Pralsetinib, an inhibitor of multiple receptor tyrosine kinases, including wild-type and mutated rearranged during transfection ( RET ) isoforms, is an antineoplastic agent.1, 2
Pralsetinib is used for treatment of adults with metastatic rearranged during transfection (RET) fusion-positive non-small cell lung cancer (NSCLC).1, 2 Patients should be selected for treatment with pralsetinib based on the presence of a RET gene fusion.1 Information on FDA-approved tests for RET gene fusion in NSCLC is available at [Web].1 The drug has been designated an orphan drug by FDA for the treatment of JAK1/2-positive or TRKC-positive NSCLC.3
RET fusions or rearrangements are a type of somatic mutation that lead to formation of distinct RET oncoproteins.4 In patients with NSCLC, RET fusion positivity is observed in 1-3% of cases with a higher frequency observed in patients younger than 60 years of age, females, non-smokers, those with lung adenocarcinoma histology, and those with previous radiation.4, 5 Abnormalities in TP-53 and cell cycle-associated genes, the P13K signaling pathway, MAPK effectors, and other tyrosine kinase families (FGFR, EGFR, ALK, HER2, PDGFRα and PGFRβ) as well as MET amplification have been observed in patients with RET fusions.5 RET fusion-positive NSCLC also has been related to a low response to immune checkpoint inhibitors due to low tumor mutational burden and low PD-L1 expression.5 RET fusions ( CCDC6-RET , NCOA4-RET , and CDC123-RET ) have been reported as an acquired resistance mechanism to EGFR or ALK tyrosine kinase inhibitors in NSCLC with adenocarcinoma histology.12
This indication for pralsetinib is based on results for a cohort of 87 adults with metastatic RET fusion-positive NSCLC previously treated with platinum-based chemotherapy and 27 adults with treatment-naïve metastatic RET fusion-positive NSCLC in a multi-cohort, open-label, phase 1/2 clinical trial (ARROW).1, 6 Presence of RET fusion was determined by next generation sequencing (NGS), fluorescence in situ hybridization (FISH), or other tests.1, 6 In the phase 2 portion of the trial, patients received pralsetinib 400 mg once daily until disease progression, unacceptable toxicity, or study withdrawal occurred.1, 6 The primary efficacy end point was overall response rate according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) as evaluated by a blinded independent central review (BICR) committee; additional outcome measures included duration of response and clinical benefit rate (proportion of patients with a confirmed complete or partial response or stable disease for ≥16 weeks).1, 6
In the previously treated cohort, the median age was 60 years (range: 28-85); 49% were female, 53% were White, 35% were Asian, 6% were Hispanic/Latino, 94% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, 99% had metastatic disease, and 43% had either a history of or current CNS metastasis.1 Patients in this cohort previously received a median of 2 systemic therapies (range: 1-6); 45% previously received an anti-programmed-death receptor-1 (anti-PD-1) or anti-programmed-death ligand-1 (anti-PD-L1) monoclonal antibody and 25% previously received a kinase inhibitor.1 Approximately one-half (52%) of the patients in the previously treated cohort received prior radiation therapy.1 The most common RET fusions were KIF5B-RET and CCDC6-RET .1 The overall response rate in the previously treated cohort was 57%; complete response was achieved in 5.7% of patients.1 At the time of analysis, the duration of response was 6 months or more in 80% of patients.1 In an exploratory subgroup analysis of 39 patients who previously received anti-PD-1 or anti-PD-L1 therapy, either sequentially or concurrently with platinum-based chemotherapy the overall response rate was 59%; the median duration of response had not been reached at the time of analysis.1 In the subgroup of patients with measurable CNS metastases at baseline, intracranial complete response was achieved in 4 of 8 patients and the duration of response was 6 months or more in 75% of these patients.1
