Retevmo (Selpercatinib)

RETEVMO^® is a kinase inhibitor indicated for the treatment of:

• Adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with a
  rearranged during transfection (RET)
  gene fusion, as detected by an FDA-approved test (
  1.1

  RET

  Fusion-Positive Non-Small Cell Lung Cancer

  RETEVMO^®is indicated for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with a

  rearranged during transfection (RET)

  gene fusion, as detected by an FDA-approved test.
  )
• Adult and pediatric patients 2 years of age and older with advanced or metastatic medullary thyroid cancer (MTC) with a
  RET
  mutation, as detected by an FDA-approved test, who require systemic therapy (
  1.2

  RET

  -Mutant Medullary Thyroid Cancer

  RETEVMO is indicated for the treatment of adult and pediatric patients 2 years of age and older with advanced or metastatic medullary thyroid cancer (MTC) with a

  RET

  mutation, as detected by an FDA-approved test, who require systemic therapy.
  )
• Adult and pediatric patients 2 years of age and older with advanced or metastatic thyroid cancer with a RET gene fusion, as detected by an FDA-approved test, who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate) (
  1.3

  RET

  Fusion-Positive Thyroid Cancer

  RETEVMO is indicated for the treatment of adult and pediatric patients 2 years of age and older with advanced or metastatic thyroid cancer with a

  RET

  gene fusion, as detected by an FDA-approved test, who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate).
  )
• Adult and pediatric patients 2 years of age and older with locally advanced or metastatic solid tumors with a RET gene fusion, as detected by an FDA-approved test, that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options¹ (
  1.4 Other

  RET

  Fusion-Positive Solid Tumors

  RETEVMO is indicated for the treatment of adult and pediatric patients 2 years of age and older with locally advanced or metastatic solid tumors with a

  RET

  gene fusion, as detected by an FDA-approved test, that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options.

  This indication is approved under accelerated approval based on overall response rate and duration of response

  [see Clinical Studies ]

  . Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).
  )

¹ 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).

• Select patients for treatment with RETEVMO based on the presence of a
  RET
  gene fusion (NSCLC, thyroid, or other solid tumors) or specific
  RET
  gene mutation (MTC). (
  2.1 Patient Selection

  Select patients for treatment with RETEVMO based on the presence of a

  RET

  gene fusion (NSCLC, thyroid cancer, or other solid tumors) or specific

  RET

  gene mutation (MTC) in tumor specimens

  [see Clinical Studies ]

  . Information on FDA-approved test(s) for the detection of

  RET

  gene fusions and

  RET

  gene mutations is available at: http://www.fda.gov/CompanionDiagnostics. An FDA-approved companion diagnostic test for the detection of

  RET

  gene fusions and

  RET

  gene mutations in plasma is not available.
  ,
  14 CLINICAL STUDIES

  14.1

  RET

  Fusion-Positive Non-Small Cell Lung Cancer

  LIBRETTO-001

  The efficacy of RETEVMO was evaluated in patients with advanced

  RET

  fusion-positive NSCLC enrolled in a multicenter, open-label, multi-cohort clinical trial (LIBRETTO-001, NCT03157128). The study enrolled patients with advanced or metastatic

  RET

  fusion-positive NSCLC who had progressed on platinum-based chemotherapy and patients with locally advanced (stage III who were not candidates for surgical resection or definitive chemoradiation) or metastatic NSCLC without prior systemic therapy in separate cohorts. Identification of a

  RET

  gene alteration was prospectively determined in local laboratories using next generation sequencing (NGS), polymerase chain reaction (PCR), fluorescence in situ hybridization (FISH) or other local testing methods. Adult patients received RETEVMO 160 mg orally twice daily until unacceptable toxicity or disease progression; patients enrolled in the dose escalation phase were permitted to adjust their dose to 160 mg twice daily. The major efficacy outcome measures were confirmed overall response rate (ORR) and duration of response (DOR), as determined by a blinded independent review committee (BIRC) according to RECIST v1.1.

  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.

