Gavreto

GAVRETO is a kinase inhibitor indicated for treatment of:

• Adult patients with metastatic rearranged during transfection
  
  
  (RET
  ) fusion-positive non-small cell lung cancer as detected by an FDA approved test (NSCLC). (
  
  
  1.1 Metastatic

  RET

  Fusion-Positive Non-Small Cell Lung Cancer

  GAVRETO is indicated for the treatment of adult patients with metastatic

  RET

  fusion-positive non-small cell lung cancer (NSCLC) as detected by an FDA approved test.
  )
  
• Adult and pediatric patients 12 years of age and older with advanced or metastatic
  
  
  RET
  fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate).
  
  
  This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). (
  
  
  1.2

  RET

  Fusion-Positive Thyroid Cancer

  GAVRETO is indicated for the treatment of adult and pediatric patients 12 years of age and older with advanced or metastatic

  RET

  fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate).

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

  [see Clinical Studies (14.2)]

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

• Select patients for treatment with GAVRETO based on the presence of a
  
  
  RET
  gene fusion. (
  
  
  2.1 Patient Selection

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

  RET

  gene fusion (NSCLC or thyroid cancer)

  [see Clinical Studies (14)]

  .

  Information on FDA-approved tests for

  RET

  gene fusion (NSCLC) is available at http://www.fda.gov/CompanionDiagnostics.

  An FDA-approved test for the detection of

  RET

  gene fusion (thyroid cancer) is not currently available.
  ,
  
  
  14 CLINICAL STUDIES

  14.1 Metastatic

  RET

  Fusion-Positive Non-Small Cell Lung Cancer

  The efficacy of GAVRETO was evaluated in patients with

  RET

  fusion-positive metastatic NSCLC in a multicenter, non-randomized, open-label, multi-cohort clinical trial (ARROW, NCT03037385). The study enrolled, in separate cohorts, patients with metastatic

  RET

  fusion-positive NSCLC who had progressed on platinum-based chemotherapy and treatment-naïve patients with metastatic NSCLC. Identification of a

  RET

  gene fusion was determined by local laboratories using next generation sequencing (NGS), fluorescence in situ hybridization (FISH), and other tests. Among the 237 patients in the efficacy population(s) described in this section, samples from 40% of patients were retrospectively tested with the LIFE Technologies Corporation Oncomine Dx Target Test (ODxTT). Patients with asymptomatic central nervous system (CNS) metastases, including patients with stable or decreasing steroid use within 2 weeks prior to study entry, were enrolled. Patients received GAVRETO 400 mg orally once daily until disease progression or unacceptable toxicity.

  The major efficacy outcome measures were overall response rate (ORR) and duration of response (DOR), as assessed by a blinded independent central review (BICR) according to RECIST v1.1.

  Metastatic

  RET

  Fusion-Positive NSCLC Previously Treated with Platinum Chemotherapy

  Efficacy was evaluated in 130 patients with

  RET

  fusion-positive NSCLC with measurable disease who were previously treated with platinum chemotherapy enrolled into a cohort of ARROW.

  The median age was 59 years (range: 26 to 85); 51% were female, 40% were White, 50% were Asian, 4.6% were Hispanic/Latino. ECOG performance status was 0-1 (95%) or 2 (3.8%), 99% of patients had metastatic disease, and 41% had either a history of or current CNS metastasis. Patients received a median of 2 prior systemic therapies (range 1–6); 42% had prior anti-PD-1/PD-L1 therapy and 27% had prior kinase inhibitors. A total of 48% of the patients received prior radiation therapy.

  RET

  fusions were detected in 80% of patients using NGS (37% tumor samples; 15% blood or plasma samples, 28% unknown), 13% using FISH, and 2% using other methods. The most common

  RET

  fusion partners were KIF5B (70%) and CCDC6 (19%).

  Efficacy results for

  RET

  fusion-positive NSCLC patients who received prior platinum-based chemotherapy are summarized in Table 10.

  Table 10: Efficacy Results in ARROW (Metastatic RET Fusion-Positive NSCLC Previously Treated with Platinum Chemotherapy)

  Efficacy Parameter	GAVRETO N=130
  NE = not estimable
  Overall Response Rate (ORR) Confirmed overall response rate assessed by BICR(95% CI)	63 (54, 71)
  Complete Response, %	6
  Partial Response, %	57
  Duration of Response (DOR)	N=82
  Median, months (95% CI)	38.8 (14.8, NE)
  Patients with DOR ≥ 12-monthsBased on observed duration of response, %	66

  For the 54 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 59% (95% CI: 45, 72) and the median DOR was 22.3 months (95% CI: 8.0, NE).

  Among the 130 patients with

  RET

  -fusion positive NSCLC, 10 had measurable CNS metastases at baseline as assessed by BICR. No patients received radiation therapy (RT) to the brain within 2 months prior to study entry. Responses in intracranial lesions were observed in 7 of these 10 patients including 2 patients with a CNS complete response; 71% of responders had a DOR of ≥ 6 months.

  Treatment-naïve

  RET

  Fusion-Positive NSCLC

  Efficacy was evaluated in 107 patients with treatment-naïve

  RET

  fusion-positive NSCLC with measurable disease enrolled into ARROW.

  The median age was 62 years (range 30 to 87); 53% were female, 49% were White, 45% were Asian, and 2.8% were Hispanic or Latino. ECOG performance status was 0-1 for 99% of the patients and 98% of patients had metastatic disease; 28% had either history of or current CNS metastasis.

