These Highlights Do Not Include All The Information Needed To Use Gavreto Safely And Effectively. See Full Prescribing Information For Gavreto.

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).

RET Fusion-Positive Non-Small Cell Lung Cancer

The safety of GAVRETO was evaluated as a single agent at 400 mg orally once daily in 281 patients with metastatic rearranged during transfection (RET fusion-positive) non-small cell lung cancer (NSCLC) in ARROW [see Clinical Studies (14.1)]. Among the 281 patients who received GAVRETO, 72% were exposed for 6 months or longer and 56% were exposed for ≥1 year.

The median age was 60 years (range: 26 to 87 years); 54% were female, 46% were White, 46% were Asian, and 4% were Hispanic/Latino.

Serious adverse reactions occurred in 65% of patients who received GAVRETO. The most frequent serious adverse reactions (in ≥ 2% of patients) were pneumonia, anemia, pneumonitis, pyrexia, sepsis, urinary tract infection, coronavirus infection, pleural effusion, dyspnea, musculoskeletal pain, pulmonary embolism, and seizure. Fatal adverse reactions occurred in 7% of patients; fatal adverse reactions which occurred in > 1 patient included pneumonia (n=8), sepsis (n=3) and COVID (n=3).

Permanent discontinuation due to an adverse reaction occurred in 20% of patients who received GAVRETO. Adverse reactions resulting in permanent discontinuation which occurred in ≥ 2% of patients included pneumonitis (3.2%), and pneumonia (2.8%).

Dosage interruptions due to an adverse reaction occurred in 73% of patients who received GAVRETO. Adverse reactions requiring dosage interruption in ≥ 2% of patients included anemia, pneumonia, pneumonitis, neutropenia, hypertension, increased blood creatine phosphokinase, fatigue, pyrexia, increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), coronavirus infection, diarrhea, hypophosphatemia, musculoskeletal pain, thrombocytopenia, dyspnea, hemorrhage, leukopenia, lymphopenia, edema, sepsis, and vomiting.

Dose reductions due to adverse reactions occurred in 51% of patients who received GAVRETO. Adverse reactions requiring dosage reductions in ≥ 2% of patients included anemia, neutropenia, pneumonitis, increased blood creatine phosphokinase, leukopenia, hypertension, fatigue, pneumonia, and lymphopenia.

Table 5 summarizes the adverse reactions in patients with NSCLC in ARROW.

Clinically relevant adverse reactions occurring in < 15% of patients included pneumonitis (14%), vomiting (14%), abdominal pain (14%), and stomatitis (6%).

Table 6 summarizes the laboratory abnormalities in ARROW.

Clinically relevant laboratory abnormalities occurring in < 20% of patients who received GAVRETO included increased magnesium (14%).

Store at 20°C to 25°C (68°F to 77°F); excursions are permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from moisture.

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.

Pralsetinib is an oral receptor tyrosine kinase inhibitor. The chemical name for pralsetinib is (cis)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)cyclohexanecarboxamide. The molecular formula for pralsetinib is C₂₇H₃₂FN₉O₂, and the molecular weight is 533.61 g/mol. Pralsetinib has the following structure:

The solubility of pralsetinib in aqueous media decreases over the range pH 1.99 to pH 7.64 from 0.880 mg/mL to < 0.001 mg/mL, indicating a decrease in solubility with increasing pH.

GAVRETO (pralsetinib) is supplied for oral use as immediate release hydroxypropyl methylcellulose (HPMC) hard capsules containing 100 mg pralsetinib. The capsules also contain inactive ingredients:

citric acid, hydroxypropyl methylcellulose (HPMC), magnesium stearate, microcrystalline cellulose (MCC), pregelatinized starch and sodium bicarbonate. The capsule shell consists of FD&C Blue #1 (Brilliant Blue FCF), hypromellose and titanium dioxide. The white printing ink contains butyl alcohol, dehydrated alcohol, isopropyl alcohol, potassium hydroxide, propylene glycol, purified water, shellac, strong ammonia solution and titanium dioxide.

Hypertension occurred in 35% of patients, including Grade 3 hypertension in 18% of patients [see Adverse Reactions (6.1)]. Overall, 8% had their dose interrupted and 4.8% had their dose reduced for hypertension. Treatment-emergent hypertension was most commonly managed with anti-hypertension medications.