  Table 15: Efficacy Results in LIBRETTO-001 (RET Fusion-Positive NSCLC Previously Treated with Platinum Chemotherapy)

  1Confirmed overall response rate assessed by BIRC.
  2Based on observed duration of response.
  NE = not estimable
  	RETEVMO (n = 247)
  Overall Response Rate1(95% CI)	61% (55%, 67%)
  Complete response	7.3%
  Partial response	54%
  Duration of Response
  Median in months (95% CI)	28.6 (20, NE)
  % with ≥ 12 months2	63%

  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.

  Table 16: Efficacy Results in LIBRETTO-001 (Treatment-Naïve RET Fusion-Positive NSCLC)

  1Confirmed overall response rate assessed by BIRC.
  2Based on observed duration of response.
  NE = not estimable
  	RETEVMO (n =69)
  Overall Response Rate1(95% CI)	84% (73%, 92%)
  Complete response	5.8%
  Partial response	78%
  Duration of Response
  Median in months (95% CI)	20.2 (13, NE)
  % with ≥ 12 months2	50%

  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.

  Table 17: Efficacy Results in LIBRETTO-431: RETEVMO versus Chemotherapy with Pembrolizumab

  1Based on the stratified Cox proportional hazard model, stratified by geographic location (East Asia versus elsewhere), brain metastases at baseline according to investigator (presence versus absence or unknown).
  2Based on stratified log-rank test, stratified by geographic location (East Asia versus elsewhere), brain metastases at baseline according to investigator (presence versus absence or unknown).
  3Based on observed duration of response.
  NE = not estimable
  	RETEVMO (n = 129)	Chemotherapy with pembrolizumab (n = 83)
  Progression-Free Survival
  Number (%) of patients with an event	49 (38%)	49 (59%)
  Medians in months (95% CI)	24.8 (16.9, NE)	11.2 (8.8, 16.8)
  Hazard ratio1(95% CI)	0.46 (0.31, 0.70)
  p-value2	0.0002
  Overall Response Rate (95% CI)	84% (76, 90)	65% (54, 75)
  Complete response	7%	6%
  Partial response	77%	59%
  Duration of Response
  Median in months (95% CI) % with ≥ 12 months3	24.2 (17.9, NE) 60%	11.5 (9.7, 23.3) 30%

  Figure 1: Kaplan-Meier Curves of Progression-Free Survival in LIBRETTO-431: RETEVMO versus Chemotherapy with Pembrolizumab

  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.

  

  14.2

  RET

  -Mutant Medullary Thyroid Cancer

  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.

  Table 18: Mutations used to Identify and Enroll Patients with RET-Mutant MTC in LIBRETTO-001

  1Somatic or germline mutations; protein change.
  2Extracellular cysteine mutations involving cysteine residues 609, 611, 618, 620, 630, and 634.
  3Other included: K666N (1), D631_L633delinsV (2), D631_L633delinsE (5), D378_G385delinsE (1), D898_E901del (2), A883F (4), E632_L633del (4), L790F (2), T636_V637insCRT(1), D898_E901del + D903_S904delinsEP (1).
  4One patient also had a M918T mutation.
  RET Mutation Type 1	Previously Treated (n = 55)	Cabozantinib/ Vandetanib Naïve (n = 88)	Total (n = 143)
  M918T	33	49	82
  Extracellular cysteine mutation2	7	20	27
  V804M or V804L	54	6	11
  Other3	10	13	23

  Efficacy results for

  RET-

  mutant MTC are summarized in Table 19.

  Table 19: Efficacy Results in LIBRETTO-001 (RET-Mutant MTC Previously Treated with Cabozantinib or Vandetanib)

  1Confirmed overall response rate assessed by BIRC.
  2Based on observed duration of response.
  NE = not estimable
  	RETEVMO (n = 55)
  Overall Response Rate1(95% CI)	76% (63%, 87%)
  Complete response	18%
  Partial response	58%
  Duration of Response
  Median in months (95% CI)	45.3 (29.9, NE)
  % with ≥12 months2	76%

  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.

