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RET Watch Videos

A destination for busy HCPs to hear about Retevmo from top thought leaders

Ret Watch

Understanding how RET fusions and mutations drive RET-altered tumors

[Music with a medium beat begins, in and under. Title animates into view.]

[Thought leader, his title, and institutional affiliation appear on screen]

Narrator: Hello! I am Dr. Bryan McIver, an endocrine oncologist at Moffitt Cancer Center. Thank you for your time today.

I want to talk with you about the RET fusions and mutations and how they contribute to RET-driven cancers and discuss a precision medicine for these cancers.1

[Retevmo indication appears on screen]

Narrator: Retevmo is a kinase inhibitor that was evaluated in LIBRETTO-001, an open-label, multicenter, phase 1/2 multi-cohort trial. Based on the results of this trial, Retevmo is indicated for the treatment of adult patients with metastatic RET fusion-positive non-small cell lung cancer (NSCLC), adult and pediatric patients 12 years of age and older with advanced or metastatic RET-mutant medullary thyroid cancer, or MTC, who require systemic therapy. It's also indicated for adult and pediatric patients 12 years and older with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and are radioactive iodine-refractory, if radioactive iodine is appropriate.1

These indications are approved under accelerated approval based on overall response rate and duration of response. Continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials.1

[Select important safety information for Retevmo appears on screen]

Narrator: Retevmo carries a warning and precaution for hepatotoxicity. Serious hepatic adverse reactions occurred in 2.6% of patients treated with Retevmo. Increased aspartate aminotransferase, or AST, occurred in 51% of patients, including Grade 3 or 4 events in 8% and increased alanine aminotransferase, or ALT, occurred in 45% of patients, including Grade 3 or 4 events in 9%. The median time to first onset for increased AST was 4.1 weeks with a range of 5 days to 2 years, and increased ALT was 4.1 weeks with a range of 6 days to 1.5 years. Monitor ALT and AST prior to initiating Retevmo, every 2 weeks during the first 3 months, then monthly thereafter and as clinically indicated. Withhold, reduce dose or permanently discontinue Retevmo based on the severity.

[Thought leader appears on screen, addressing the camera]

Narrator: I'd like to start by discussing the significance of RET-driven metastatic NSCLC and thyroid cancers. RET alterations are a primary driver of uncontrolled cell proliferation and tumor survival.2-4 They can exist as a RET fusion or as point mutations.5

[Text and visual information on the prevalence of RET mutations slides onto screen]

Narrator: RET fusions occur in up to 2% of patients with NSCLC5 and 10-20% of patients with papillary thyroid cancer.6,7 RET point mutations are found in more than 60% of sporadic MTC5 and approximately 98% of germline MTC.8 Although RET point mutations may be present in other tumors, they are believed to only be a driver of MTC.2,9,10

[Timeline and disclaimer text addressing approval of RET targeted therapy slide onto screen]

Narrator: RET fusions were identified in papillary thyroid cancer over 30 years ago and in NSCLC a decade ago, but until 2020, no therapies were approved specifically for patients with RET-altered NSCLC or thyroid cancer.5 Therefore, selective inhibition of RET marks an advancement in precision oncology.1,11-13

[Thought leader shown split screen with text describing information about chromosomal rearrangements]

Narrator: Let's briefly discuss the role of RET fusions in RET-driven cancers. RET fusions can be found in metastatic NSCLC and non-MTC,6,7 and are driven by two main mechanisms.5 RET fusions produced by chromosomal rearrangements may produce …

[Thought leader shown split screen with text describing information about constitutive activation of RET kinase]

Narrator: … hybrid proteins that are constitutively activated.5 Unlike normal RET expression, rearrangements with unrestricted partner genes may lead to increased expression of the RET kinase protein.5

Upstream fusion partners are also frequently observed in RET-rearranged cancers and may increase RET kinase activity.