Do not initiate GAVRETO in patients with uncontrolled hypertension. Optimize blood pressure prior to initiating GAVRETO. Monitor blood pressure after 1 week, at least monthly thereafter and as clinically indicated. Initiate or adjust anti-hypertensive therapy as appropriate. Withhold, reduce dose, or permanently discontinue GAVRETO based on the severity [see Dosage and Administration (2.3)].

Serious hepatic adverse reactions occurred in 1.5% of patients treated with GAVRETO. Increased AST occurred in 49% of patients, including Grade 3 or 4 in 7% and increased ALT occurred in 37% of patients, including Grade 3 or 4 in 4.8% [see Adverse Reactions (6.1)]. The median time to first onset for increased AST was 15 days (range: 5 days to 2.5 years) and for increased ALT was 24 days (range: 7 days to 3.7 years).

Monitor AST and ALT prior to initiating GAVRETO, every 2 weeks during the first 3 months, then monthly thereafter and as clinically indicated. Withhold, reduce dose or permanently discontinue GAVRETO based on severity [see Dosage and Administration (2.3)].

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.

Of the 540 patients in ARROW who received the recommended dose of GAVRETO at 400 mg once daily, 31% were 65 years or and over, while 7% were 75 years and over.

No overall differences in pharmacokinetics (PK), safety or effectiveness were observed between patients aged 65 years or older and younger patients.

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.

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.

None.

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.1)]
• Hypertension [see Warnings and Precautions (5.2)]
• Hepatotoxicity [see Warnings and Precautions (5.3)]
• Hemorrhagic Events [see Warnings and Precautions (5.4)]
• Tumor Lysis Syndrome [see Warnings and Precautions (5.5)]
• Risk of Impaired Wound Healing [see Warnings and Precautions (5.6)]
• Embryo-Fetal Toxicity [see Warnings and Precautions (5.7)]

• Strong or moderate CYP3A inhibitors and/or P-gp inhibitors: Avoid coadministration. If coadministration cannot be avoided, reduce the dose of GAVRETO. (2.4, 7.1, 12.3)
• Strong or moderate CYP3A inducers: Avoid coadministration. If coadministration cannot be avoided, increase the dose of GAVRETO. (2.5, 7.1, 12.3)

Pralsetinib exposure-response relationships and the time course of pharmacodynamics response have not been fully characterized.

At 400 mg GAVRETO once daily under fasting conditions, the steady state geometric mean [% coefficient of variation (CV%)] of maximum observed plasma concentration (C_max) and area under the concentration-time curve (AUC_0-24h) of pralsetinib was 2470 (55.1%) ng/mL and 36700 (66.3%) h∙ng/mL, respectively. Pralsetinib C_max and AUC increased inconsistently over the dose range of 60 mg to 600 mg once daily (0.15 to 1.5 times the recommended dose). Pralsetinib plasma concentrations reached steady state by 3 to 5 days. The mean accumulation ratio was approximately 2-fold after once-daily repeated oral administration.

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.

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.

Serious, including fatal, hemorrhagic events can occur with GAVRETO. Grade ≥ 3 hemorrhagic events occurred in 4.1% of patients treated with GAVRETO including one patient with a fatal hemorrhagic event.

Permanently discontinue GAVRETO in patients with severe or life-threatening hemorrhage [see Dosage and Administration (2.3)].

No dose adjustment is required for patients with mild (total bilirubin ≤ ULN and AST > ULN or total bilirubin > 1 to 1.5 × ULN and any AST), moderate (total bilirubin > 1.5 to 3 × ULN and any AST) or severe hepatic impairment (total bilirubin > 3 × ULN and any AST) [see Clinical Pharmacology (12.3)].

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)
• 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)

Pralsetinib is a kinase inhibitor of wild-type RET and oncogenic RET fusions (CCDC6-RET) and mutations (RET V804L, RET V804M and RET M918T) with half maximal inhibitory concentrations (IC_50s) less than 0.5 nM. In purified enzyme assays, pralsetinib inhibited DDR1, TRKC, FLT3, JAK1-2, TRKA, VEGFR2, PDGFRB, and FGFR1 at higher concentrations that were still clinically achievable at C_max. In cellular assays, pralsetinib inhibited RET at approximately 14-, 40-, and 12-fold lower concentrations than VEGFR2, FGFR2, and JAK2, respectively.

