FDA Approval Summary: Selpercatinib for the Treatment of Lung and Thyroid Cancers with <i>RET</i> Gene Mutations or Fusions

Bradford, Diana; Larkins, Erin; Mushti, Sirisha; Rodríguez, Lisa; Skinner, Amy M.; Helms, Whitney S.; Price, Lauren; Zirkelbach, Jeanne Fourie; Li, Yangbing; Liu, Jiang; Charlab, Rosane; Turcu, Francisca Reyes; Liang, Dun; Ghosh, Soma; Roscoe, Donna; Philip, Reena; Zack-Taylor, Autumn; Tang, Shenghui; Kluetz, Paul G.; Beaver, Julia A.; Pazdur, Richard; Theoret, Marc R.; Singh, Harpreet

doi:10.1158/1078-0432.ccr-20-3558

Cited by 97 publications

(73 citation statements)

References 21 publications

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“…Pralsetinib has been demonstrated to inhibit the growth of tumors driven by various RET mutations and fusions in vivo, and it showed durable clinical responses in patients with RET-altered NSCLC [15,16]. Selpercatinib also showed promising activity in patients with RET-fused NSCLC and RET-fused or mutated MTC [7,8,14,17]. Two patients with RET-mutated mCRC were included in a clinical trial (NCT03037385), and the e cacy of pralsetinib is still under evaluation in these two patients.…”

Section: Discussionmentioning

confidence: 99%

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Association between somatic RET mutations and clinical and genetic characteristics in patients with metastatic colorectal cancer

Yang

Xia

et al. 2021

Preprint

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Background Rearranged during transfection (RET) is a targetable oncogene. RET fusions have been reported in patients with metastatic colorectal cancer (mCRC). However, RET mutations in mCRC are less studied. Here, we aimed to characterize the clinical, pathological, and molecular landscape of RET-mutated mCRC. Methods Five hundred and eighty-two patients were included in this study. Next-generation sequencing was performed to detect RET mutations and calculate tumor mutation burden (TMB). We compared the clinical, pathological, and molecular characteristics of mCRC cases with tumors that harbored somatic RET mutations (N = 16, 2.7%) or had wild-type RET (N = 566, 97.3%). Results Males comprised the absolute majority of cases with RET mutations (15/16 [93.8%]) compared to their fraction among cases with wild-type RET (339/566 [59.9%]). Furthermore, all patients with RET mutations were younger than 60 years (16/16 [100%]), whereas such patients were less predominant in the group with wild-type RET (379/566 [67.0%]). Individuals with tumors positive for RET mutations more frequently exhibited mucinous histology (5/16 [31.2%] versus 55/566 [9.7%]), exhibited a lower incidence of liver metastasis (4/16 [25.0%] versus 335/566 [59.2%]) and higher incidence of peritoneal metastasis (9/16 [56.2%] versus 161/566 [28.4%]), expressed wild-type TP53 (8/16 [50.0%] versus 120/566 [21.2%]), and showed an increased frequency of MSI-high (6/16 [37.5%] versus 18/566 [3.2%]). In those with microsatellite-stable mCRC, patients with RET mutations had a higher median TMB than patients with wild-type RET (9.4 versus 6.7 mutations/Mb, respectively, P = 0.001). The median progression-free survival was similar in individuals with mutated and wild-type RET on the oxaliplatin-based regimen (7.1 versus 8.7 months, P = 0.516). Conclusions Our study suggests that cases with RET mutations represent a separate mCRC subtype. Further studies are needed to evaluate the efficacy of RET inhibitors in mCRC patients with RET mutations.

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Section: Discussionmentioning

confidence: 99%

“…Thus, RET has emerged as a therapeutic target in patients with aberrant RET activation. Two selective RET inhibitors, selpercatinib (LOXO-292) and pralsetinib (BLU-667), have shown promising anti-cancer activities and are currently widely evaluated in clinical trials [2,[5][6][7][8].…”

Section: Introductionmentioning

confidence: 99%

Association between somatic RET mutations and clinical and genetic characteristics in patients with metastatic colorectal cancer

Yang

Xia

et al. 2021

Preprint

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“…The study is still ongoing and a longer follow-up of the patients involved in this trial will be needed to define the ultimate durability of Selpercatinib efficacy across all cohorts. On the basis of these results, on 8 May 2020, the FDA granted accelerated approval to selpercatinib among other (i.e., non-small cells lung cancers [NSCLC]) for adult and pediatric patients ≥ 12 years of age with advanced or metastatic RET-mutant TC, both MTC and DTC/ATC, who require systemic therapy [104]. The approved dose was 160 mg twice daily for patients with body weight ≥ 50 kg and 120 mg twice daily for patients with a lower body weight.…”

