On May 8, 2020, the FDA granted accelerated approval to selpercatinib for (i) adult patients with metastatic RET fusion–positive non–small cell lung cancer (NSCLC), (ii) adult and pediatric patients ≥12 years of age with advanced or metastatic RET-mutant medullary thyroid cancer who require systemic therapy, and (iii) adult and pediatric patients ≥12 years of age with advanced or metastatic RET fusion–positive thyroid cancer who require systemic therapy and who are radioactive iodine refractory (if radioactive iodine is appropriate). Approval was granted on the basis of the clinically important effects on the overall response rate (ORR) with prolonged duration of responses observed in a multicenter, open-label, multicohort clinical trial (LIBRETTO-001, NCT03157128) in patients whose tumors had RET alterations. ORRs within the approved patient populations ranged from 64% [95% confidence interval (CI), 54–73] in prior platinum-treated RET fusion–positive NSCLC to 100% (95% CI, 63–100) in systemic therapy–naïve RET fusion–positive thyroid cancer, with the majority of responders across indications demonstrating responses of at least 6 months. The product label includes warnings and precautions for hepatotoxicity, hypertension, QT interval prolongation, hemorrhagic events, hypersensitivity, risk of impaired wound healing, and embryo-fetal toxicity. This is the first approval of a drug specifically for patients with RET alterations globally.

Alterations in the gene encoding the receptor tyrosine kinase RET are recognized as oncogenic drivers in different cancers. Although some approved kinase inhibitors demonstrate activity against RET, prior to the approval of selpercatinib, there were no approved therapies specifically for patients with RET alterations. RET alterations with oncogenic potential consist of fusions and point mutations. RET fusions occur most frequently in non–small cell lung cancer (NSCLC, 1%–2%) and papillary thyroid cancer (5%–10%; refs. 1, 2). Somatic RET mutations occur in approximately 50% of sporadic cases of medullary thyroid cancer (MTC), most commonly the M918T mutation (3–5). Identifiable germline mutations, including M918T, extracellular cysteine mutations, and V804M mutations, have been reported in up to 98% of familial cases, which include the hereditary syndromes multiple endocrine neoplasia types 2A and 2B (1, 4, 6). V804M mutations have been described as associated with resistance to some multikinase inhibitors (7).

Prior to the approval of selpercatinib, standard therapies for patients with RET fusion–positive metastatic NSCLC, advanced or metastatic RET-mutant MTC, and advanced or metastatic RET fusion–positive thyroid cancer were the same as therapies available for patients with these tumor types without molecularly defined disease. Table 1 outlines these diseases and available therapies for patients with these diseases (8–25).

Table 1.

Summary of conditions and available therapies.