Certain RET fusion proteins and activating point mutations can drive tumorigenic potential through hyperactivation of downstream signaling pathways leading to uncontrolled cell proliferation. Pralsetinib exhibited anti-tumor activity in cultured cells and animal tumor implantation models harboring oncogenic RET fusions or mutations including KIF5B-RET, CCDC6-RET, RET M918T, RET C634W, RET V804E, RET V804L and RET V804M. In addition, pralsetinib prolonged survival in mice implanted intracranially with tumor models expressing KIF5B-RET or CCDC6-RET.

Cases of tumor lysis syndrome (TLS) have been reported in patients with medullary thyroid carcinoma receiving GAVRETO [see Adverse Reactions (6.1)]. Patients may be at risk of TLS if they have rapidly growing tumors, a high tumor burden, renal dysfunction, or dehydration. Closely monitor patients at risk, consider appropriate prophylaxis including hydration, and treat as clinically indicated.

Based on findings from animal studies and its mechanism of action, GAVRETO can cause fetal harm when administered to a pregnant woman. Oral administration of pralsetinib to pregnant rats during the period of organogenesis resulted in malformations and embryolethality at maternal exposures below the human exposure at the clinical dose of 400 mg once daily.

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with GAVRETO and for 2 weeks after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with GAVRETO and for 1 week after the last dose [see Use in Specific Populations (8.1, 8.3)].

• Interstitial Lung Disease (ILD)/Pneumonitis: Withhold GAVRETO for Grade 1 or 2 reactions until resolution and then resume at a reduced dose. Permanently discontinue for recurrent ILD/pneumonitis. Permanently discontinue for Grade 3 or 4 reactions. (2.3, 5.1)
• Hypertension: Do not initiate GAVRETO in patients with uncontrolled hypertension. Optimize blood pressure (BP) prior to initiating GAVRETO. Monitor BP after 1 week, at least monthly thereafter and as clinically indicated. Withhold, reduce dose, or permanently discontinue GAVRETO based on severity. (2.3, 5.2)
• Hepatotoxicity: Monitor ALT and AST prior to initiating GAVRETO, every 2 weeks during the first 3 months, then monthly thereafter and as clinically indicated. Withhold, reduce dose, or permanently discontinue GAVRETO based on severity. (2.3, 5.3)
• Hemorrhagic Events: Permanently discontinue GAVRETO in patients with severe or life-threatening hemorrhage. (2.3, 5.4)
• Tumor Lysis Syndrome: Closely monitor patients at risk and treat as clinically indicated. (2.3, 5.5)
• Risk of Impaired Wound Healing: Withhold GAVRETO for at least 5 days prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of GAVRETO after resolution of wound healing complications has not been established. (5.6)
• Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective non-hormonal contraception. (5.7, 8.1, 8.3)

Select patients for treatment with GAVRETO based on the presence of a RET gene fusion. (2.1, 14)

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)

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

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The pooled safety population in the WARNINGS AND PRECAUTIONS reflect exposure to GAVRETO as a single agent at 400 mg orally once daily in 540 patients in ARROW [see Clinical Studies (14)]. Among 540 patients who received GAVRETO, 71% were exposed for 6 months or longer and 57% were exposed for greater than one year. The most common adverse reactions (≥ 25%) were musculoskeletal pain, constipation, hypertension, diarrhea, fatigue, edema, pyrexia, and cough. The most common Grade 3-4 laboratory abnormalities (≥ 2%) were decreased lymphocytes, decreased neutrophils, decreased hemoglobin, decreased phosphate, decreased leukocytes, decreased sodium, increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), decreased calcium (corrected), decreased platelets, increased alkaline phosphatase, increased potassium, decreased potassium and increased bilirubin.

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Impaired wound healing can occur in patients who receive drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway. Therefore, GAVRETO has the potential to adversely affect wound healing.

Withhold GAVRETO for at least 5 days prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of GAVRETO after resolution of wound healing complications has not been established.

GAVRETO (pralsetinib) 100 mg, light blue, opaque, immediate release, hydroxypropyl methylcellulose (HPMC) hard capsule printed with "BLU-667" on the capsule shell body and "100 mg" on the capsule shell cap are supplied as follows:

• Bottles of 60 capsules (NDC 50242-210-60).
• Bottles of 90 capsules (NDC 50242-210-90).
• Bottles of 120 capsules (NDC 50242-210-12).