  Table 20: Efficacy Results in LIBRETTO-001 (Cabozantinib and Vandetanib-naïve RET-Mutant MTC)

  1Confirmed overall response rate assessed by BIRC.
  2Based on observed duration of response.
  NR = not reached, NE = not estimable
  	RETEVMO (n = 88)
  Overall Response Rate1(95% CI)	81% (71%, 88%)
  Complete response	28%
  Partial response	52%
  Duration of Response
  Median in months (95% CI)	NR (51.3, NE)
  % with ≥12 months2	90%

  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 21and Figure 2. At the time of this analysis, overall survival data were immature with 18 deaths observed (14% of pre-specified events).

  Table 21: Efficacy Results in LIBRETTO-531: RETEVMO versus Cabozantinib or Vandetanib

  Data from the pre-planned interim efficacy analysis.
  1Based on the stratified Cox proportional hazard model.
  2Based on stratified log-rank test.
  NR = Not reached; NE = not evaluable
  	RETEVMO N = 193	Cabozantinib or Vandetanib N = 98
  PFS
  Number (%) of patients with an event	26 (14%)	33 (34%)
  Median in months (95% CI)	NR (NE, NE)	16.8 (12.2, 25.1)
  Hazard ratio (95% CI)1	0.280 (95% CI: 0.165, 0.475)
  p-value2	<0.0001
  Overall Response Rate
  ORR (95% CI)	69% (62%, 76%)	39% (29%, 49%)
  Complete response	12%	4%
  Partial response	58%	35%
  Duration of Response
  Median in months (95% CI)	NR (NE, NE)	16.6 (10.4, NE)
  Median follow-up time (months)	11.1	12.8

  Figure 2: Kaplan-Meier Curves of Progression-Free Survival in LIBRETTO-531: RETEVMO versus Cabozantinib or Vandetanib

  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.

  Table 22. Descriptive Summary of Patient-reported Overall Side Effect Impact While on Treatment in LIBRETTO-531

  	RETEVMO (N=145)	Cabozantinib or Vandetanib (N=77)
  Mean proportion of time with high side effect bother (95% CI)	8% (4.8%, 10%)	24% (17%, 31%)
  % Patients with high side effect bother 0% of time ≤25% of time	61% 90%	30% 66%

  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-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). Patients received RETEVMO 92 mg/m²orally twice daily until disease progression, unacceptable toxicity, or other reason for treatment discontinuation. Tumor assessments were performed every 8 weeks for one year, then every 12 weeks; responses were assessed according to RECIST 1.1 per BIRC.

  Efficacy was evaluated in 14 patients with

  RET

  -mutant MTC who were non-responsive to available therapies or had no standard systemic curative therapy available. The median age was 14 years (range 2 to 20); 64% were male; 71% were White, 14% were Black or African American; and 14% were Hispanic/Latino. Patients had metastatic (71%) or locally advanced (29%) disease; 43% had measurable disease at baseline; 21% had received prior systemic therapy.

  RET

  -mutant status was detected in 79% of patients using NGS tumor samples and in 21% using PCR.

  Efficacy results for

  RET-

  mutant MTC in pediatric and young adult patients are summarized in Table 23.

  Table 23: Efficacy Results in LIBRETTO-121 (RET-Mutant MTC)

  1Confirmed overall response rate assessed by BIRC.
  2Based on observed duration of response.
  + Denotes ongoing response.
  	RETEVMO (n = 14)
  Overall Response Rate 1 (95% CI)	57% (29, 82)
  Complete response	36%
  Partial response	21%
  Duration of Response
  Median in months (range)	Not reached (8.3+, 49.7+)
  % with ≥ 18 months2	88%
  % with ≥ 24 months2	75%

  14.3

  RET

  Fusion-Positive Thyroid Cancer

  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.