In the treatment-naïve cohort, the median age was 65 years (range: 30-87 years); 52% were female, 59% were White, 33% were Asian, 4% were Hispanic/Latino, 96% had an ECOG performance status of 0 or 1, 100% had metastatic disease, and 37% had either a history of or current CNS metastasis.1 The most common RET fusions were KIF5B-RET and CCDC6-RET .1 The overall response rate in the treatment-naïve cohort was 70%; complete response was achieved in 11% of patients.1 At the time of analysis, the median duration of response was 9 months; 58 or 26% of patients had a duration of response of 6 months or more or 12 months, respectively.1
An international, open-label, randomized phase 3 trial (AcceleRET Lung) comparing pralsetinib and standard of care for the first-line treatment of advanced or metastatic RET fusion-positive NSCLC has been completed but publication of final results is pending.2, 8
The American Society of Clinical Oncology (ASCO) living guideline for stage IV NSCLC with driver alterations states that for patients with a RET rearrangement, clinicians should offer selpercatinib as a first-line treatment option.14 If selpercatinib is unavailable, then clinicians may offer pralsetinib.14 In the second-line and subsequent treatment option arena, clinicians should offer selpercatinib or pralsetinib to patients who have not received a RET inhibitor.14
Pralsetinib is used for the treatment of advanced or metastatic RET fusion-positive thyroid cancer in adult and pediatric patients 12 years of age or older who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate).1 Patients should be selected for treatment with pralsetinib based on the presence of a RET gene fusion.1 .1 An FDA-approved test for RET gene fusion detection in thyroid cancer is not currently available.4
The accelerated approval of pralsetinib for this indication is based on objective response rate and duration of response.1 Continued approval for this indication may be contingent on verification and description of clinical benefit of pralsetinib in confirmatory studies.1 Pralsetinib has been designated an orphan drug by FDA for the treatment of this cancer.3
The most common malignancy of the thyroid gland accounting for approximately 80% of thyroid cancers is papillary thyroid carcinoma.12 Gene fusions, including RET , NTRK , ALK , HGFR , and BRAF , are common in papillary thyroid carcinoma.12 RET fusions occur in about 10-20% of papillary thyroid carcinoma cases and are more frequent in radiation-associated papillary thyroid carcinoma compared to sporadic papillary thyroid carcinoma; RET fusions also are more common in pediatric patients.12 The RET fusions CCDC6-RET and NCOA4-RET are the most common in papillary thyroid carcinoma.12
This indication for pralsetinib is based principally on the results for several cohorts with RET fusion-positive thyroid cancer in a multicenter, open-label, phase 1/2, clinical study (ARROW).1, 9 Presence of RET aberrations (e.g., mutation, gene fusion) was determined by NGS, FISH, or other tests.1 In the phase 2 portion of the trial, patients received pralsetinib 400 mg once daily until disease progression, unacceptable toxicity, or study withdrawal occurred.9 The primary efficacy end point was overall response rate according to the RECIST 1.1 as evaluated by a BICR committee; additional outcome measures included duration of response and clinical benefit rate (proportion of patients with a confirmed complete or partial response or stable disease for ≥16 weeks).9
The cohort of patients with RET fusion-positive thyroid cancer included 9 adults who were refractory to radioactive iodine therapy, sorafenib, lenvatinib, or both sorafenib and lenvatinib.1 In this cohort, the median age of patients was 61 years; 67% were male, 78% were White, 11% were Hispanic/Latino, 22% were Asian, 100% had an ECOG performance status of 0 or 1, 100% had metastatic disease, and 56% had a history of CNS metastases.1 Patients in this cohort received a median of 2 prior therapies.1 The objective response rate in the RET fusion-positive thyroid cancer cohort was 89%; complete response was achieved in none of the patients.1, 9 At a median follow-up duration of 9.5 months, responses were ongoing; however, 100% of patients had durable responses of at least 6 months.1, 9
