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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||thyroid gland medullary 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||thyroid gland medullary 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||thyroid gland medullary carcinoma||sensitive||Selpercatinib||FDA approved||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||thyroid gland medullary carcinoma||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 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 detail...|
|RET C634X||thyroid gland medullary 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||thyroid gland medullary 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||thyroid gland medullary 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 C634X||thyroid gland medullary 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...|