DiseaseAnalysis of conditionCurrent treatment options
RET fusion–positive NSCLC The 5-year survival for patients with metastatic NSCLC is less than 5%; there is no randomized trial data available regarding survival specifically for patients with RET fusion–positive metastatic NSCLC. (8) Prior to the approval of selpercatinib, there were no approved therapies specifically for patients with RET fusion–positive NSCLC. Treatment options for these patients was consistent with first-line systemic therapy of an unselected population of patients with NSCLC or nonsquamous NSCLC [i.e., chemotherapy and/or anti–PD-(L)1 antibody]. The highest ORRs, 48% and 58%, have been reported for platinum-based chemotherapy plus pembrolizumab (regardless of histology) and platinum-based chemotherapy plus atezolizumab and bevacizumab (nonsquamous NSCLC), respectively. (9, 10) 
  In the second line, there are several therapeutic options for patients with metastatic NSCLC, with a maximum ORR of 23% (ramucirumab/docetaxel). (11) Other options include single-agent chemotherapy or single-agent immunotherapy. 
RET-mutant MTC Medullary thyroid cancer accounts for 3%–4% of all thyroid cancers. (12) Although relative survival for patients with MTC is 80% at 5 years, 5-year relative survival for patients with stage IV disease is approximately 40%. (13) Cabozantinib and vandetanib are approved for patients with advanced or metastatic, progressive, or symptomatic MTC regardless of RET status, although subgroup analyses suggest improved response in patients with RET mutations or M918T mutations specifically. (14, 15) These products inhibit RET in addition to other kinases. The ORRs for vandetanib and cabozantinib as evaluated in the studies to support approval were 45% and 27%, respectively. (16, 17) 
RET fusion–positive thyroid cancer RET fusions can occur in thyroid cancer of multiple histologies including differentiated thyroid cancers (DTC), poorly differentiated thyroid cancer (PDTC), and anaplastic thyroid cancer (ATC). (18) Up to 30% of patients with DTC experience recurrence; in patients with distant metastases, 5-year survival is 50%, regardless of tumor histology. (19, 20) PDTC comprises 2%–3% of thyroid malignancies in North America and carries an intermediate prognosis compared with DTC and ATC. (21) ATC is a more aggressive form of thyroid cancer, and these patients have a median survival of 5 months and a 1-year survival rate of 20%. (22) Approved treatment options for patients with advanced RET fusion–positive thyroid cancer not amenable to local therapy include radioactive iodine (if appropriate based on the underlying histology), lenvatinib and sorafenib for patients with DTC that is RAI refractory, and doxorubicin (approved for thyroid carcinoma). There are no approved treatment options for PDTC, and postsurgical treatment may include radioactive iodine, or external beam radiation. (22) 
  The ORR demonstrated in the studies supporting the approvals of lenvatinib and sorafenib in patients with RAI-refractory DTC were 65% and 12%, respectively. (23, 24) Results reported in patients receiving doxorubicin concomitantly with radiation in patients with ATC are variable but include few long-term survivors; regimens including taxanes have also been used in ATC. (22, 25) 
DiseaseAnalysis of conditionCurrent treatment options
RET fusion–positive NSCLC The 5-year survival for patients with metastatic NSCLC is less than 5%; there is no randomized trial data available regarding survival specifically for patients with RET fusion–positive metastatic NSCLC. (8) Prior to the approval of selpercatinib, there were no approved therapies specifically for patients with RET fusion–positive NSCLC. Treatment options for these patients was consistent with first-line systemic therapy of an unselected population of patients with NSCLC or nonsquamous NSCLC [i.e., chemotherapy and/or anti–PD-(L)1 antibody]. The highest ORRs, 48% and 58%, have been reported for platinum-based chemotherapy plus pembrolizumab (regardless of histology) and platinum-based chemotherapy plus atezolizumab and bevacizumab (nonsquamous NSCLC), respectively. (9, 10) 
  In the second line, there are several therapeutic options for patients with metastatic NSCLC, with a maximum ORR of 23% (ramucirumab/docetaxel). (11) Other options include single-agent chemotherapy or single-agent immunotherapy. 
RET-mutant MTC Medullary thyroid cancer accounts for 3%–4% of all thyroid cancers. (12) Although relative survival for patients with MTC is 80% at 5 years, 5-year relative survival for patients with stage IV disease is approximately 40%. (13) Cabozantinib and vandetanib are approved for patients with advanced or metastatic, progressive, or symptomatic MTC regardless of RET status, although subgroup analyses suggest improved response in patients with RET mutations or M918T mutations specifically. (14, 15) These products inhibit RET in addition to other kinases. The ORRs for vandetanib and cabozantinib as evaluated in the studies to support approval were 45% and 27%, respectively. (16, 17) 
RET fusion–positive thyroid cancer RET fusions can occur in thyroid cancer of multiple histologies including differentiated thyroid cancers (DTC), poorly differentiated thyroid cancer (PDTC), and anaplastic thyroid cancer (ATC). (18) Up to 30% of patients with DTC experience recurrence; in patients with distant metastases, 5-year survival is 50%, regardless of tumor histology. (19, 20) PDTC comprises 2%–3% of thyroid malignancies in North America and carries an intermediate prognosis compared with DTC and ATC. (21) ATC is a more aggressive form of thyroid cancer, and these patients have a median survival of 5 months and a 1-year survival rate of 20%. (22) Approved treatment options for patients with advanced RET fusion–positive thyroid cancer not amenable to local therapy include radioactive iodine (if appropriate based on the underlying histology), lenvatinib and sorafenib for patients with DTC that is RAI refractory, and doxorubicin (approved for thyroid carcinoma). There are no approved treatment options for PDTC, and postsurgical treatment may include radioactive iodine, or external beam radiation. (22) 
  The ORR demonstrated in the studies supporting the approvals of lenvatinib and sorafenib in patients with RAI-refractory DTC were 65% and 12%, respectively. (23, 24) Results reported in patients receiving doxorubicin concomitantly with radiation in patients with ATC are variable but include few long-term survivors; regimens including taxanes have also been used in ATC. (22, 25) 