Pralsetinib is administered orally once daily on an empty stomach (i.e., at least 2 hours after and at least 1 hour before food).1
If a dose of pralsetinib is missed, the missed dose should be taken as soon as it is remembered on the same day and the next dose should be taken at the regularly scheduled time.1 If a dose is vomited following administration, an additional dose should not be administered to make up for the vomited dose and the next dose should be taken at the regularly scheduled time.1
Pralsetinib capsules should be stored at 20-25°C (excursions permitted between 15-30°C).1
The recommended dosage of pralsetinib for the treatment of metastatic RET fusion-positive NSCLC in adults is 400 mg once daily.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1
For the treatment of advanced or metastatic RET fusion-positive thyroid cancer in adult and pediatric patients 12 years of age or older who require systemic therapy and are refractory to radioactive iodine therapy (for those who are candidates for such therapy), the recommended dosage of pralsetinib is 400 mg once daily.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1
If adverse reactions occur during pralsetinib therapy, temporary interruption of therapy, dosage reduction, and/or permanent discontinuance of the drug may be necessary.1 If dosage reduction is required, the dosage of pralsetinib should be reduced as described in Table 1.1
Dose Reduction Level | Recommended Dosage Reduction |
|---|---|
First | 300 mg once daily |
Second | 200 mg once daily |
Third | 100 mg once daily |
Fourth | Permanently discontinue pralsetinib |
The following Dosage Modification for Pralsetinib Toxicity table indicates the recommended dosage modification (i.e., temporary interruption of therapy, dosage reduction, discontinuance of therapy) for certain adverse effects according to severity.1
Adverse Reaction and Severity | Modification |
|---|---|
Serious Infections, Including Opportunistic Infections | |
Grade 2 or 3 | Withhold therapy; when serious infections resolve, resume at reduced dosage (see Table 1) |
Grade 4 | Permanently discontinue therapy |
Pulmonary Effects | |
Grade 1 or 2 interstitial lung disease or pneumonitis | Withhold therapy; when interstitial lung disease or pneumonitis resolves, resume at reduced dosage (see Table 1) |
If grade 1 or 2 interstitial lung disease or pneumonitis recurs, permanently discontinue therapy | |
Grade 3 or 4 interstitial lung disease or pneumonitis | Permanently discontinue therapy |
Hepatotoxicity | |
Grade 3 or 4 | Withhold therapy and monitor AST and ALT concentrations once weekly |
When the toxicity resolves to baseline or grade 1, resume at reduced dosage (see Table 1) | |
If toxicity recurs at grade 3 or higher, discontinue therapy | |
Hypertension | |
Grade 3 | Withhold therapy if grade 3 hypertension occurs despite optimal antihypertensive therapy |
When hypertension is controlled, resume at reduced dosage (see Table 1) | |
Grade 4 | Discontinue therapy |
Hemorrhagic Events | |
Grade 3 or 4 | Withhold therapy until toxicity improves to baseline or grade 1 or less |
If severe or life-threatening hemorrhagic events occur, discontinue therapy | |
Growth Plate Abnormality | |
Any grade | Consider interrupting or discontinuing therapy based on severity and individual risk-benefit assessment |
Other Toxicity | |
Grade 3 or 4 | Withhold therapy until toxicity improves to baseline or grade 2 or less; resume at reduced dosage (see Table 1) |
If grade 4 toxicity recurs, permanently discontinue therapy |
Concomitant Use with P-glycoprotein (P-gp) and/or CYP3A Inhibitors
Concomitant use of pralsetinib with any of the following should be avoided: strong or moderate CYP3A inhibitors, P-gp inhibitors, combined P-gp and strong CYP3A inhibitors, or combined P-gp and moderate CYP3A inhibitors.1 If concomitant use cannot be avoided, the manufacturer recommends reducing the dosage of pralsetinib as described in Table 3.1 When concomitant use of the P-gp and/or CYP3A inhibitor is discontinued, the pralsetinib dosage should be returned (after 3-5 elimination half-lives) to the dosage used prior to initiation of the P-gp and/or CYP3A inhibitor.1