Severe, life-threatening, and fatal interstitial lung disease (ILD) / pneumonitis can occur in patients treated with GAVRETO. Pneumonitis occurred in 12% of patients who received GAVRETO, including 3.3% with Grade 3-4, and 0.2% with fatal reactions.

Monitor for pulmonary symptoms indicative of ILD/pneumonitis. Withhold GAVRETO and promptly investigate for ILD in any patient who presents with acute or worsening of respiratory symptoms which may be indicative of ILD (e.g., dyspnea, cough, and fever). Withhold, reduce dose or permanently discontinue GAVRETO based on severity of confirmed ILD [see Dosage and Administration (2.3)].

In 28-day rat and monkey toxicology studies, once daily oral administration of pralsetinib resulted in histologic necrosis and hemorrhage in the heart of preterm decedents at exposures ≥ 1.3 times and ≥ 3.1 times, respectively, the human exposure based on AUC at the clinical dose of 400 mg. Pralsetinib induced hyperphosphatemia (rats) and multi-organ mineralization (rats and monkeys) in 13-week toxicology studies at exposures approximately 2.8 times and ≥ 0.13 times, respectively, the human exposure based on AUC at the clinical dose of 400 mg.

The recommended dose reductions and dosage modifications for adverse reactions are provided in Table 1 and Table 2.

Permanently discontinue GAVRETO in patients who are unable to tolerate 100 mg taken orally once daily.

The recommended dosage modifications for adverse reactions are provided in Table 2.

Based on animal data, GAVRETO can cause embryolethality and malformations at doses resulting in exposures below the human exposure at the clinical dose of 400 mg daily [see Use in Specific Populations (8.1)].

Avoid coadministration of GAVRETO with any of the following:

• Strong CYP3A inducers
• Moderate CYP3A inducers

If coadministration with any of the above inducers cannot be avoided, increase the starting dose of GAVRETO as recommended in Table 4 starting on Day 7 of coadministration of GAVRETO with the inducer. After the inducer has been discontinued for at least 14 days, resume GAVRETO at the dose taken prior to initiating the inducer [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

NDC 50242-210-60

Gavreto^®

(pralsetinib)

capsules

100 mg

For Oral Use

Rx only

60 Capsules

Genentech

blueprint™

MEDICINES

10242131

Carcinogenicity studies with pralsetinib have not been conducted. Pralsetinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay with or without metabolic activation and was not clastogenic in either an in vitro micronucleus assay in TK6 cells or an in vivo bone marrow micronucleus assay in rats.

In a dedicated fertility and early embryonic development study conducted in treated male rats mated to treated female rats, although pralsetinib did not have clear effects on male or female mating performance or ability to become pregnant, at the 20 mg/kg dose level (approximately 2.9 times the human exposure (AUC) at the clinical dose of 400 mg based on toxicokinetic data from the 13-week rat toxicology study) 82% of female rats had totally resorbed litters, with 92% post-implantation loss (early resorptions); post-implantation loss occurred at doses as low as 5 mg/kg (approximately 0.35 times the human exposure (AUC) at the clinical dose of 400 mg based on toxicokinetic data from the 13-week rat toxicology study). In a separate fertility and early embryonic development study in which male rats administered 20 mg/kg pralsetinib were mated to untreated female rats, there were no clear pralsetinib-related effects on intrauterine survival of embryos or on male reproductive performance at a dose approximately 1.7 times the human exposure (AUC) at the clinical dose of 400 mg. In a 13-week repeat-dose toxicology study, male rats exhibited histopathological evidence of tubular degeneration/atrophy in the testis with secondary cellular debris and reduced sperm in the lumen of the epididymis, which correlated with lower mean testis and epididymis weights and gross observations of soft and small testis. Female rats exhibited degeneration of the corpus luteum in the ovary. For both sexes, these effects were observed at pralsetinib doses ≥ 10 mg/kg/day, approximately 1 times the human exposure based on AUC at the clinical dose of 400 mg.

Avoid coadministration of GAVRETO with any of the following:

• Strong CYP3A inhibitors
• Moderate CYP3A inhibitors
• P-gp inhibitors
• Combined P-gp and strong CYP3A inhibitors
• Combined P-gp and moderate CYP3A inhibitors

If coadministration with any of the above inhibitors cannot be avoided, reduce the current dose of GAVRETO as recommended in Table 3. After the inhibitor has been discontinued for 3 to 5 elimination half-lives, resume GAVRETO at the dose taken prior to initiating the inhibitor [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

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).