The FDA granted accelerated approval to selpercatinib on May 8, 2020, for the following indications:

  • (i) Adult patients with metastatic RET fusion–positive NSCLC;

  • (ii) Adult and pediatric patients ≥12 years of age with advanced or metastatic RET-mutant MTC who require systemic therapy;

  • (iii) Adult and pediatric patients ≥12 years of age with advanced or metastatic RET fusion–positive thyroid cancer who require systemic therapy and who are radioactive iodine (RAI) refractory (if RAI is appropriate; ref. 26).

Herein, we provide a summary of the FDA's review of the marketing application that led to approval of selpercatinib.

Breakthrough therapy designation was granted to selpercatinib in 2018 for the treatment of patients with metastatic RET fusion–positive NSCLC, RET-mutant MTC, and RET fusion–positive thyroid cancer based on early efficacy data from the first-in-human study of selpercatinib, LIBRETTO-001 (27). The FDA met with Loxo Oncology Inc. (now a fully owned subsidiary of Eli Lilly and Company) through several multidisciplinary meetings in 2018 and 2019 to discuss the contents of the new drug application (NDA) and the design of potential confirmatory trials. The NDA was submitted on December 4, 2019, and was granted priority review. The application utilized the Assessment Aid, a voluntary submission from the applicant to facilitate FDA's assessment (28).

Selpercatinib is a kinase inhibitor that inhibits wild-type RET and multiple mutated RET isoforms as well as VEGFR1 and VEGFR3 with IC50 values ranging from 0.92 to 67.8 nmol/L (26, 29). In other types of in vitro enzyme assays, selpercatinib also inhibited FGFR 1, 2, and 3 at higher concentrations (26, 29). In cellular assays, selpercatinib inhibited RET at approximately 60-fold lower concentrations than FGFR1 and 2 and approximately 8-fold lower concentrations than VEGFR3 (26, 29).

Certain point mutations in RET or chromosomal rearrangements involving in-frame fusions of RET with various partners can result in constitutive activation of the kinase, acting as oncogenic drivers by promoting cell proliferation of tumor cell lines (26). In in vitro and in vivo tumor models, selpercatinib demonstrated antitumor activity in cells harboring constitutive activation of RET proteins resulting from gene mutations and fusions, including RET V804M, RET M918T, CCDC6-RET, and KIF5B-RET (26).

The FDA reviewed subject-level data collected in the pivotal trial and several healthy volunteer studies to characterize pharmacokinetics, pharmacodynamics, food effect, and drug–drug interactions. Following oral administration in healthy volunteers, the half-life is 32 hours (29). The approved dose of selpercatinib is 160 mg twice daily for patients with a body weight of at least 50 kg, and 120 mg twice daily for patients with body weight less than 50 kg. The recommended dose for patients with low body weight was based on simulations (body weight range 29.8–192.3 kg) matching drug exposure to that in patients with a body weight of at least 50 kg and consideration of the exposure–response relationships for efficacy and concentration-dependent QT prolongation.

The product label recommends specific dose modification strategies for concomitant use of selpercatinib with strong and moderate CYP3A inhibitors and acid-reducing agents. The product label recommends monitoring for increased risk of QT interval prolongation for patients who are coadministered strong and moderate CYP3A inhibitors or drugs known to prolong QT interval.