Current Dosage | Recommended Pralsetinib Dosage when Coadministered with: | Recommended Pralsetinib Dosage when Coadministered with: |
|---|---|---|
Combined P-gp and Strong CYP3A Inhibitors | Strong CYP3A Inhibitors, Moderate CYP3A Inhibitors, P-gp Inhibitors, Combined P-gp and Moderate CYP3A Inhibitors | |
400 mg once daily | 200 mg once daily | 300 mg once daily |
300 mg once daily | 200 mg once daily | 200 mg once daily |
200 mg once daily | 100 mg once daily | 100 mg once daily |
Concomitant Use with Moderate or Strong CYP3A Inducers
Concomitant use of pralsetinib with moderate or strong CYP3A inducers should be avoided.1 If concomitant use cannot be avoided, the manufacturer recommends increasing the dose of pralsetinib as described in Table 4, starting on day 7 of concomitant use of pralsetinib with a moderate or strong CYP3A inducer.1 After the moderate or strong CYP3A inducer has been discontinued for at least 14 days, the pralsetinib dosage should be returned to the dosage used prior to initiation of the moderate or strong CYP3A inducer.1
Current Dosage | Recommended Pralsetinib Dosage when Coadministered with: | Recommended Pralsetinib Dosage when Coadministered with: |
|---|---|---|
Strong CYP3A Inducers | Moderate CYP3A Inducers | |
400 mg once daily | 800 mg once daily | 600 mg once daily |
300 mg once daily | 600 mg once daily | 500 mg once daily |
200 mg once daily | 400 mg once daily | 300 mg once daily |
No dosage adjustment is necessary in patients with mild (total bilirubin concentrations not exceeding the upper limit of normal [ULN] with AST concentrations exceeding the ULN, or total bilirubin concentrations exceeding 1 to 1.5 times the ULN with any AST concentration), moderate (total bilirubin concentration exceeding 1.5 to 3 times the ULN and any AST concentration), or severe (total bilirubin concentration exceeding 3 times the ULN and any AST concentration) hepatic impairment.1
The manufacturer makes no specific dosage recommendations for patients with renal impairment.1
The manufacturer makes no specific dosage recommendation for geriatric patients.1
Serious Infections, Including Opportunistic Infections
The prescribing information for pralsetinib contains a boxed warning regarding the risk for serious infections, including fatal and opportunistic infections.1 In the AcceleRET-Lung trial, infections occurred in 72% of patients administered pralsetinib; 18% with Grade 3 infection, 3.7% with Grade 4 infection, and 7% with fatal outcomes.1 Over half (52%) of patients who received chemotherapy/immunotherapy experienced an infection, including 10% with a Grade 3 infection.1 Reported infections in the pralsetinib group included pneumonia, urinary tract infection, and opportunistic infections (such as Pneumocystis jirovecii pneumonia, and fungal infections) among others.1 Patients should be monitored for signs and symptoms of infection and treated appropriately.1 The dose of pralsetinib should be withheld, reduced, or permanently discontinued based on severity.1
Interstitial Lung Disease/Pneumonitis
Severe, life-threatening, and fatal interstitial lung disease (ILD) or pneumonitis may occur in patients receiving pralsetinib therapy.1 Pneumonitis occurred in 12% of patients who received pralsetinib with grade 3 or 4 in 3.3%; 0.2% of these resulted in fatality.1
Monitor patients for pulmonary symptoms indicative of ILD or pneumonitis such as cough, dyspnea, and fever.1 Withhold pralsetinib and promptly investigate for ILD in any patient who presents with acute or worsening of respiratory symptoms suggestive of ILD (e.g., dyspnea, cough, and fever).1 If ILD is confirmed, temporary interruption of pralsetinib therapy, dosage reduction, or discontinuance of therapy may be necessary.1
