Selcaxen

Metastatic RET Fusion-Positive Non-Small Cell Lung Cancer
: Selcaxen is indicated for the treatment of adult patients with metastatic RET fusion-positive non-small cell lung cancer (NSCLC). This indication is approved under accelerated approval based on overall response rate and
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Metastatic RET Fusion-Positive Non-Small Cell Lung Cancer
: Selcaxen is indicated for the treatment of adult patients with metastatic RET fusion-positive non-small cell lung cancer (NSCLC). This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).
RET-Mutant Medullary Thyroid Cancer
: Selcaxen is indicated for the treatment of adult and pediatric patients 12 years of age and older with advanced or metastatic RET-mutant medullary thyroid cancer (MTC) who require systemic therapy. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).
RET Fusion-Positive Thyroid Cancer
: Selcaxen is indicated for the treatment of 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). This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

The recommended dosage of Selpercatinib based on body weight is:
Less than 50 kg: 120 mg
50 kg or greater: 160 mg
Take Selpercatinib orally twice daily (approximately every 12 hours) until disease progression or unacceptable toxicity. Swallow the capsules whole. Do not crush or chew the capsules. Do not take a missed dose unless it is more than 6 hours until next scheduled dose. If vomiting occurs after Selpercatinib administration, do not take an additional dose and continue to the next scheduled time for the next dose.
Dosage Modifications for Concomitant Use of Acid-Reducing Agents Avoid concomitant use of a PPI, a histamine-2 (H2) receptor antagonist, or a locally-acting antacid with Selpercatinib. If concomitant use cannot be avoided:
Take Selpercatinib with food when co-administered with a PPI.
Take Selpercatinib 2 hours before or 10 hours after administration of an H2 receptor antagonist.
Take Selpercatinib 2 hours before or 2 hours after administration of a locally-acting antacid.

The most common side effects of Selcaxen are:
higher levels of liver enzymes
higher blood sugar levels
lower white blood cell count
lower protein (albumin) levels in the blood
lower calcium levels in the blood
dry mouth
diarrhea
higher creatinine levels (this measures kidney function)
high blood pressure
tiredness
swelling of your arms, legs, hands, and feet (peripheral edema)
lower platelet count
higher cholesterol levels
rash
lower salt (sodium) levels in the blood
constipation

Hepatotoxicity
: Serious hepatic adverse reactions occurred in 2.6% of patients treated with Selcaxen. Monitor ALT and AST prior to initiating Selcaxen, every 2 weeks during the first 3 months, then monthly thereafter and as clinically indicated. Withhold, reduce dose or permanently discontinue Selcaxen based on the severity.
Hypertension
: 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 Selcaxen in patients with uncontrolled hypertension. Optimize blood pressure prior to initiating Selcaxen. 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 Selcaxen based on the severity.
QT Interval Prolongation
: Selcaxen 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. Selcaxen 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 Selcaxen and during treatment. Monitor the QT interval more frequently when Selcaxen is concomitantly administered with strong and moderate CYP3A inhibitors or drugs known to prolong QTc interval. Withhold and dose reduce or permanently discontinue Selcaxen based on the severity.
Hemorrhagic Events
: Serious including fatal hemorrhagic events can occur with Selcaxen. Grade >3 hemorrhagic events occurred in 2.3% of patients treated with Selcaxen, including 3 (0.4%) patients with fatal hemorrhagic events, including one case each of cerebral hemorrhage, tracheostomy site hemorrhage, and hemoptysis. Permanently discontinue Selcaxen in patients with severe or life-threatening hemorrhage.
Hypersensitivity
: Hypersensitivity occurred in 4.3% of patients receiving Selcaxen, 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 Selcaxen and begin corticosteroids at a dose of 1 mg/kg prednisone (or equivalent). Upon resolution of the event, resume Selcaxen at a reduced dose and increase the dose of Selcaxen 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 Selcaxen for recurrent hypersensitivity.
Tumor Lysis Syndrome
: Tumor lysis syndrome (TLS) occurred in 1% of patients with medullary thyroid carcinoma receiving Selcaxen. 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.

Selpercatinib is a kinase inhibitor. Selpercatinib inhibited wild-type RET and multiple mutated RET isoforms as well as VEGFR1 and VEGFR3 with IC50 values ranging from 0.92 nM to 67.8 nM. In other enzyme assays, Selpercatinib also inhibited FGFR 1, 2, and 3 at higher concentrations that were still clinically achievable. In cellular assays, Selpercatinib inhibited RET at approximately 60-fold lower concentrations than FGFR1 and 2 and approximately 8-fold lower concentration than VEGFR3.