The efficacy of selpercatinib was evaluated in patients with advanced solid tumors with RET fusions and mutations enrolled in a phase I/II single-arm, multicenter, open-label, multicohort clinical trial (LIBRETTO-001, NCT03157128; refs. 30, 31). Identification of a qualifying RET alteration was prospectively determined in local laboratories using next-generation sequencing, PCR, or FISH. 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 (26).

The recommended phase II dose of selpercatinib was 160 mg orally twice daily; selpercatinib was administered until disease progression or unacceptable toxicity. Patients were permitted to continue selpercatinib postprogression at the discretion of the investigator; patients enrolled in the dose-escalation phase were permitted to escalate to the recommended dose of 160 mg orally twice daily.

Disposition and demographics

As of the data cutoff used for safety and efficacy analyses for the NDA, LIBRETTO-001 had enrolled 702 patients. The efficacy populations included the first consecutively enrolled patients in each disease type who had received the appropriate prior therapy as discussed below, received at least one dose of selpercatinib, had been followed for 6 months from the first dose of selpercatinib, and had a qualifying protocol-defined RET mutation or RET fusion. The safety population included all patients who had received at least one dose of selpercatinib.

Metastatic RET fusion–positive NSCLC

Efficacy was evaluated in 105 patients with RET fusion–positive NSCLC previously treated with platinum chemotherapy and 39 patients with RET fusion–positive NSCLC who had not received prior therapy (see Table 2). Patients previously treated with platinum therapy received a median of three prior systemic therapies (range, 1–15); 55% had prior anti–PD-1/PD-L1 therapy. Six percent of previously treated and 10% of treatment-naïve patients were 75 years of age or older. Efficacy results for patients with metastatic RET fusion–positive NSCLC are shown in Table 3 (26). The most common RET fusion partner in patients with NSCLC was CCDC6, followed by NCOA4 (29).

Table 2.

Baseline characteristics and demographics for RET fusion–positive NSCLC, RET-mutant MTC, and RET fusion–positive thyroid cancer efficacy populations.

