Selpercatinib 160 Mg Oral Tablet

RETEVMO 40 mg tablets for Oral Administration

To prepare RETEVMO tablet as a dispersion:

RETEVMO 40 mg tablets for Feeding Tubes (Gastrostomy or Nasogastric Tube) Administration

Use only polyurethane (French size 8 or larger) or vinyl chloride (French size 10 or larger) nasogastric tube or silicone (French size 14 or larger) gastrostomy tube.

RET Gene Fusion or Gene Mutation Positive Solid Tumors

Increased Creatinine

In healthy subjects administered RETEVMO 160 mg orally twice daily, serum creatinine increased 18% after 10 days. Consider alternative markers of renal function if persistent elevations in serum creatinine are observed [see Clinical Pharmacology (12.3)].

RET-Mutant Medullary Thyroid Cancer

LIBRETTO-531

The safety population described below reflects exposure to RETEVMO as a single agent administered at 160 mg (adults) or at 92 mg/m² (adolescent, not to exceed 160 mg) orally twice daily, in patients with progressive, advanced, kinase inhibitor naïve, RET-mutant medullary thyroid cancer in LIBRETTO-531 [see Clinical Studies (14.2)]. Among the 193 patients who received RETEVMO, the observed median duration of exposure was 14.5 months (range: 25 days to 36 months); 80% were exposed for 6 months or longer and 59% were exposed for one year or longer.

The median age was 55 years (range: 12 to 84 years); 63% were male; and 69% were White, 28% were Asian, 2.9% were Black or African American and ethnicity was not routinely collected.

Serious adverse reactions occurred in 22% of patients who received RETEVMO. The most frequent serious adverse reactions were pneumonia and pyrexia (n = 3, each) and hypertension and urinary tract infection (n = 2, each). Fatal adverse reactions occurred in 2.1% of patients; fatal adverse reactions included COVID-19, diabetic ketoacidosis, multiple organ dysfunction syndrome, and sudden death (n=1 each).

Permanent discontinuation due to an adverse reaction occurred in 4.7% of patients who received RETEVMO. Adverse reactions resulting in permanent discontinuation were edema, multiple organ dysfunction syndrome, sudden death, AST increased, diabetic ketoacidosis, chronic kidney disease, retinopathy, COVID-19, and somatic symptom disorder (n = 1, each).

Dosage interruptions due to an adverse reaction occurred in 49% of patients who received RETEVMO. Adverse reactions requiring dosage omission in ≥5% of patients included ALT increased (9%) and hypertension (7%).

Dose reductions due to an adverse reaction occurred in 39% of patients who received RETEVMO. One adverse reaction, increased ALT (7%), required a dose reduction in ≥5% of patients.

The most common adverse reactions (≥25%) in patients who received RETEVMO were hypertension, edema, dry mouth, fatigue, and diarrhea.

The most common Grade 3 or 4 laboratory abnormalities (≥5%) in patients who received RETEVMO were decreased lymphocytes, increased ALT, decreased neutrophils, increased ALP, increased blood creatinine, decreased calcium, and increased AST.

Table 12 summarizes the adverse reactions in LIBRETTO-531.

Clinically relevant adverse reactions in ≤10% of patients who received RETEVMO include dizziness (8%); urinary tract infections (8%); vomiting (8%); pneumonia, interstitial lung disease/pneumonitis, chylous ascites, and hypersensitivity (all < 2%).

Table 13 summarizes the laboratory abnormalities in LIBRETTO-531.

Increased Creatinine

In healthy subjects administered RETEVMO 160 mg orally twice daily, serum creatinine increased 18% after 10 days. Consider alternative markers of renal function if persistent elevations in serum creatinine are observed [see Clinical Pharmacology (12.3)].

Acid-Reducing Agents

Concomitant use of RETEVMO with acid-reducing agents decreases selpercatinib plasma concentrations [see Clinical Pharmacology (12.3)], which may reduce RETEVMO anti-tumor activity.

Avoid concomitant use of PPIs, 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) [see Dosage and Administration (2.4)].

