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| Profile Name | RET C634Y |
| Gene Variant Detail | |
| Relevant Treatment Approaches | RET Inhibitor |
| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
|---|---|---|---|---|---|---|---|
| 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 | 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 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 | 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 C634X | medullary thyroid carcinoma | not applicable | N/A | Guideline | Risk Factor | Germline RET C634X mutations result in multiple endocrine neoplasia, type 2A (MEN 2A), which is associated with high risk of developing thyroid medullary carcinoma (NCCN.org). | detail... |
| 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 | 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 | 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 C634X | 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 65% (51/79, 5% complete response, 59% partial response) in patients with advanced or metastatic medullary thyroid cancer harboring RET mutations, 28% of the patients harbored RET C634X (Ann Oncol. Vol 31, Supplement 4, S1084, Sep 1, 2020; NCT03037385). | detail... |
| 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 | 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 | 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 | Guideline | Actionable | Retevmo (selpercatinib) is included in guidelines 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 (category 2B) for patients with medullary thyroid carcinoma harboring RET mutations (NCCN.org). | 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 | 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 | 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... |