RET Fusion-Positive Non-Small Cell Lung Cancer

The safety of GAVRETO was evaluated as a single agent at 400 mg orally once daily in 281 patients with metastatic rearranged during transfection (RET fusion-positive) non-small cell lung cancer (NSCLC) in ARROW [see Clinical Studies (14.1)]. Among the 281 patients who received GAVRETO, 72% were exposed for 6 months or longer and 56% were exposed for ≥1 year.

The median age was 60 years (range: 26 to 87 years); 54% were female, 46% were White, 46% were Asian, and 4% were Hispanic/Latino.

Serious adverse reactions occurred in 65% of patients who received GAVRETO. The most frequent serious adverse reactions (in ≥ 2% of patients) were pneumonia, anemia, pneumonitis, pyrexia, sepsis, urinary tract infection, coronavirus infection, pleural effusion, dyspnea, musculoskeletal pain, pulmonary embolism, and seizure. Fatal adverse reactions occurred in 7% of patients; fatal adverse reactions which occurred in > 1 patient included pneumonia (n=8), sepsis (n=3) and COVID (n=3).

Permanent discontinuation due to an adverse reaction occurred in 20% of patients who received GAVRETO. Adverse reactions resulting in permanent discontinuation which occurred in ≥ 2% of patients included pneumonitis (3.2%), and pneumonia (2.8%).

Dosage interruptions due to an adverse reaction occurred in 73% of patients who received GAVRETO. Adverse reactions requiring dosage interruption in ≥ 2% of patients included anemia, pneumonia, pneumonitis, neutropenia, hypertension, increased blood creatine phosphokinase, fatigue, pyrexia, increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), coronavirus infection, diarrhea, hypophosphatemia, musculoskeletal pain, thrombocytopenia, dyspnea, hemorrhage, leukopenia, lymphopenia, edema, sepsis, and vomiting.

Dose reductions due to adverse reactions occurred in 51% of patients who received GAVRETO. Adverse reactions requiring dosage reductions in ≥ 2% of patients included anemia, neutropenia, pneumonitis, increased blood creatine phosphokinase, leukopenia, hypertension, fatigue, pneumonia, and lymphopenia.

Table 5 summarizes the adverse reactions in patients with NSCLC in ARROW.

Clinically relevant adverse reactions occurring in < 15% of patients included pneumonitis (14%), vomiting (14%), abdominal pain (14%), and stomatitis (6%).

Table 6 summarizes the laboratory abnormalities in ARROW.

Clinically relevant laboratory abnormalities occurring in < 20% of patients who received GAVRETO included increased magnesium (14%).

Store at 20°C to 25°C (68°F to 77°F); excursions are permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from moisture.

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.

Pralsetinib is an oral receptor tyrosine kinase inhibitor. The chemical name for pralsetinib is (cis)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)cyclohexanecarboxamide. The molecular formula for pralsetinib is C₂₇H₃₂FN₉O₂, and the molecular weight is 533.61 g/mol. Pralsetinib has the following structure:

The solubility of pralsetinib in aqueous media decreases over the range pH 1.99 to pH 7.64 from 0.880 mg/mL to < 0.001 mg/mL, indicating a decrease in solubility with increasing pH.

GAVRETO (pralsetinib) is supplied for oral use as immediate release hydroxypropyl methylcellulose (HPMC) hard capsules containing 100 mg pralsetinib. The capsules also contain inactive ingredients:

citric acid, hydroxypropyl methylcellulose (HPMC), magnesium stearate, microcrystalline cellulose (MCC), pregelatinized starch and sodium bicarbonate. The capsule shell consists of FD&C Blue #1 (Brilliant Blue FCF), hypromellose and titanium dioxide. The white printing ink contains butyl alcohol, dehydrated alcohol, isopropyl alcohol, potassium hydroxide, propylene glycol, purified water, shellac, strong ammonia solution and titanium dioxide.

Hypertension occurred in 35% of patients, including Grade 3 hypertension in 18% of patients [see Adverse Reactions (6.1)]. Overall, 8% had their dose interrupted and 4.8% had their dose reduced for hypertension. Treatment-emergent hypertension was most commonly managed with anti-hypertension medications.