Strong and Moderate CYP3A Inhibitors

Concomitant use of RETEVMO with a strong or moderate CYP3A inhibitor increases selpercatinib plasma concentrations [see Clinical Pharmacology (12.3)], 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 strong and moderate CYP3A inhibitors cannot be avoided, reduce the RETEVMO dosage and monitor the QT interval with ECGs more frequently [see Dosage and Administration (2.6), Warning and Precautions (5.4)].

Strong and Moderate CYP3A Inducers

Concomitant use of RETEVMO with a strong or moderate CYP3A inducer decreases selpercatinib plasma concentrations [see Clinical Pharmacology (12.3)], which may reduce RETEVMO anti-tumor activity.

Avoid coadministration of strong or moderate CYP3A inducers with RETEVMO.

CYP2C8 and CYP3A Substrates

RETEVMO is a moderate CYP2C8 inhibitor and a weak CYP3A inhibitor. Concomitant use of RETEVMO with CYP2C8 and CYP3A substrates increases their plasma concentrations [see Clinical Pharmacology (12.3)], 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.

Certain P-gp and BCRP Substrates

RETEVMO is a P-gp and BCRP inhibitor. Concomitant use of RETEVMO with P-gp or BCRP substrates increases their plasma concentrations [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions related to these substrates. Avoid coadministration of RETEVMO with P-gp or BCRP substrates where minimal concentration changes may lead to increased adverse reactions. If coadministration cannot be avoided, follow recommendations for P-gp and BCRP substrates provided in their approved product labeling.

Risk Summary

Based on findings from animal studies, and its mechanism of action [see Clinical Pharmacology (12.1)], RETEVMO can cause fetal harm when administered to a pregnant woman. There are no available data on RETEVMO use in pregnant women to inform drug-associated risk. Administration of selpercatinib to pregnant rats during the period of organogenesis resulted in embryolethality and malformations at maternal exposures that were approximately equal to the human exposure at the clinical dose of 160 mg twice daily. Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Risk Summary

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 last dose.

Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to initiating RETEVMO [see Use in Specific Populations (8.1)].

Contraception

Infertility

RETEVMO may impair fertility in females and males of reproductive potential [see Use in Specific Populations (8.4), Nonclinical Toxicology (13.1)].

Juvenile Animal Toxicity Data

In a juvenile rat toxicity study, animals were dosed daily with selpercatinib from post-natal day 21 to day 70 (approximately equivalent to a human child to late adolescent). Selpercatinib increased physeal thickness of multiple bones, extending into the metaphysis and associated with decreased trabecular bone, which was not reversible at doses approximately equivalent to or greater than the adult human exposure at the clinical dose of 160 mg twice daily. Growth plate changes were associated with impairment of bone modeling, resulting in decreased femur length and with reduction in bone mineral density. Selpercatinib also induced reversible hypocellularity of bone marrow in males at ≥30 mg/kg (approximately equivalent to or greater than the adult human exposure at the clinical dose of 160 mg twice daily), and reversible alterations of dentin composition at ≥50 mg/kg (approximately 3 times the adult human exposure at the clinical dose of 160 mg twice daily). Irreversible, dose-dependent degeneration of testicular germinal epithelium, with vacuolation of Sertoli cells and corresponding depletion of spermatozoa in the epididymides, was also observed at ≥ 30 mg/kg (approximately equivalent to or greater than the adult human exposure at the clinical dose of 160 mg twice daily) and affected male reproductive performance at 50 mg/kg (approximately 3 times the adult human exposure at the clinical dose of 160 mg twice daily). Females exhibited delay in attainment of vaginal patency, a marker of sexual maturity, at 125 mg/kg (approximately 4 times the adult human exposure at the clinical dose of 160 mg twice daily); this effect was associated with lower mean body weight. Similar effects in irregular thickening of growth plates in adult rats and minipigs, and tooth dysplasia and malocclusion, resulting in tooth loss in adult rats were observed in repeat dose studies of up to 13-week duration with selpercatinib.

Monitor growth plates in pediatric patients with open growth plates. Consider interrupting or discontinuing therapy based on the severity of any growth plate abnormalities and based on an individual risk-benefit assessment.

Exposure-Response Relationship

Selpercatinib exposure-response relationships and the time course of pharmacodynamic response have not been fully characterized.