Section: Systemic Treatment In Dtc Pdtc Atc and Mtc: Specific Inhimentioning

confidence: 99%

Thyroid Cancers: From Surgery to Current and Future Systemic Therapies through Their Molecular Identities

Lorusso

Cappagli

Valerio

et al. 2021

IJMS

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Differentiated thyroid cancers (DTC) are commonly and successfully treated with total thyroidectomy plus/minus radioiodine therapy (RAI). Medullary thyroid cancer (MTC) is only treated with surgery but only intrathyroidal tumors are cured. The worst prognosis is for anaplastic (ATC) and poorly differentiated thyroid cancer (PDTC). Whenever a local or metastatic advanced disease is present, other treatments are required, varying from local to systemic therapies. In the last decade, the efficacy of the targeted therapies and, in particular, tyrosine kinase inhibitors (TKIs) has been demonstrated. They can prolong the disease progression-free survival and represent the most important therapeutic option for the treatment of advanced and progressive thyroid cancer. Currently, lenvatinib and sorafenib are the approved drugs for the treatment of RAI-refractory DTC and PDTC while advanced MTC can be treated with either cabozantinib or vandetanib. Dabrafenib plus trametinib is the only approved treatment by FDA for BRAFV600E mutated ATC. A new generation of TKIs, specifically for single altered oncogenes, is under evaluation in phase 2 and 3 clinical trials. The aim of this review was to provide an overview of the current and future treatments of thyroid cancer with regards to the advanced and progressive cases that require systemic therapies that are becoming more and more targeted on the molecular identity of the tumor.

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“…RET fusions have been identified in 1–2% of NSCLCs and have been suggested to be associated with a relatively high frequency of brain metastases [ 18 , 19 ]. Selpercatinib was studied in a multi-center, open-label trial (LIBRETTO-001) that included patients with RET fusion-positive NSCLC and thyroid cancer, as well as RET -mutant medullary thyroid cancer [ 20 , 21 ]. One hundred five patients with metastatic NSCLC who were previously treated with platinum chemotherapy were included.…”

Section: Marketing Approvals Relevant To Neuro-oncology In 2020mentioning

confidence: 99%

“…In total, 11 patients with measurable brain metastases by RECIST criteria (version 1.1) were treated; no patient received CNS radiation therapy within 2 months of study entry. Objective responses in intracranial lesions were observed in 10 patients as assessed by independent centralized review, with 3 complete responses and 7 partial responses; all responders had duration of response of ≥ 6 months [ 21 ].…”

Section: Marketing Approvals Relevant To Neuro-oncology In 2020mentioning

confidence: 99%

US Food and Drug Administration regulatory updates in neuro-oncology

et al. 2021

Self Cite

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Objective Contemporary management of patients with neuro-oncologic disease requires an understanding of approvals by the US Food and Drug Administration (FDA) related to nervous system tumors. To summarize FDA updates applicable to neuro-oncology practitioners, we sought to review oncology product approvals and Guidances that were pertinent to the field in the past year. Methods Oncology product approvals between January 1, 2020, and December 31, 2020, were reviewed for clinical trial outcomes involving tumors of the nervous system. FDA Guidances relevant to neuro-oncology were also reviewed. Results Five oncology product approvals described outcomes for nervous system tumors in the year 2020. These included the first regulatory approval for neurofibromatosis type 1: selumetinib for children with symptomatic, inoperable plexiform neurofibromas. Additionally, there were 4 regulatory approvals for non-central nervous system (CNS) cancers that described clinical outcomes for patients with brain metastases. These included the approval of tucatinib for metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer including patients with brain metastases, brigatinib for anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC), and pralsetinib and selpercatinib for RET fusion-positive NSCLC. Finally, two FDA Guidances for Industry, “Cancer Clinical Trial Eligibility Criteria: Brain Metastases” and “Evaluating Cancer Drugs in Patients with Central Nervous System Metastases” were published to facilitate drug development for and inclusion of patients with CNS metastases in clinical trials. Conclusions Despite the challenges of the past year brought on by the COVID-19 pandemic, progress continues to be made in neuro-oncology. These include first-of-their-kind FDA approvals and Guidances that are relevant to the management of patients with nervous system tumors.

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FDA Approval Summary: Selpercatinib for the Treatment of Lung and Thyroid Cancers with RET Gene Mutations or Fusions

Cited by 97 publications

References 21 publications

Association between somatic RET mutations and clinical and genetic characteristics in patients with metastatic colorectal cancer

Association between somatic RET mutations and clinical and genetic characteristics in patients with metastatic colorectal cancer

Thyroid Cancers: From Surgery to Current and Future Systemic Therapies through Their Molecular Identities

US Food and Drug Administration regulatory updates in neuro-oncology

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