RET fusion–positive NSCLCRET-mutant MTCRET fusion–positive thyroid cancer
Previously treatedTreatment naïvePreviously treated with cabozantinib or vandetanibCabozantinib and vandetanib naïveRAI refractory (if appropriate)
(N = 105)(N = 39)(N = 55)(N = 88)(N = 27)
Median age (range) 61.0 (23–81) 61.0 (23–86) 57 (17–84) 58 (15–82) 54 (20–88) 
Age group, n (%) 
 <65 years 69 (65.7) 22 (56.4) 37 (67.3) 65 (73.9) 18 (66.6) 
 ≥65 years 36 (34.2) 17 (43.6) 18 (32.7) 23 (26.1) 9 (33.3) 
Sex, n (%) 
 Male 43 (41.0) 17 (43.6) 36 (65.6) 58 (65.9) 14 (51.9) 
 Female 62 (59.0) 22 (56.4) 19 (34.5) 30 (34.1) 13 (48.1) 
Race, n (%) 
 White 55 (52.4) 28 (71.8) 49 (89.1) 75 (85.2) 20 (74.1) 
 Black 5 (4.8) 3 (7.7) 1 (1.8) 1 (1.1) 1 (3.7) 
 Asian 40 (38.1) 7 (17.9) 4 (4.5) 2 (7.4) 
 Other/missing 5 (4.8) 1 (2.6) 5 (9.1) 8 (9.1) 4 (14.8) 
Baseline ECOG, n (%) 
 0 31 (29.5) 19 (48.7) 11 (20.0) 43 (48.9) 8 (29.6) 
 1 72 (68.6) 20 (51.3) 41 (74.5) 42 (47.7) 16 (59.3) 
 2 2 (1.9) 3 (5.5) 3 (3.4) 3 (11.1) 
Smoking history, n (%) 
 Never smoked 75 (71.4) 29 (74.4) 31 (56.4) 49 (55.7) 21 (77.8) 
 Former/current smoker 30 (28.6) 10 (25.6) 23 (41.8) 39 (44.3) 6 (22.2) 
CNS metastases at baseline as determined by investigator, n (%) 
 Yes 38 (36.2) 7 (17.9) — — 7 (25.9) 
 No 67 (63.8) 32 (82.1) — — 20 (74.1) 
RET fusion–positive NSCLCRET-mutant MTCRET fusion–positive thyroid cancer
Previously treatedTreatment naïvePreviously treated with cabozantinib or vandetanibCabozantinib and vandetanib naïveRAI refractory (if appropriate)
(N = 105)(N = 39)(N = 55)(N = 88)(N = 27)
Median age (range) 61.0 (23–81) 61.0 (23–86) 57 (17–84) 58 (15–82) 54 (20–88) 
Age group, n (%) 
 <65 years 69 (65.7) 22 (56.4) 37 (67.3) 65 (73.9) 18 (66.6) 
 ≥65 years 36 (34.2) 17 (43.6) 18 (32.7) 23 (26.1) 9 (33.3) 
Sex, n (%) 
 Male 43 (41.0) 17 (43.6) 36 (65.6) 58 (65.9) 14 (51.9) 
 Female 62 (59.0) 22 (56.4) 19 (34.5) 30 (34.1) 13 (48.1) 
Race, n (%) 
 White 55 (52.4) 28 (71.8) 49 (89.1) 75 (85.2) 20 (74.1) 
 Black 5 (4.8) 3 (7.7) 1 (1.8) 1 (1.1) 1 (3.7) 
 Asian 40 (38.1) 7 (17.9) 4 (4.5) 2 (7.4) 
 Other/missing 5 (4.8) 1 (2.6) 5 (9.1) 8 (9.1) 4 (14.8) 
Baseline ECOG, n (%) 
 0 31 (29.5) 19 (48.7) 11 (20.0) 43 (48.9) 8 (29.6) 
 1 72 (68.6) 20 (51.3) 41 (74.5) 42 (47.7) 16 (59.3) 
 2 2 (1.9) 3 (5.5) 3 (3.4) 3 (11.1) 
Smoking history, n (%) 
 Never smoked 75 (71.4) 29 (74.4) 31 (56.4) 49 (55.7) 21 (77.8) 
 Former/current smoker 30 (28.6) 10 (25.6) 23 (41.8) 39 (44.3) 6 (22.2) 
CNS metastases at baseline as determined by investigator, n (%) 
 Yes 38 (36.2) 7 (17.9) — — 7 (25.9) 
 No 67 (63.8) 32 (82.1) — — 20 (74.1) 

Source: RETEVMO Approval Package (29).

Table 3.

Efficacy results in LIBRETTO-001.