Cardiac Electrophysiology

The effect of RETEVMO on the QTc interval was evaluated in a thorough QT study in healthy subjects. The largest mean increase in QTc is predicted to be 10.6 msec (upper 90% confidence interval: 12.1 msec) at the mean steady-state maximum concentration (C_max) observed in patients after administration of 160 mg twice daily. The increase in QTc was concentration-dependent.

Absorption

The median t_max of selpercatinib is 2 hours. The mean absolute bioavailability of RETEVMO capsules is 73% (60% to 82%) in healthy subjects.

Distribution

The apparent volume of distribution (V_ss/F) of selpercatinib is 203 L.

Protein binding of selpercatinib is 96% in vitro and is independent of concentration. The blood-to-plasma concentration ratio is 0.7.

Elimination

The apparent clearance (CL/F) of selpercatinib is 6 L/h in patients and the half-life is 32 hours following oral administration of RETEVMO in healthy subjects.

Specific Populations

The apparent volume of distribution and clearance of selpercatinib increase with increasing body weight (9.6 kg to 179 kg).

No clinically significant differences in the pharmacokinetics of selpercatinib were observed based on age (2 years to 92 years), sex, or mild, moderate, or severe renal impairment (eGFR ≥15 to 89 mL/min). The effect of ESRD on selpercatinib pharmacokinetics has not been studied.

Drug Interaction Studies

RET Fusion-Positive NSCLC Previously Treated with Platinum Chemotherapy

Efficacy was evaluated in 247 patients with RET fusion-positive NSCLC previously treated with platinum chemotherapy enrolled into a cohort of LIBRETTO-001.

The median age was 61 years (range: 23 to 81); 57% were female; 44% were White, 48% were Asian, 4.9% were Black or African American; and 2.8% were Hispanic/Latino. ECOG performance status was 0-1 (97%) or 2 (3%) and 97% of patients had metastatic disease. Patients received a median of 2 prior systemic therapies (range 1–15); 58% had prior anti-PD1/PD-L1 therapy. RET fusions were detected in 94% of patients using NGS (84.6% tumor samples; 9.3% blood or plasma samples), 4.0% using FISH, 1.6% using PCR and 0.4% by other local testing methods.

Efficacy results for previously treated RET fusion-positive NSCLC are summarized in Table 15.

For the 144 patients who received an anti-PD-1 or anti-PD-L1 therapy, either sequentially or concurrently with platinum-based chemotherapy, an exploratory subgroup analysis of ORR was 63% (95% CI: 54%, 70%) and the median DOR was 28.6 months (95% CI: 14.8, NE).

Among the 247 patients with previously treated RET fusion-positive NSCLC, 16 had measurable CNS metastases at baseline as assessed by BIRC. One patient received radiation therapy (RT) to the brain within 2 months prior to study entry. Responses in intracranial lesions were observed in 14 of these 16 patients; 39% of responders had an intracranial DOR of ≥ 12 months.

Treatment-naïve RET Fusion-Positive NSCLC

Efficacy was evaluated in 69 patients with treatment-naïve RET fusion-positive NSCLC enrolled into a cohort of LIBRETTO-001.

The median age was 63 years (range 23 to 92); 62% were female; 70% were White, 19% were Asian, and 6% were Black or African American. ECOG performance status was 0-1 (94%) or 2 (6%) and 99% of patients had metastatic disease. RET fusions were detected in 91% of patients using NGS (60.9% tumor samples; 30.4% in blood), 7.2% using FISH and 1.4% using PCR.

Efficacy results for treatment naïve RET fusion-positive NSCLC are summarized in Table 16.

Among the 69 patients with treatment-naïve RET fusion-positive NSCLC, 5 had measurable CNS metastases at baseline as assessed by BIRC. Two patients received RT to the brain within 2 months prior to study entry. Responses in intracranial lesions were observed in 4 of these 5 patients; 38% of responders had an intracranial DOR of ≥ 12 months.

LIBRETTO-431

The efficacy of RETEVMO was evaluated in patients with unresectable, locally advanced or metastatic, RET fusion-positive NSCLC enrolled in a multicenter, open-label, active-controlled, randomized trial (LIBRETTO-431, NCT04194944). The trial evaluated RETEVMO compared to platinum-based and pemetrexed chemotherapy with or without pembrolizumab in patients with RET fusion-positive, unresectable locally advanced or metastatic NSCLC with no previous systemic therapy for metastatic disease.