  Table 24: Efficacy Results in LIBRETTO-001 (RET Fusion-Positive Thyroid Cancer)

  1Confirmed overall response rate assessed by BIRC.
  2Based on observed duration of response.
  NE = not estimable
  	RETEVMO Previously Treated (n = 41)	RETEVMO Systemic Therapy Naïve (n = 24)
  Overall Response Rate 1 (95% CI)	85% (71%, 94%)	96% (79%, 100%)
  Complete response	12%	21%
  Partial response	73%	75%
  Duration of Response
  Median in months (95% CI)	26.7 (12.1, NE)	NE (42.8, NE)
  % with ≥12 months2	54	65

  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 ].

  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.

  Table 25: Efficacy Results in LIBRETTO-121 (RET Fusion-Positive Thyroid Cancer)

  1Confirmed overall response rate assessed by BIRC.
  2Based on observed duration of response.
  + Denotes ongoing response.
  	RETEVMO (n = 15)
  Overall Response Rate 1 (95% CI)	53% (27, 79)
  Complete response	27%
  Partial response	27%
  Duration of Response
  Median in months (range)	Not reached (12.9+, 44.2)
  % with ≥ 18 months2	88%
  % with ≥ 24 months2	75%

  14.4 Other

  RET

  Fusion-Positive Solid Tumors

  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 26and Table 27.

  Table 26: Efficacy Results in LIBRETTO-001 (Other RET Fusion-Positive Solid Tumors)

  1Confirmed overall response rate assessed by BIRC.
  2Based on observed duration of response.
  NE = not estimable
  	RETEVMO (n = 41)
  Overall Response Rate 1 (95% CI)	44% (28, 60)
  Complete response	4.9%
  Partial response	39%
  Duration of Response
  Median in months (95% CI)	24.5 (9.2, NE)
  % with ≥6 months2	67%

  Table 27: Efficacy Results by Tumor Type in LIBRETTO-001 (Other RET Fusion-Positive Solid Tumors)

  + denotes ongoing response.
  1Confirmed overall response rate assessed by BIRC.
  2Best overall response for each patient is presented for tumor types with ≤2 patients.
  CI = confidence interval, CR = complete response, DOR = duration of response, NA = not applicable, NE = not evaluable, ORR = overall response rate, PR = partial response, SD = stable disease.
  Tumor Type	Patients (n = 41)	ORR 1,2		DOR Range (months)
  		n (%)	95% CI
  Pancreatic adenocarcinoma	11	6 (55%)	(23, 83)	2.5, 38.3+
  Colorectal	10	2 (20%)	(2.5, 56)	5.6, 13.3
  Salivary	4	2 (50%)	(7, 93)	5.7, 28.8+
  Unknown primary	3	1 (33%)	(0.8, 91)	9.2
  Breast	2	PR, CR	NA	2.3+, 17.3
  Sarcoma (soft tissue)	2	PR, SD	NA	14.9+
  Xanthogranuloma	2	NE, NE	NA	NA
  Carcinoid (bronchial)	1	PR	NA	24.1+
  Carcinoma of the skin	1	NE	NA	NA
  Cholangiocarcinoma	1	PR	NA	5.6+
  Ovarian	1	PR	NA	14.5+
  Pulmonary carcinosarcoma	1	NE	NA	NA
  Rectal neuroendocrine	1	NE	NA	NA
  Small intestine	1	CR	NA	24.5

  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 ].

  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 ].
  )
• Adult and adolescent patients 12 years of age or older
  :
  
  the recommended dosage is based on weight (
  2.3 Recommended Dosage

  The recommended dosage of RETEVMO administered as recommended

  [see Dosage and Administration ]

  given until disease progression or unacceptable toxicity is shown in Table 1:

  Table 1: Recommended RETEVMO Dosage

  Population	RETEVMO Dosage
  Adult and adolescent patients 12 years of age or older based on body weight
  Less than 50 kg	120 mg twice daily
  50 kg or greater	160 mg twice daily
  Pediatric patients 2 to less than 12 years of age based on body surface area
  0.33 to 0.65 m2	40 mg three times daily
  0.66 to 1.08 m2	80 mg twice daily
  1.09 to 1.52 m2	120 mg twice daily
  ≥1.53 m2	160 mg twice daily
  Dosing pediatric patients with body surface area less than 0.33 m2is not recommended

  Missed Dose

  Do not take a missed dose unless it is more than 6 hours until next scheduled dose.