RET fusion–positive NSCLC
Previously treatedTreatment naïve
(N = 105)(N = 39)
Overall response ratea (95% CI) 64% (54%–73%) 85% (70%–94%) 
 Complete response 1.9% 
 Partial response 62% 85% 
Duration of response 
 Median in months (95% CI) 17.5 (12–NE) NE (12–NE) 
 % with 6 monthsb 81 58 
RET-mutant MTC 
 Previously treated Cabozantinib/vandetanib naïve 
 (N = 55) (N = 88) 
Overall response ratea (95% CI) 69% (55%–81%) 73% (62%–82%) 
 Complete response 9% 11% 
 Partial response 60% 61% 
Duration of response 
 Median in months (95% CI) NE (19.1–NE) 22.0 (NE–NE) 
 % with 6 monthsb 76 61 
RET fusion–positive thyroid cancer 
 Previously treated Systemic therapy naïve 
 (N = 19) (N = 8) 
Overall response ratea (95% CI) 79% (54%–94%) 100% (63%–100%) 
 Complete response 5.3% 12.5% 
 Partial response 74% 88% 
Duration of response 
 Median in months (95% CI) 18.4 (7.6–NE) NE (NE–NE) 
 % with 6 monthsb 87 75 
RET fusion–positive NSCLC
Previously treatedTreatment naïve
(N = 105)(N = 39)
Overall response ratea (95% CI) 64% (54%–73%) 85% (70%–94%) 
 Complete response 1.9% 
 Partial response 62% 85% 
Duration of response 
 Median in months (95% CI) 17.5 (12–NE) NE (12–NE) 
 % with 6 monthsb 81 58 
RET-mutant MTC 
 Previously treated Cabozantinib/vandetanib naïve 
 (N = 55) (N = 88) 
Overall response ratea (95% CI) 69% (55%–81%) 73% (62%–82%) 
 Complete response 9% 11% 
 Partial response 60% 61% 
Duration of response 
 Median in months (95% CI) NE (19.1–NE) 22.0 (NE–NE) 
 % with 6 monthsb 76 61 
RET fusion–positive thyroid cancer 
 Previously treated Systemic therapy naïve 
 (N = 19) (N = 8) 
Overall response ratea (95% CI) 79% (54%–94%) 100% (63%–100%) 
 Complete response 5.3% 12.5% 
 Partial response 74% 88% 
Duration of response 
 Median in months (95% CI) 18.4 (7.6–NE) NE (NE–NE) 
 % with 6 monthsb 87 75 

Source: RETEVMO US Product Information (26).

Abbreviation: NE, not estimable.

aConfirmed overall response rate assessed by blinded independent central review.

bBased on observed duration of response.

Among the 105 patients with previously treated RET fusion–positive NSCLC, 11 had measurable central nervous system (CNS) metastases at baseline as assessed by BIRC. No patients received radiotherapy to the brain within 2 months prior to study entry. Responses in intracranial lesions were observed in 10 of these 11 patients; all responders had an intracranial DOR of ≥ 6 months.

RET-mutant MTC

Efficacy was evaluated in 55 patients with RET-mutant advanced MTC previously treated with cabozantinib or vandetanib and 88 patients who had not received prior cabozantinib or vandetanib (see Table 2). The protocol excluded patients with synonymous, frameshift or nonsense RET mutations. RET mutations used to identify and enroll patients are described in Supplementary Table S1 (26). Previously treated patients received a median of two prior systemic therapies (range, 1–8). Among cabozantinib- and vandetanib-naïve patients, 18% had received one or two prior systemic therapies (including 8% kinase inhibitors, 4.5% chemotherapy, 2.3% anti-PD1/PD-L1 therapy, and 1.1% RAI). Eleven percent of previously treated patients and 10% of cabozantinib/vandetanib-naïve patients were ≥ 75 years of age; the MTC efficacy populations included three patients < 18 years of age. Efficacy results for patients with metastatic RET-mutant MTC are shown in Table 3 (26). Responses were observed in patients with M918T mutations, V804M/L mutations, extracellular cysteine mutations, and other mutations (29).

RET fusion–positive thyroid cancer

Efficacy was evaluated in 27 patients with RET fusion–positive thyroid cancer who were RAI refractory (if RAI was an appropriate treatment option) and were systemic therapy naïve or had received sorafenib, lenvatinib, or both (see Table 2; ref. 29). Primary tumor histologies included papillary thyroid cancer (78%), poorly differentiated thyroid cancer (11%), anaplastic thyroid cancer (7%) and Hurthle cell thyroid cancer (4%). Patients had received a median of three prior therapies (range, 1–7). Fifteen percent of patients were 75 years of age or older. Efficacy results for patients with metastatic RET fusion–positive thyroid cancer are shown in Table 3. The most common RET fusion partner in patients with thyroid cancer was CCDC6 (29).

Nonclinical toxicology

In repeat dose studies of oral selpercatinib in rats and minipigs, target organs included the gastrointestinal tract, bone marrow, skin, lung, and reproductive organs. Elevations in liver enzymes and phosphate were also present. These findings were generally consistent with the increased transaminases, gastrointestinal adverse effects, decreases in leukocytes and platelets, and rash observed in the clinical study. Growth plate abnormalities and tooth abnormalities that occurred in both species were not observed in clinical studies but may be relevant to the ongoing pediatric evaluation of selpercatinib (29).