Do not initiate GAVRETO in patients with uncontrolled hypertension. Optimize blood pressure prior to initiating GAVRETO. Monitor blood pressure after 1 week, at least monthly thereafter and as clinically indicated. Initiate or adjust anti-hypertensive therapy as appropriate. Withhold, reduce dose, or permanently discontinue GAVRETO based on the severity [see Dosage and Administration (2.3)].

Serious hepatic adverse reactions occurred in 1.5% of patients treated with GAVRETO. Increased AST occurred in 49% of patients, including Grade 3 or 4 in 7% and increased ALT occurred in 37% of patients, including Grade 3 or 4 in 4.8% [see Adverse Reactions (6.1)]. The median time to first onset for increased AST was 15 days (range: 5 days to 2.5 years) and for increased ALT was 24 days (range: 7 days to 3.7 years).

Monitor AST and ALT prior to initiating GAVRETO, every 2 weeks during the first 3 months, then monthly thereafter and as clinically indicated. Withhold, reduce dose or permanently discontinue GAVRETO based on severity [see Dosage and Administration (2.3)].

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.

Of the 540 patients in ARROW who received the recommended dose of GAVRETO at 400 mg once daily, 31% were 65 years or and over, while 7% were 75 years and over.

No overall differences in pharmacokinetics (PK), safety or effectiveness were observed between patients aged 65 years or older and younger patients.

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.

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.

None.

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.1)]
• Hypertension [see Warnings and Precautions (5.2)]
• Hepatotoxicity [see Warnings and Precautions (5.3)]
• Hemorrhagic Events [see Warnings and Precautions (5.4)]
• Tumor Lysis Syndrome [see Warnings and Precautions (5.5)]
• Risk of Impaired Wound Healing [see Warnings and Precautions (5.6)]
• Embryo-Fetal Toxicity [see Warnings and Precautions (5.7)]

• Strong or moderate CYP3A inhibitors and/or P-gp inhibitors: Avoid coadministration. If coadministration cannot be avoided, reduce the dose of GAVRETO. (2.4, 7.1, 12.3)
• Strong or moderate CYP3A inducers: Avoid coadministration. If coadministration cannot be avoided, increase the dose of GAVRETO. (2.5, 7.1, 12.3)

Pralsetinib exposure-response relationships and the time course of pharmacodynamics response have not been fully characterized.

At 400 mg GAVRETO once daily under fasting conditions, the steady state geometric mean [% coefficient of variation (CV%)] of maximum observed plasma concentration (C_max) and area under the concentration-time curve (AUC_0-24h) of pralsetinib was 2470 (55.1%) ng/mL and 36700 (66.3%) h∙ng/mL, respectively. Pralsetinib C_max and AUC increased inconsistently over the dose range of 60 mg to 600 mg once daily (0.15 to 1.5 times the recommended dose). Pralsetinib plasma concentrations reached steady state by 3 to 5 days. The mean accumulation ratio was approximately 2-fold after once-daily repeated oral administration.

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.

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.

Serious, including fatal, hemorrhagic events can occur with GAVRETO. Grade ≥ 3 hemorrhagic events occurred in 4.1% of patients treated with GAVRETO including one patient with a fatal hemorrhagic event.

Permanently discontinue GAVRETO in patients with severe or life-threatening hemorrhage [see Dosage and Administration (2.3)].

No dose adjustment is required for patients with mild (total bilirubin ≤ ULN and AST > ULN or total bilirubin > 1 to 1.5 × ULN and any AST), moderate (total bilirubin > 1.5 to 3 × ULN and any AST) or severe hepatic impairment (total bilirubin > 3 × ULN and any AST) [see Clinical Pharmacology (12.3)].

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)
• 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)

Pralsetinib is a kinase inhibitor of wild-type RET and oncogenic RET fusions (CCDC6-RET) and mutations (RET V804L, RET V804M and RET M918T) with half maximal inhibitory concentrations (IC_50s) less than 0.5 nM. In purified enzyme assays, pralsetinib inhibited DDR1, TRKC, FLT3, JAK1-2, TRKA, VEGFR2, PDGFRB, and FGFR1 at higher concentrations that were still clinically achievable at C_max. In cellular assays, pralsetinib inhibited RET at approximately 14-, 40-, and 12-fold lower concentrations than VEGFR2, FGFR2, and JAK2, respectively.