Patients (N=261) were randomized to receive either RETEVMO (160 mg orally twice daily) in continuous 21-day cycles or pemetrexed intravenously (IV) (500 mg per square meter of body-surface area) along with the investigator’s choice of platinum therapy (carboplatin IV [AUC 5, maximum dose 750 mg] or cisplatin IV [75 mg per square meter]) with or without pembrolizumab IV (200 mg) every 21 days. Treatment continued until disease progression or unacceptable toxicity. Crossover from the control arm to RETEVMO was permitted following disease progression. Patients were stratified according to geographic region (East Asia vs. elsewhere), brain metastases at baseline (presence vs. absence or unknown), and the investigator’s intent (before randomization) to treat the patient with or without pembrolizumab. Tumor assessments were performed every 6 weeks for two assessments, then every 9 weeks for four assessments, and then every 12 weeks thereafter.

The major efficacy outcome measure was progression-free survival (PFS) in patients intended to be treated with chemotherapy in combination with pembrolizumab and in the overall study population as determined by a blinded independent review committee (BIRC) according to RECIST v1.1. Other efficacy outcome measures included overall survival (OS) and overall response rate (ORR).

A total of 212 patients were enrolled in LIBRETTO-431 with an intent to treat with pembrolizumab if randomized to the control arm (129 into RETEVMO arm and 83 into chemotherapy with pembrolizumab arm). The median age was 61.5 years (range: 31 to 84 years); 47% were male; 41% White, 55% Asian, and 0.9% Black or African American, 1.4% American Indian or Alaska Native, 1.9% were race not reported; ethnicity was not reported in 96% of patients. ECOG performance status was 0-1 (97%) or 2 (3%), 68% were never smokers, 93% of patients had metastatic disease, and 14% had measurable intracranial metastases at baseline, as determined by a neuroradiologic BIRC. RET fusions were detected in 60% of patients using NGS and 40% using PCR (89% tumor samples; 11% in blood).

Efficacy results from the pre-planned interim efficacy analysis are summarized in Table 17.

Among the 212 randomized patients, 29 had measurable CNS metastases at baseline as assessed by BIRC. Responses in intracranial lesions were observed in 14 of 17 patients treated with RETEVMO and 7 of 12 patients treated with chemotherapy with pembrolizumab.

Overall survival was immature at the time of the PFS interim analysis. At the time of an updated descriptive analysis of OS (43% of prespecified OS events needed for the final analysis), a total of 49 (31%) and 26 (25%) patients died in the RETEVMO and the control arm, respectively. The OS HR was 1.26 (95% CI: 0.78, 2.04). Overall survival may be affected by the imbalance in post-progression therapies. Of 68 control arm patients who had disease progression, 50 patients (74%) received RETEVMO at progression. Of 71 RETEVMO arm patients who had disease progression, 16 (23%) received chemotherapy and/or immune checkpoint inhibitor therapy, and 44 (62%) continued receiving RETEVMO.

LIBRETTO-001

The efficacy of RETEVMO was evaluated in patients with RET-mutant MTC enrolled in a multicenter, open-label, multi-cohort clinical trial (NCT03157128). The study enrolled patients with advanced or metastatic RET-mutant MTC who had been previously treated with cabozantinib or vandetanib (or both) and patients with advanced or metastatic RET-mutant MTC who were naïve to cabozantinib and vandetanib in separate cohorts.

RET -Mutant MTC Previously Treated with Cabozantinib or Vandetanib

Efficacy was evaluated in 55 patients with RET-mutant advanced MTC who had previously treated with cabozantinib or vandetanib enrolled into a cohort of LIBRETTO-001.

The median age was 57 years (range: 17 to 84); 66% were male; 89% were White, 7% were Hispanic/Latino, and 1.8% were Black. ECOG performance status was 0-1 (95%) or 2 (5%) and 98% of patients had metastatic disease. Patients received a median of 2 prior systemic therapies (range 1 – 8). RET mutation status was detected in 82% of patients using NGS (78% tumor samples; 4% blood or plasma), 16% using PCR, and 2% using an unknown test. The protocol excluded patients with synonymous, frameshift or nonsense RET mutations; the specific mutations used to identify and enroll patients are described in Table 18.