  Vomiting

  If vomiting occurs after RETEVMO administration, do not take an additional dose and continue to the next scheduled time for the next dose.
  ):
  • Less than 50 kg: 120 mg orally twice daily
  • 50 kg or greater: 160 mg orally twice daily
• Pediatric patients 2 to less than 12 years of age:
  
  
  the recommended dosage is based on body surface area (
  2.3 Recommended Dosage

  The recommended dosage of RETEVMO administered as recommended

  [see Dosage and Administration ]

  given until disease progression or unacceptable toxicity is shown in Table 1:

  Table 1: Recommended RETEVMO Dosage

  Population	RETEVMO Dosage
  Adult and adolescent patients 12 years of age or older based on body weight
  Less than 50 kg	120 mg twice daily
  50 kg or greater	160 mg twice daily
  Pediatric patients 2 to less than 12 years of age based on body surface area
  0.33 to 0.65 m2	40 mg three times daily
  0.66 to 1.08 m2	80 mg twice daily
  1.09 to 1.52 m2	120 mg twice daily
  ≥1.53 m2	160 mg twice daily
  Dosing pediatric patients with body surface area less than 0.33 m2is not recommended

  Missed Dose

  Do not take a missed dose unless it is more than 6 hours until next scheduled dose.

  Vomiting

  If vomiting occurs after RETEVMO administration, do not take an additional dose and continue to the next scheduled time for the next dose.
  ):
  • 0.33 m² to 0.65 m²: 40 mg orally three times daily
  • 0.66 m² to 1.08 m²: 80 mg orally twice daily
  • 1.09 m² to 1.52 m²: 120 mg orally twice daily
  • ≥1.53 m²: 160 mg orally twice daily
• For patients who cannot swallow, disperse 40 mg RETEVMO tablets and administer orally or via gastrostomy or nasogastric tube (
  2.8 Alternative Administration for Patients Unable to Swallow Tablets or Capsules

  For patients unable to swallow whole capsules or tablets, the 40 mg tablet may be dispersed and administered orally or via gastrostomy or nasogastric tube. Use only the 40 mg tablet to make the dispersion.

  RETEVMO 40 mg tablets for Oral Administration

  To prepare RETEVMO tablet as a dispersion:

  • In a glass or medicine cup, add the correct number of 40 mg RETEVMO tablets required for the prescribed dose (1, 2, 3, or 4 tablets), to approximately 1 tablespoon (15 mL) of room temperature or chilled water or 100% carrot puree.
  • Stir intermittently until tablet(s) have dispersed (approximately 7 to 10 minutes). Some settling may occur and the dispersion may appear cloudy if water is used.
  • Administer the entire dispersion immediately.
  • Add 1 tablespoon (15 mL) of water to the glass or medicine cup, swirl or stir to collect any remaining medicine and administer immediately.
  • Discard RETEVMO dispersion if not taken within 2 hours.

  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.

  • In a glass or medicine cup, add the correct number of 40 mg RETEVMO tablet(s) required for the prescribed dose (1, 2, 3, or 4 tablets), to a minimum of 10 mL of room temperature water.
  • Stir intermittently until tablet(s) have dispersed (approximately 7 to 10 minutes). Some settling may occur and the dispersion may appear cloudy.
  • Flush the feeding tube according to manufacturer's instructions.
  • Draw the dispersion into an enteral syringe and administer the dispersion via the feeding tube immediately.
  • Add 5 mL of water to the glass or medicine cup, swirl or stir to collect any remaining medicine, and deliver this rinse via the feeding tube using the same syringe.
  • Repeat rinse as necessary to ensure full dose is delivered.
  • Flush the feeding tube according to manufacturer's instructions.
  • Discard RETEVMO dispersion if not taken within 2 hours.
  )
• Only RETEVMO 40 mg tablets may be used to create the dispersion (
  2.2 Important Administration Instructions