Certain RET fusion proteins and activating point mutations can drive tumorigenic potential through hyperactivation of downstream signaling pathways leading to uncontrolled cell proliferation. Pralsetinib exhibited anti-tumor activity in cultured cells and animal tumor implantation models harboring oncogenic RET fusions or mutations including KIF5B-RET, CCDC6-RET, RET M918T, RET C634W, RET V804E, RET V804L and RET V804M. In addition, pralsetinib prolonged survival in mice implanted intracranially with tumor models expressing KIF5B-RET or CCDC6-RET.

Cases of tumor lysis syndrome (TLS) have been reported in patients with medullary thyroid carcinoma receiving GAVRETO [see Adverse Reactions (6.1)]. Patients may be at risk of TLS if they have rapidly growing tumors, a high tumor burden, renal dysfunction, or dehydration. Closely monitor patients at risk, consider appropriate prophylaxis including hydration, and treat as clinically indicated.

Based on findings from animal studies and its mechanism of action, GAVRETO can cause fetal harm when administered to a pregnant woman. Oral administration of pralsetinib to pregnant rats during the period of organogenesis resulted in malformations and embryolethality at maternal exposures below the human exposure at the clinical dose of 400 mg once daily.

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with GAVRETO and for 2 weeks after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with GAVRETO and for 1 week after the last dose [see Use in Specific Populations (8.1, 8.3)].

• Interstitial Lung Disease (ILD)/Pneumonitis: Withhold GAVRETO for Grade 1 or 2 reactions until resolution and then resume at a reduced dose. Permanently discontinue for recurrent ILD/pneumonitis. Permanently discontinue for Grade 3 or 4 reactions. (2.3, 5.1)
• Hypertension: Do not initiate GAVRETO in patients with uncontrolled hypertension. Optimize blood pressure (BP) prior to initiating GAVRETO. Monitor BP after 1 week, at least monthly thereafter and as clinically indicated. Withhold, reduce dose, or permanently discontinue GAVRETO based on severity. (2.3, 5.2)
• Hepatotoxicity: Monitor ALT and AST prior to initiating GAVRETO, every 2 weeks during the first 3 months, then monthly thereafter and as clinically indicated. Withhold, reduce dose, or permanently discontinue GAVRETO based on severity. (2.3, 5.3)
• Hemorrhagic Events: Permanently discontinue GAVRETO in patients with severe or life-threatening hemorrhage. (2.3, 5.4)
• Tumor Lysis Syndrome: Closely monitor patients at risk and treat as clinically indicated. (2.3, 5.5)
• Risk of Impaired Wound Healing: Withhold GAVRETO for at least 5 days prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of GAVRETO after resolution of wound healing complications has not been established. (5.6)
• Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective non-hormonal contraception. (5.7, 8.1, 8.3)

Select patients for treatment with GAVRETO based on the presence of a RET gene fusion. (2.1, 14)

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)

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

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The pooled safety population in the WARNINGS AND PRECAUTIONS reflect exposure to GAVRETO as a single agent at 400 mg orally once daily in 540 patients in ARROW [see Clinical Studies (14)]. Among 540 patients who received GAVRETO, 71% were exposed for 6 months or longer and 57% were exposed for greater than one year. The most common adverse reactions (≥ 25%) were musculoskeletal pain, constipation, hypertension, diarrhea, fatigue, edema, pyrexia, and cough. The most common Grade 3-4 laboratory abnormalities (≥ 2%) were decreased lymphocytes, decreased neutrophils, decreased hemoglobin, decreased phosphate, decreased leukocytes, decreased sodium, increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), decreased calcium (corrected), decreased platelets, increased alkaline phosphatase, increased potassium, decreased potassium and increased bilirubin.

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Impaired wound healing can occur in patients who receive drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway. Therefore, GAVRETO has the potential to adversely affect wound healing.

Withhold GAVRETO for at least 5 days prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of GAVRETO after resolution of wound healing complications has not been established.

GAVRETO (pralsetinib) 100 mg, light blue, opaque, immediate release, hydroxypropyl methylcellulose (HPMC) hard capsule printed with "BLU-667" on the capsule shell body and "100 mg" on the capsule shell cap are supplied as follows:

• Bottles of 60 capsules (NDC 50242-210-60).
• Bottles of 90 capsules (NDC 50242-210-90).
• Bottles of 120 capsules (NDC 50242-210-12).