Efficacy results for RET-mutant MTC are summarized in Table 19.

Cabozantinib and Vandetanib-naïve RET -Mutant MTC

Efficacy was evaluated in 88 patients with RET-mutant MTC who were cabozantinib and vandetanib treatment-naïve enrolled into a cohort of LIBRETTO-001.

The median age was 58 years (range: 15 to 82) with two patients (2.3%) aged 12 to 16 years; 66% were male; and 86% were White, 4.5% were Asian, and 2.3% were Hispanic/Latino. ECOG performance status was 0-1 (97%) or 2 (3.4%). All patients (100%) had metastatic disease and 18% had received 1 or 2 prior systemic therapies (including 8% kinase inhibitors, 4.5% chemotherapy, 2.3% anti-PD1/PD-L1 therapy, and 1.1% radioactive iodine). RET mutation status was detected in 77.3% of patients using NGS (75.0% tumor samples; 2.3% blood samples), 18.2% using PCR, and 4.5% using an unknown test. The mutations used to identify and enroll patients are described in Table 18.

Efficacy results for cabozantinib and vandetanib-naïve RET-mutant MTC are summarized in Table 20.

LIBRETTO-531

LIBRETTO-531 was a randomized (2:1), multicenter, open-label study (NCT04211337) in adults and adolescents with advance or metastatic RET-mutant MTC. The study evaluated the efficacy of RETEVMO versus physicians’ choice of cabozantinib or vandetanib in patients with progressive, advanced, kinase inhibitor naïve, RET-mutant medullary thyroid cancer.

Patients were randomized to receive either RETEVMO (160 mg twice daily) or physicians’ choice of cabozantinib (140 mg once daily) or vandetanib (300 mg once daily). Patients were stratified based on RET mutation (M918T vs. other) and intended treatment if randomized to the control arm (cabozantinib vs. vandetanib). The primary outcome was progression-free survival (PFS), as determined by a blinded independent review committee (BIRC) according to RECIST v1.1.

The median age was 55 years (range: 12 to 84), 63% were male, 58% were White, 23% were Asian, 2.4% were Black or African American, and 17% had unknown race. ECOG performance status was 0-1 (98%) or 2 (1.0%) with 0.7% unknown status. 77% of patients had metastatic disease and 6 patients (2.1%) had received 1 prior systemic therapy. RET mutation status was detected in 90% of patients using NGS (89% tumor samples; 8% blood or plasma), and 10% using PCR. Of patients enrolled in LIBRETTO-531, 63% had M918T RET mutations and 37% had other RET mutations.

Efficacy results for LIBRETTO-531 based on the preplanned interim efficacy analysis are provided in Table 21 and Figure 2. At the time of this analysis, overall survival data were immature with 18 deaths observed (14% of pre-specified events).

Patient-reported overall side effect impact was evaluated weekly in 222 patients (RETEVMO N = 145; cabozantinib or vandetanib N=77) who received at least one dose of treatment by at least 6 months prior to the data cutoff date and responded to the Functional Assessment of Cancer Therapy item GP5 (FACT GP5). Patient-reported overall side effect impact was derived as a proportion of time on treatment with high side effect bother (defined as response of 3 “Quite a bit” or 4 “Very much”) per FACT GP5.

Patient-reported overall side effect impact results for LIBRETTO-531 are provided in Table 22.

Patient-reported overall side effect impact results were supported by a lower incidence of treatment discontinuation due to adverse reactions for RETEVMO (4.7%) compared to cabozantinib or vandetanib (27%) in patients who received at least one dose of study treatment. The median time on treatment at the data cutoff was 14.5 months in the RETEVMO arm and 8.3 months in the cabozantinib or vandetanib arm in patients who received at least one dose of study treatment.