Safety in the intended population

Safety was assessed in 702 patients who received selpercatinib; 65% were exposed for 6 months or longer and 34% were exposed for greater than 1 year (26). Among these patients, 95% received at least one dose of selpercatinib at the recommended dosage of 160 mg orally twice daily.

The most common (≥15%) treatment-emergent adverse reactions (ARs) that occurred on or within 28 days after the last dose of selpercatinib are listed in Table 4; laboratory values are presented in Supplementary Table S3 (26). The most common grade ≥3 ARs were hypertension (18%), alanine aminotransferase (ALT) increased (9%), and aspartate aminotransferase (AST) increased (8%). No major differences in safety trends were identified in a small exploratory analysis of patients with identified germline RET mutations (29).

Table 4.

Adverse reactions (≥15%) in patients who received selpercatinib in LIBRETTO-001.

Selpercatinib
(N = 702)
Adverse reactionGrades 1–4 (%)Grades 3–4 (%)
Gastrointestinal 
 Dry mouth 39 
 Diarrheaa 37 3.4b 
 Constipation 25 0.6b 
 Nausea 23 0.6b 
 Abdominal paina 23 1.9b 
 Vomiting 15 0.3b 
Vascular 
 Hypertension 35 18 
General 
 Fatiguea 35 2b 
 Edemaa 33 0.3b 
Skin   
 Rasha 27 0.7b 
Nervous system 
 Headachea 23 1.4b 
Respiratory 
 Cougha 18 
 Dyspneaa 16 2.3 
Investigations 
 Prolonged QT interval 17 4b 
Blood and lymphatic system 
 Hemorrhagea 15 1.9 
Selpercatinib
(N = 702)
Adverse reactionGrades 1–4 (%)Grades 3–4 (%)
Gastrointestinal 
 Dry mouth 39 
 Diarrheaa 37 3.4b 
 Constipation 25 0.6b 
 Nausea 23 0.6b 
 Abdominal paina 23 1.9b 
 Vomiting 15 0.3b 
Vascular 
 Hypertension 35 18 
General 
 Fatiguea 35 2b 
 Edemaa 33 0.3b 
Skin   
 Rasha 27 0.7b 
Nervous system 
 Headachea 23 1.4b 
Respiratory 
 Cougha 18 
 Dyspneaa 16 2.3 
Investigations 
 Prolonged QT interval 17 4b 
Blood and lymphatic system 
 Hemorrhagea 15 1.9 

Source: RETEVMO US Product Information (26).

aIncludes grouped terms. See Supplementary Table S2 for further information.

bOnly includes a grade 3 adverse reaction.

Permanent discontinuation due to an AR occurred in 5% of patients who received selpercatinib, including increased ALT (0.4%), sepsis (0.4%), increased AST (0.3%), drug hypersensitivity (0.3%), fatigue (0.3%), and thrombocytopenia (0.3%). Dosage interruptions due to an AR occurred in 42% of patients; ARs prompting dose interruptions in ≥2% of patients included ALT increased, AST increased, hypertension, diarrhea, pyrexia, and QT prolongation. Dose reductions due to an AR occurred in 31% of patients; ARs requiring dosage reductions in ≥2% of patients included ALT increased, AST increased, QT prolongation, and fatigue (26).

Serious ARs occurred in 33% of patients who received selpercatinib. The most frequent serious AR (in ≥2% of patients) was pneumonia. Fatal ARs occurred in 3% of patients; fatal ARs which occurred in > 1 patient included sepsis (n = 3), cardiac arrest (n = 3), and respiratory failure (n = 3; ref. 26).