  RET

  fusions were detected in 68% of patients using NGS (30% tumor samples; 17% blood or plasma; 22% unknown) and 19% using FISH. The most common

  RET

  fusion partners were

  KIF5B

  (71%) and

  CCDC6

  (18%).

  Efficacy results for treatment-naïve

  RET

  fusion-positive NSCLC are summarized in Table 11.

  Table 11: Efficacy Results for ARROW (Treatment-Naïve Metastatic RET Fusion-Positive NSCLC)

  Efficacy Parameter	GAVRETO N=107
  Overall Response Rate (ORR) Confirmed overall response rate assessed by BICR(95% CI)	78 (68, 85)
  Complete Response, %	7
  Partial Response, %	71
  Duration of Response (DOR)	N=83
  Median, months (95% CI)	13.4 (9.4, 23.1)
  Patients with DOR ≥ 12-monthsBased on observed duration of response, %	45

  14.2

  RET

  Fusion-Positive Thyroid Cancer

  The efficacy of GAVRETO was evaluated in

  RET

  fusion-positive metastatic thyroid cancer patients in a multicenter, open-label, multi-cohort clinical trial (ARROW, NCT03037385). All patients with

  RET

  fusion-positive thyroid cancer were required to have disease progression following standard therapy, measurable disease by RECIST version 1.1, and have

  RET

  fusion status as detected by local testing (89% NGS tumor samples and 11% using FISH).

  The median age was 61 years (range: 46 to 74); 67% were male, 78% were White, 22% were Asian, 11% were Hispanic/Latino. All patients (100%) had papillary thyroid cancer. ECOG performance status was 0-1 (100%), all patients (100%) had metastatic disease, and 56% had a history of CNS metastases. Patients had received a median of 2 prior therapies (range 1-8). Prior systemic treatments included prior radioactive iodine (100%) and prior sorafenib and/or lenvatinib (56%).

  Efficacy results are summarized in Table 12.

  Table 12: Efficacy Results for RET Fusion-Positive Thyroid Cancer (ARROW)

  Efficacy Parameters	GAVRETO N=9
  NR = Not Reached; NE = Not Estimable
  Overall Response Rate (ORR) Confirmed overall response rate assessed by BICR(95% CI)	89 (52, 100)
  Complete Response, %	0
  Partial Response, %	89
  Duration of Response (DOR)	N=8
  Median in months (95% CI)	NR (NE, NE)
  Patients with DOR ≥ 6 monthsBased on observed duration of response, %	100
  )
  
• The recommended dosage in adults and pediatric patients 12 years and older is 400 mg orally once daily on an empty stomach (no food intake for at least 2 hours before and at least 1 hour after taking GAVRETO). (
  
  
  2.2 Recommended Dosage

  The recommended dosage of GAVRETO is 400 mg orally once daily on an empty stomach (no food intake for at least 2 hours before and at least 1 hour after taking GAVRETO

  ) [see Clinical Pharmacology (12.3)]

  . Continue treatment until disease progression or until unacceptable toxicity.

  If a dose of GAVRETO is missed, it can be taken as soon as possible on the same day. Resume the regular daily dose schedule for GAVRETO the next day.

  Do not take an additional dose if vomiting occurs after GAVRETO but continue with the next dose as scheduled.
  )
  

Capsules: 100 mg, light blue, opaque, hard hydroxypropyl methylcellulose (HPMC) capsule printed with "BLU-667" on the capsule shell body and "100 mg" on the capsule shell cap.

• Lactation
  : Advise not to breastfeed. (
  
  
  8.2 Lactation

  Risk Summary

  There are no data on the presence of pralsetinib or its metabolites in human milk or their effects on either 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 GAVRETO and for 1 week after the last dose.
  )
  
• Pediatric Use
  : Monitor open growth plates in adolescent patients. Consider interrupting or discontinuing GAVRETO if abnormalities occur. (
  
  
  8.4 Pediatric Use

  The safety and effectiveness of GAVRETO have been established in pediatric patients aged 12 years and older for

  RET

  fusion-positive thyroid cancer. Use of GAVRETO in this age group is supported by evidence from an adequate and well-controlled study of GAVRETO in adults with additional population pharmacokinetic data demonstrating that age and body weight had no clinically meaningful effect on the pharmacokinetics of pralsetinib, that the exposure of pralsetinib is expected to be similar between adults and pediatric patients age 12 years and older, and that the course of

  RET

  fusion-positive thyroid cancer is sufficiently similar in adults and pediatric patients to allow extrapolation of data in adults to pediatric patients

  [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.2)].

  The safety and effectiveness of GAVRETO have not been established in pediatric patients with

  RET

  fusion-positive NSCLC or in pediatric patients younger than 12 years old with

  RET

  fusion-positive thyroid cancer.

  Animal Toxicity Data

  In a 4-week repeat-dose toxicology study in non-human primates, physeal dysplasia in the femur occurred at doses resulting in exposures similar to the human exposure (AUC) at the clinical dose of 400 mg. In rats there were findings of increased physeal thickness in the femur and sternum as well as tooth (incisor) abnormalities (fractures, dentin matrix alteration, ameloblast/odontoblast degeneration, necrosis) in both 4- and 13-week studies at doses resulting in exposures similar to the human exposure (AUC) at the clinical dose of 400 mg. Recovery was not assessed in the 13-week toxicology study, but increased physeal thickness in the femur and incisor degeneration did not show evidence of complete recovery in the 28-day rat study.

  Monitor growth plates in adolescent 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.
  )