LIBRETTO-001

The efficacy of RETEVMO was evaluated in patients with advanced RET fusion-positive thyroid cancer enrolled in a multicenter, open-label, multi-cohort clinical trial (LIBRETTO-001, NCT03157128). Efficacy was evaluated in 65 patients with RET fusion-positive thyroid cancer who were radioactive iodine (RAI)-refractory (if RAI was an appropriate treatment option) and were systemic therapy naïve and patients who were previously treated, in separate cohorts.

The median age was 59 years (range 20 to 88); 49% were male; 65% were White, 20% were Asian, 4.6% were Black or African American; and 11% were Hispanic/Latino. ECOG performance status was 0-1 (94%) or 2 (6%). All (100%) patients had metastatic disease with primary tumor histologies including papillary thyroid cancer (83%), poorly differentiated thyroid cancer (9%), anaplastic thyroid cancer (6%) and Hurthle cell thyroid cancer (1.5%). Previously treated patients had received a median of 1 prior therapy (range 1–4). RET fusion-positive status was detected in 97% of patients using NGS (89% tumor samples; 8% blood or plasma samples), and 3% using other local testing methods.

Efficacy results for RET fusion-positive thyroid cancer are summarized in Table 24.

Responses were observed in patients with each histology represented, including 3 of 4 patients with anaplastic thyroid cancer (all partial responses) and 6 of 6 patients with poorly differentiated thyroid cancer (1 complete response, 5 partial responses).

LIBRETTO-121

The efficacy of RETEVMO was evaluated in pediatric and young adult patients with advanced RET-activated solid tumors enrolled in a multicenter, open-label, multi-cohort clinical trial (LIBRETTO-121, NCT03899792) [see Clinical Studies (14.2)].

Efficacy was evaluated in 15 patients with RET fusion-positive thyroid cancer who were non-responsive to available therapies or had no standard systemic curative therapy available. The median age was 12 years (range 6 to 20); 53% were male; 40% were White, 47% were Asian, 13% were other races; and 27% were Hispanic/Latino. Patients had metastatic (87%) or locally advanced (13%) disease and 100% had papillary thyroid cancer histology; 47% had measurable disease at baseline; 20% had received prior systemic therapy. RET fusion-positive status was detected in 93% of patients using NGS tumor samples and in 7% using FISH. Efficacy results for RET fusion-positive thyroid cancer in pediatric and young adult patients are summarized in Table 25.

LIBRETTO-001

The efficacy of RETEVMO was evaluated in patients with locally advanced or metastatic RET fusion-positive solid tumors enrolled in a multicenter, open-label, multi-cohort clinical trial (LIBRETTO-001, NCT03157128). Efficacy was evaluated in 41 patients with RET fusion-positive tumors other than NSCLC and thyroid cancer with disease progression on or following prior systemic treatment or who had no satisfactory alternative treatment options.

The median age was 50 years (range 21 to 85), 54% were female, 68% were White, 24% were Asian, and 4.9% were Black; and 7% were Hispanic/Latino. ECOG performance status was 0-1 (95%) or 2 (5%) and 95% of patients had metastatic disease. Thirty-seven patients (90%) received prior systemic therapy (median 2 [range 0 – 9]; 32% received 3 or more). The most common cancers were pancreatic adenocarcinoma (27%), colorectal (24%), salivary (10%) and unknown primary (7%). RET fusion-positive status was detected in 97.6% of patients using NGS and 2.4% using FISH.

Efficacy results for RET fusion-positive solid tumors other than NSCLC and thyroid cancer are summarized in Table 26 and Table 27.

LIBRETTO-121

The efficacy of RETEVMO was evaluated in pediatric and young adult patients with advanced RET-activated solid tumors enrolled in a multicenter, open-label, multi-cohort clinical trial (LIBRETTO-121, NCT03899792) [see Clinical Studies (14.2)].

Efficacy was evaluated in 3 patients with locally advanced refractory RET-fusion positive other solid tumors who were unresponsive to available therapies or had no standard systemic curative therapy available. The median age was 15 years (range 6 to 15). One patient with congenital infantile fibrosarcoma and one patient with a spindle cell sarcoma had a partial response. One patient with malignant peripheral nerve sheath tumor did not respond. Responses were observed in patients with RET fusion-positive thyroid cancer [see Clinical Studies (14.3)].