Hepatotoxicity was observed in LIBRETTO-001, most commonly early in treatment (median time to onset for increased AST and ALT 4.1 weeks; range, 5 days to 2 years). Increased AST occurred in 51% of patients (8% were grade 3–4) and increased ALT occurred in 45% of patients (9% were grade 3–4). Hypertension was also commonly observed (35% were all grades, 18% were grade 3–4). Selpercatinib 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. The product label advises careful monitoring and supportive care, with particular attention to risk factors such as diarrhea, which is common in patients with MTC and in patients receiving selpercatinib (26, 29).

Hypersensitivity occurred in 4.3% (grade 3 in 1.6%) of patients receiving selpercatinib. Signs and symptoms of hypersensitivity included fever, rash, and arthralgias or myalgias with concurrent decreased platelets or elevated transaminases. The median time to onset was 1.7 weeks (range, 6 days to 1.5 years). Most patients were able to reinitiate selpercatinib at a lower dose in combination with corticosteroids, as described in the product label (29).

Serious events of hemorrhage were observed in LIBRETTO-001. Grade ≥ 3 hemorrhagic events occurred in 2.3% of patients treated with selpercatinib, including three (0.4%) patients with fatal hemorrhagic events (26).

The FDA approval of selpercatinib for patients with RET fusion–positive NSCLC, RET-mutant MTC, and RET fusion–positive thyroid cancer is the first approval specifically for patients with RET alterations globally. The approval was supported by the results of a single study, LIBRETTO-001, which demonstrated substantial response rates better than that of available therapies with evidence of durability in patients with three tumor types. Rapid drug development and strong efficacy signals allowed for regulatory approval approximately 3 years from the time of the original investigational new drug application for selpercatinib.

Though the FDA has granted regular approval in certain instances in molecularly defined patient populations on the basis of a high ORR with significant durability and in the setting of a favorable benefit-risk profile, the FDA determined that additional information was needed to verify clinical benefit in the indications studied (32). As a condition of this approval, additional clinical trials that verify and further describe the clinical benefit may be required. Taking into consideration equipoise and the feasibility of conducting these trials in these rare patient populations, these data were agreed to be obtained through additional single-arm ORR and DOR data in patients with RET fusion–positive metastatic NSCLC and in patients with RET fusion–positive thyroid cancer and evidence of improvement in progression-free survival in a randomized trial for patients with RET-mutant MTC.

The simultaneous review of an application with three different molecularly defined tumor types was unprecedented and posed unique considerations for the review team. For example, although the application included a small number of patients with RAI-refractory RET fusion–positive thyroid cancer, FDA considered the substantial ORR and DOR supported by the data in other tumor types. This approach overlaps with FDA's approach to tumor agnostic indications based on a biomarker rather than primary disease site (33).

Although a limited number of adolescent patients enrolled on LIBRETTO-001, FDA considered the available safety and efficacy data, extrapolation from the adult population, and unmet medical need in adolescent patients with RET-driven thyroid cancers favored approval in this population. A lower dosage was approved for patients with body weight less than 50 kg, which may include adolescent patients. Additional safety data in adolescent patients will be submitted as a postmarketing requirement.

During the review, FDA considered the lack of approved testing to identify patients with RET-driven cancers. FDA generally expects that companion in vitro diagnostic devices will be approved simultaneously with the drug. However, FDA considered that the benefits of selpercatinib in the proposed populations were substantial and that the benefits of approval in the absence of a companion diagnostic device outweighed the risks, consistent with FDA guidance (34). FDA and Loxo/Lilly agreed that companion diagnostic tests for detection of RET alterations in NSCLC and thyroid cancers may be developed as a postmarketing committment.

The benefit-risk evaluation of the results of LIBRETTO-001 supported accelerated approval of selpercatinib in adult patients with metastatic RET fusion–positive NSCLC and in adult and pediatric patients ≥12 years of age with advanced or metastatic RET-mutant MTC who require systemic therapy and with advanced or metastatic RET fusion–positive thyroid cancer who require systemic therapy and who are RAI refractory (if RAI is appropriate). Additional trials to verify the clinical benefit of selpercatinib are ongoing.

No disclosures were reported.

The editor handling the peer review and decision-making process for this article has no relevant employment associations to disclose.

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Supplementary data