). | 27825636 |
| RET rearrange | lung non-small cell carcinoma | sensitive | Vandetanib | Phase II | Actionable | In a Phase II trial, treatment with Caprelsa (vandetanib) resulted in an objective response rate of 18% (3/17, all partial responses) and disease control rate of 65% (stable disease in 47% (8/17) + partial response in 18% (3/17)) and median progression-free survival of 4.5 months in patients with RET-rearranged metastatic or recurrent non-small cell lung cancer (PMID: 27803005; NCT01823068). | 27803005 |
| RET rearrange | lung non-small cell carcinoma | sensitive | Vandetanib | Clinical Study | Actionable | In a clinical study, analysis of patients with RET-rearranged non-small cell lung cancer treated with RET inhibitors demonstrated a response rate of 18% (2/11, all partial responses) and stable disease in 27% (3/11) of patients following Caprelsa (vandetanib) treatment (PMID: 28447912). | 28447912 |