Upstream fusion partners can contribute dimerization domains, resulting in ligand-independent dimerization and constitutive activation of the RET kinase.5 It's through this constitutive RET kinase activation that RET fusions may promote uncontrolled cell proliferation and tumor survival.5 

[An animation of RET mutations appears on screen]

Narrator: In terms of RET mutations in medullary thyroid cancer, activating RET point mutations may drive pathology in subsets of sporadic and hereditary cancers via increased RET kinase activity.5 

Just like RET fusions, RET point mutations promote oncogenesis via increased activation of RET kinase.5 This increased activity may result from RET amino acid substitutions, which potentially enable ligand-independent dimerization and increased RET kinase activity.5 

[Thought leader shown split screen with text describing information about targeting the RET kinase]

Narrator: To address this increased activity, Retevmo was designed to target the RET protein.1,5 As mentioned, Retevmo is approved to treat three disease states: metastatic RET fusion-positive NSCLC, advanced or metastatic RET-mutant MTC, and advanced or metastatic RET fusion-positive thyroid cancer.1

It's important to note that patients with RET-mutant NSCLC and RET-mutant non-MTC were not enrolled in the trial because RET alterations are not primary drivers of tumor growth in these cancers.2,9,10 Additionally, Retevmo may affect both healthy cells and tumor cells, which can result in side effects, and some may be serious.1 

[Select important safety information for Retevmo appears on screen]

Narrator: The labeling for Retevmo also carries a warning and precaution for hypertension. Hypertension occurred in 35% of patients, including Grade 3 hypertension in 17% and Grade 4 in one patient, or 0.1%. Overall, 4.6% had their dose interrupted and 1.3% had their dose reduced for hypertension. Treatment-emergent hypertension was most commonly managed with anti-hypertensive medications. Do not initiate Retevmo in patients with uncontrolled hypertension. Optimize blood pressure prior to initiating Retevmo. Monitor blood pressure after 1 week, at least monthly thereafter, and as clinically indicated. Initiate or adjust any anti-hypertensive therapy as appropriate. Withhold, reduce dose, or permanently discontinue Retevmo based on the severity.

[An animated graphic on RET fusions vs mutations appears on screen]

Narrator: RET fusions have been shown to drive metastatic NSCLC or non-MTC in some patients, while RET point mutations may drive MTC in other patients.1,5,14 Retevmo is the first FDA-approved treatment option specifically for patients with RET-driven NSCLC or thyroid cancers.1,5

So, test for RET in your patients with metastatic NSCLC and thyroid cancers, and rethink what's possible with Retevmo.1 

[Thought leader appears on screen, addressing the camera]

Narrator: Thank you for your time and attention today. We appreciate the care you take to treat all your patients, including those with RET-driven cancers.

If you're interested in learning more about the safety and efficacy of Retevmo in the LIBRETTO-001 trial, including data on best change in tumor size from baseline in NSCLC and thyroid cancer as well as central nervous system activity in patients with metastatic NSCLC, visit RETwatch.com. While you're there, we invite you to review our other video presentations on Retevmo!

[Music with a medium beat begins, in and under. Closing art card shown.]

References:

  1. Retevmo (selpercatinib) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2021.
  2. Mulligan LM. RET revisited: expanding the oncogenic portfolio. Nat Rev Cancer. 2014;14(3):173-186.
  3. Qian Y, Chai S, Liang Z, et al. KIF5B-RET fusion kinase promotes cell growth by multilevel activation of STAT3 in lung cancer. Mol Cancer. 2014;13(176).
  4. Saito M, Ishigame T, Tsuta K, et al. A mouse model of KIF5B-RET fusion-dependent lung tumorigenesis. Carcinogenesis. 2014;35(11):2452-2456.
  5. Drilon A, Hu ZI, Lai GGY, et al. Targeting RET-driven cancers: lessons from evolving preclinical and clinical landscapes. Nat Rev Clin Oncol. 2018;15(3):151-167.
  6. Lee M-Y, Ku BM, Kim HS, et al. Genetic alterations and their clinical implications in high-recurrence risk papillary thyroid cancer. Cancer Res Treat. 2017;49(4):906-914.
  7. Prescott JD, Zeiger MA. The RET oncogene in papillary thyroid carcinoma. Cancer. 2015;121(13):2137-2146.
  8. Elisei R, Tactio A, Ramone T, et al. Twenty-five years experience on RET genetic screening in hereditary MTC: an update on the prevalence of germline RET mutations. Genes (Basel). 2019;10(9):698.
  9. Mulligan LM. GDNF and the RET receptor in cancer: new insights and therapeutic potential. Front Physiol. 2019;9:1873.
  10. Kato S, Subbiah V, Marchlik E, et al. RET aberrations in diverse cancers: next-generation sequencing of 4,871 patients. Clin Cancer Res. 2017;23(8):1988-1997.
  11. Amatu A, Sartore-Bianchi A, Siena S. NTRK gene fusions as novel targets of cancer therapy across multiple tumour types. ESMO Open. 2016; 1(2):e000023.
  12. Ferrara R, Auger N, Auclin E, et al. Clinical and translational implications of RET rearrangements in non-small cell lung cancer. J Thorac Oncol. 2018;13(1):27-45.
  13. Vansteenkiste JF, Van De Kerkhove C, Wauters E, et al. Capmatinib for the treatment of non-small cell lung cancer. Expert Rev Anticancer Ther. 2019;19(8):659-671.
  14. Guerra A, Crescenzo VD, Garzi A, et al. Genetic mutations in the treatment of anaplastic thyroid cancer: a systematic review. BMC Surg. 2013;13(Suppl 2):S44.

PP-SE-US-0779 11/2021
© Lilly USA, LLC 2021. All rights reserved.
Retevmo® is a registered trademark owned or licensed by Eli Lilly and Company, its subsidiaries, or affiliates.

RET=rearranged during transfection; NSCLC=non-small cell lung cancer; CNS=central nervous system.

Indications

Retevmo is a kinase inhibitor indicated for the treatment of:

  • adult patients with metastatic RET fusion-positive non-small cell lung cancer (NSCLC)
  • adult and pediatric patients 12 years of age and older with advanced or metastatic RET-mutant medullary thyroid cancer (MTC) who require systemic therapy
  • adult and pediatric patients 12 years of age and older with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate)

These indications are approved under accelerated approval based on overall response rate (ORR) and duration of response (DoR). Continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials.

Important Safety Information for Retevmo® (selpercatinib)

Hepatotoxicity: Serious hepatic adverse reactions occurred in 2.6% of patients treated with Retevmo. Increased aspartate aminotransferase (AST) occurred in 51% of patients, including Grade 3 or 4 events in 8% and increased alanine aminotransferase (ALT) occurred in 45% of patients, including Grade 3 or 4 events in 9%. The median time to first onset for increased AST was 4.1 weeks (range: 5 days to 2 years) and increased ALT was 4.1 weeks (range: 6 days to 1.5 years). Monitor ALT and AST prior to initiating Retevmo, every 2 weeks during the first 3 months, then monthly thereafter and as clinically indicated. Withhold, reduce dose or permanently discontinue Retevmo based on the severity.

Hypertension occurred in 35% of patients, including Grade 3 hypertension in 17% and Grade 4 in one (0.1%) patient. Overall, 4.6% had their dose interrupted and 1.3% had their dose reduced for hypertension. Treatment-emergent hypertension was most commonly managed with anti-hypertension medications. Do not initiate Retevmo in patients with uncontrolled hypertension. Optimize blood pressure prior to initiating Retevmo. Monitor blood pressure after 1 week, at least monthly thereafter, and as clinically indicated. Initiate or adjust anti-hypertensive therapy as appropriate. Withhold, reduce dose, or permanently discontinue Retevmo based on the severity.