Severe, life-threatening, and fatal interstitial lung disease (ILD) / pneumonitis can occur in patients treated with GAVRETO. Pneumonitis occurred in 12% of patients who received GAVRETO, including 3.3% with Grade 3-4, and 0.2% with fatal reactions.

Monitor for pulmonary symptoms indicative of ILD/pneumonitis. Withhold GAVRETO and promptly investigate for ILD in any patient who presents with acute or worsening of respiratory symptoms which may be indicative of ILD (e.g., dyspnea, cough, and fever). Withhold, reduce dose or permanently discontinue GAVRETO based on severity of confirmed ILD [see Dosage and Administration (2.3)].

In 28-day rat and monkey toxicology studies, once daily oral administration of pralsetinib resulted in histologic necrosis and hemorrhage in the heart of preterm decedents at exposures ≥ 1.3 times and ≥ 3.1 times, respectively, the human exposure based on AUC at the clinical dose of 400 mg. Pralsetinib induced hyperphosphatemia (rats) and multi-organ mineralization (rats and monkeys) in 13-week toxicology studies at exposures approximately 2.8 times and ≥ 0.13 times, respectively, the human exposure based on AUC at the clinical dose of 400 mg.

The recommended dose reductions and dosage modifications for adverse reactions are provided in Table 1 and Table 2.

Permanently discontinue GAVRETO in patients who are unable to tolerate 100 mg taken orally once daily.

The recommended dosage modifications for adverse reactions are provided in Table 2.

Based on animal data, GAVRETO can cause embryolethality and malformations at doses resulting in exposures below the human exposure at the clinical dose of 400 mg daily [see Use in Specific Populations (8.1)].

Avoid coadministration of GAVRETO with any of the following:

• Strong CYP3A inducers
• Moderate CYP3A inducers

If coadministration with any of the above inducers cannot be avoided, increase the starting dose of GAVRETO as recommended in Table 4 starting on Day 7 of coadministration of GAVRETO with the inducer. After the inducer has been discontinued for at least 14 days, resume GAVRETO at the dose taken prior to initiating the inducer [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

NDC 50242-210-60

Gavreto^®

(pralsetinib)

capsules

100 mg

For Oral Use

Rx only

60 Capsules

Genentech

blueprint™

MEDICINES

10242131

Carcinogenicity studies with pralsetinib have not been conducted. Pralsetinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay with or without metabolic activation and was not clastogenic in either an in vitro micronucleus assay in TK6 cells or an in vivo bone marrow micronucleus assay in rats.

In a dedicated fertility and early embryonic development study conducted in treated male rats mated to treated female rats, although pralsetinib did not have clear effects on male or female mating performance or ability to become pregnant, at the 20 mg/kg dose level (approximately 2.9 times the human exposure (AUC) at the clinical dose of 400 mg based on toxicokinetic data from the 13-week rat toxicology study) 82% of female rats had totally resorbed litters, with 92% post-implantation loss (early resorptions); post-implantation loss occurred at doses as low as 5 mg/kg (approximately 0.35 times the human exposure (AUC) at the clinical dose of 400 mg based on toxicokinetic data from the 13-week rat toxicology study). In a separate fertility and early embryonic development study in which male rats administered 20 mg/kg pralsetinib were mated to untreated female rats, there were no clear pralsetinib-related effects on intrauterine survival of embryos or on male reproductive performance at a dose approximately 1.7 times the human exposure (AUC) at the clinical dose of 400 mg. In a 13-week repeat-dose toxicology study, male rats exhibited histopathological evidence of tubular degeneration/atrophy in the testis with secondary cellular debris and reduced sperm in the lumen of the epididymis, which correlated with lower mean testis and epididymis weights and gross observations of soft and small testis. Female rats exhibited degeneration of the corpus luteum in the ovary. For both sexes, these effects were observed at pralsetinib doses ≥ 10 mg/kg/day, approximately 1 times the human exposure based on AUC at the clinical dose of 400 mg.

Avoid coadministration of GAVRETO with any of the following:

• Strong CYP3A inhibitors
• Moderate CYP3A inhibitors
• P-gp inhibitors
• Combined P-gp and strong CYP3A inhibitors
• Combined P-gp and moderate CYP3A inhibitors

If coadministration with any of the above inhibitors cannot be avoided, reduce the current dose of GAVRETO as recommended in Table 3. After the inhibitor has been discontinued for 3 to 5 elimination half-lives, resume GAVRETO at the dose taken prior to initiating the inhibitor [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].