  • RETEVMO may be taken with or without food unless coadministered with a proton pump inhibitor (PPI)
    [see Dosage and Administration ]
    .
  • Swallow the capsule or tablet whole. Do not crush or chew the capsules or tablets.
  • For patients unable to swallow capsules or tablets or who are using a feeding tube, prepare and administer RETEVMO as a dispersion; only RETEVMO 40 mg tablets may be used to create the dispersion
    [see Dosage and Administration ]
  )
• Reduce RETEVMO dose in patients with severe hepatic impairment. (
  2.7 Dosage Modification for Severe Hepatic Impairment

  Reduce the recommended dosage of RETEVMO for patients with severe hepatic impairment as recommended in Table 5

  [see Use in Specific Populations ]

  .

  Table 5: Recommended RETEVMO Dosage for Severe Hepatic Impairment

  Current RETEVMO Dosage	Recommended RETEVMO Dosage
  40 mg orally three times daily	40 mg orally twice daily
  80 mg orally twice daily	40 mg orally twice daily
  120 mg orally twice daily	80 mg orally twice daily
  160 mg orally twice daily	80 mg orally twice daily
  ,
  8.7 Hepatic Impairment

  Reduce the dose when administering RETEVMO to patients with severe [total bilirubin > 3 to 10 × upper limit of normal (ULN) and any AST] hepatic impairment

  [see Dosage and Administration ]

  .

  No dosage modification is recommended for patients with mild (total bilirubin ≤ ULN with AST > ULN or total bilirubin > 1 to 1.5 × ULN with any AST) or moderate (total bilirubin > 1.5 to 3 × ULN and any AST) hepatic impairment.

  Monitor for RETEVMO-related adverse reactions in patients with hepatic impairment

  [see Clinical Pharmacology ]

  .
  )

Capsules:

• 40 mg: gray opaque capsule imprinted with “Lilly”, “3977” and “40 mg” in black ink.
• 80 mg: blue opaque capsule imprinted with “Lilly”, “2980” and “80 mg” in black ink.

Tablets:

• 40 mg: light gray, film coated, round tablet debossed with “Ret 40” on one side and “5340” on the other side.
• 80 mg: dark red-purple, film coated, round tablet debossed with “Ret 80” on one side and “6082” on the other side.
• 120 mg: light purple, film coated, round tablet debossed with “Ret 120” on one side and “6120” on the other side.
• 160 mg: light pink, film coated, round tablet debossed with “Ret 160” on one side and “5562” on the other side.

• Lactation: Advise not to breastfeed.
  (
  8.2 Lactation

  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.
  )
• Pediatric Use:
  Monitor open growth plates in pediatric patients. Consider interrupting or discontinuing RETEVMO if abnormalities occur. (
  8.4 Pediatric Use

  The safety and effectiveness of RETEVMO have been established in pediatric patients aged 2 years and older for the treatment of:

  • advanced or metastatic medullary thyroid cancer (MTC) with a
    RET
    mutation who require systemic therapy
  • advanced or metastatic thyroid cancer with a
    RET
    gene fusion who require systemic therapy and are radioactive iodine-refractory (if radioactive iodine is appropriate)
  • locally advanced or metastatic solid tumors with a
    RET
    gene fusion that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options.

  Use of RETEVMO for these indications is supported by evidence from adequate and well-controlled studies in adult and pediatric patients with additional pharmacokinetic and safety data in pediatric patients aged 2 years and older

  [see Adverse Reactions , Clinical Pharmacology , Clinical Studies ]

  . The predicted exposures of selpercatinib in pediatric patients at the recommended dosages were within the range of values observed in patients ≥ 12 years and ≥ 50 kg in body weight receiving the approved recommended dosage of 160 mg twice daily

  [see Clinical Pharmacology ]

  .

  The safety and effectiveness of RETEVMO have not been established in these indications in patients aged less than 2 years.

  The safety and effectiveness of RETEVMO have not been established in pediatric patients for other indications

  [see Indications and Usage ]

  .

  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.
  )