Retevmo can cause concentration-dependent QT interval prolongation. An increase in QTcF interval to >500 ms was measured in 6% of patients and an increase in the QTcF interval of at least 60 ms over baseline was measured in 15% of patients. Retevmo has not been studied in patients with clinically significant active cardiovascular disease or recent myocardial infarction. Monitor patients who are at significant risk of developing QTc prolongation, including patients with known long QT syndromes, clinically significant bradyarrhythmias, and severe or uncontrolled heart failure. Assess QT interval, electrolytes and TSH at baseline and periodically during treatment, adjusting frequency based upon risk factors including diarrhea. Correct hypokalemia, hypomagnesemia and hypocalcemia prior to initiating Retevmo and during treatment. Monitor the QT interval more frequently when Retevmo is concomitantly administered with strong and moderate CYP3A inhibitors or drugs known to prolong QTc interval. Withhold and dose reduce or permanently discontinue Retevmo based on the severity.

Serious, including fatal, hemorrhagic events can occur with Retevmo. Grade ≥3 hemorrhagic events occurred in 2.3% of patients treated with Retevmo including 3 (0.4%) patients with fatal hemorrhagic events, including one case each of cerebral hemorrhage, tracheostomy site hemorrhage, and hemoptysis. Permanently discontinue Retevmo in patients with severe or life-threatening hemorrhage.

Hypersensitivity occurred in 4.3% of patients receiving Retevmo, including Grade 3 hypersensitivity in 1.6%. The median time to onset was 1.7 weeks (range 6 days to 1.5 years). Signs and symptoms of hypersensitivity included fever, rash and arthralgias or myalgias with concurrent decreased platelets or transaminitis. If hypersensitivity occurs, withhold Retevmo and begin corticosteroids at a dose of 1 mg/kg prednisone (or equivalent). Upon resolution of the event, resume Retevmo at a reduced dose and increase the dose of Retevmo by 1 dose level each week as tolerated until reaching the dose taken prior to onset of hypersensitivity. Continue steroids until patient reaches target dose and then taper. Permanently discontinue Retevmo for recurrent hypersensitivity.

Tumor lysis syndrome (TLS) occurred in 1% of patients with medullary thyroid carcinoma receiving Retevmo. Patients may be at risk of TLS if they have rapidly growing tumors, a high tumor burden, renal dysfunction, or dehydration. Closely monitor patients at risk, consider appropriate prophylaxis including hydration, and treat as clinically indicated.

Impaired wound healing can occur in patients who receive drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway. Therefore, Retevmo has the potential to adversely affect wound healing. Withhold Retevmo for at least 7 days prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of Retevmo after resolution of wound healing complications has not been established.

Based on data from animal reproduction studies and its mechanism of action, Retevmo can cause fetal harm when administered to a pregnant woman. Administration of selpercatinib to pregnant rats during organogenesis at maternal exposures that were approximately equal to those observed at the recommended human dose of 160 mg twice daily resulted in embryolethality and malformations. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with Retevmo and for at least 1 week after the final dose. There are no data on the presence of selpercatinib or its metabolites in human milk or on their effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with Retevmo and for 1 week after the final dose.

Severe adverse reactions (Grade 3-4) occurring in ≥15% of patients who received Retevmo in LIBRETTO-001, were hypertension (18%), prolonged QT interval (4%), diarrhea (3.4%), dyspnea (2.3%), fatigue (2%), abdominal pain (1.9%), hemorrhage (1.9%), headache (1.4%), rash (0.7%), constipation (0.6%), nausea (0.6%), vomiting (0.3%), and edema (0.3%).

Serious adverse reactions occurred in 33% of patients who received Retevmo. The most frequently reported serious adverse reaction (in ≥ 2% of patients) was pneumonia.

Fatal adverse reactions occurred in 3% of patients; fatal adverse reactions which occurred in >1 patient included sepsis (n=3), cardiac arrest (n=3) and respiratory failure (n=3).

Common adverse reactions (all grades) occurring in ≥15% of patients who received Retevmo in LIBRETTO-001, were dry mouth (39%), diarrhea (37%), hypertension (35%), fatigue (35%), edema (35%), rash (27%), constipation (25%), nausea (23%), abdominal pain (23%), headache (23%), cough (18%), prolonged QT interval (17%), dyspnea (16%), vomiting (15%), and hemorrhage (15%).

Laboratory abnormalities (all grades; Grade 3-4) ≥20% worsening from baseline in patients who received Retevmo in LIBRETTO-001, were AST increased (51%; 8%), ALT increased (45%; 9%), increased glucose (44%; 2.2%), decreased leukocytes (43%; 1.6%), decreased albumin (42%; 0.7%), decreased calcium (41%; 3.8%), increased creatinine (37%; 1.0%), increased alkaline phosphatase (36%; 2.3%), decreased platelets (33%; 2.7%), increased total cholesterol (31%; 0.1%), decreased sodium (27%; 7%), decreased magnesium (24%; 0.6%), increased potassium (24%; 1.2%), increased bilirubin (23%; 2.0%), and decreased glucose (22%; 0.7%).

Concomitant use of acid-reducing agents decreases selpercatinib plasma concentrations which may reduce Retevmo anti-tumor activity. Avoid concomitant use of proton-pump inhibitors (PPIs), histamine-2 (H2) receptor antagonists, and locally-acting antacids with Retevmo. If coadministration cannot be avoided, take Retevmo with food (with a PPI) or modify its administration time (with a H2 receptor antagonist or a locally-acting antacid).

Concomitant use of strong and moderate CYP3A inhibitors increases selpercatinib plasma concentrations which may increase the risk of Retevmo adverse reactions including QTc interval prolongation. Avoid concomitant use of strong and moderate CYP3A inhibitors with Retevmo. If concomitant use of a strong or moderate CYP3A inhibitor cannot be avoided, reduce the Retevmo dosage as recommended and monitor the QT interval with ECGs more frequently.

Concomitant use of strong and moderate CYP3A inducers decreases selpercatinib plasma concentrations which may reduce Retevmo anti-tumor activity. Avoid coadministration of Retevmo with strong and moderate CYP3A inducers.

Concomitant use of Retevmo with CYP2C8 and CYP3A substrates increases their plasma concentrations which may increase the risk of adverse reactions related to these substrates. Avoid coadministration of Retevmo with CYP2C8 and CYP3A substrates where minimal concentration changes may lead to increased adverse reactions. If coadministration cannot be avoided, follow recommendations for CYP2C8 and CYP3A substrates provided in their approved product labeling.

The safety and effectiveness of Retevmo have not been established in pediatric patients less than 12 years of age. The safety and effectiveness of Retevmo have been established in pediatric patients aged 12 years and older for medullary thyroid cancer (MTC) who require systemic therapy and for advanced RET fusion-positive thyroid cancer who require systemic therapy and are radioactive iodine-refractory (if radioactive iodine is appropriate). Use of Retevmo for these indications is supported by evidence from adequate and well-controlled studies in adults with additional pharmacokinetic and safety data in pediatric patients aged 12 years and older. Monitor open growth plates in adolescent patients. Consider interrupting or discontinuing Retevmo if abnormalities occur.

No dosage modification is recommended for patients with mild to severe renal impairment (estimated Glomerular Filtration Rate [eGFR] ≥15 to 89 mL/min, estimated by Modification of Diet in Renal Disease [MDRD] equation). A recommended dosage has not been established for patients with end-stage renal disease.

Reduce the dose when administering Retevmo to patients with severe hepatic impairment (total bilirubin greater than 3 to 10 times upper limit of normal [ULN] and any AST). No dosage modification is recommended for patients with mild or moderate hepatic impairment. Monitor for Retevmo-related adverse reactions in patients with hepatic impairment.

Please see full Prescribing Information for Retevmo.

SE HCP ISI All_25MAR2021

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