Hypertension has been reported in 35% of patients receiving pralsetinib with grade 3 in 18%.1 Temporary interruption of therapy or dosage reduction was necessary because of hypertension in 8 or 4.8% of patients, respectively.1 Treatment-emergent hypertension was most commonly managed with anti-hypertensive medications.1
Blood pressure should be assessed and controlled prior to initiating pralsetinib therapy; the drug should not be initiated in patients with uncontrolled hypertension.1 Blood pressure should be monitored after 1 week of pralsetinib therapy, at least monthly thereafter, and as clinically indicated.1 If hypertension occurs, antihypertensive therapy should be initiated or adjusted as needed to control blood pressure during therapy.1 Temporary interruption of pralsetinib therapy, dosage reduction, or permanent discontinuance of therapy may be necessary if hypertension occurs during therapy with the drug.1
Serious hepatic adverse reactions have been reported in 1.5% of patients receiving pralsetinib.1 Increased AST or ALT concentrations have been reported in 49 or 37% of patients, respectively.1 Grade 3 or 4 elevations of AST or ALT concentrations were reported in 7 or 4.8% of patients, respectively.1 The median time to initial onset of increased AST or ALT concentration was 15 (range: 5 days to 2.5 years) or 24 days (range: 7 days to 3.7 years), respectively.1
Liver function tests (i.e., ALT and AST concentrations) should be evaluated prior to initiation of therapy and monitored every 2 weeks for the first 3 months of therapy, monthly thereafter, and as clinically indicated.1 Temporary interruption of pralsetinib therapy, dosage reduction, or permanent discontinuance of therapy may be necessary if hepatotoxicity occurs during therapy with the drug.1
Serious, sometimes fatal, hemorrhagic have been reported in patients receiving pralsetinib.1 Grade 3 or greater hemorrhagic events have been reported in 4.1% of patients receiving pralsetinib, including 1 fatal hemorrhagic event.1
If a severe or life-threatening hemorrhagic event occurs, permanently discontinue pralsetinib therapy.1
Tumor lysis syndrome has been reported in patients with medullary thyroid carcinoma receiving pralsetinib.1 The risk of tumor lysis syndrome is increased if they have rapidly growing tumors, a high tumor burden, renal dysfunction, or dehydration.1 Patients at risk for tumor lysis syndrome (e.g., high tumor burden, rapidly growing tumors, renal dysfunction, dehydration) should be monitored closely and appropriate prophylaxis (e.g., adequate hydration) should be considered.1 If tumor lysis syndrome occurs, appropriate treatment should be initiated as clinically indicated.1
Inhibitors of vascular endothelial growth factor (VEGF) signaling pathway, such as pralsetinib, may impair wound healing.1
The manufacturer recommends temporary interruption of pralsetinib therapy for at least 5 days prior to elective surgery.1 The drug should not be administered for at least 2 weeks following major surgery; pralsetinib therapy should not be resumed postoperative until adequate wound healing has occurred.1 Safety of resuming pralsetinib therapy following resolution of wound healing complications has not been established.1
Fetal/Neonatal Morbidity and Mortality
Pralsetinib may cause fetal harm if administered to pregnant women; embryotoxicity and malformations have been demonstrated in animals.1 There are no available data regarding use of pralsetinib in pregnant women to inform a drug-associated risk.1 In animal reproduction studies, malformation and increased implantation loss were observed when the drug was administered to pregnant animals during the period of organogenesis at maternal exposures less than the human exposure at the recommended dosage of 400 mg once daily based on the AUC.1
Pregnancy should be avoided during pralsetinib therapy.1 The manufacturer states that a pregnancy test should be performed prior to initiation of pralsetinib therapy in females of reproductive potential and states that such females should be advised to use effective non-hormonal contraceptive methods while receiving pralsetinib and for 2 weeks after the final dose.1 Males who are partners of such females should use effective methods of contraception while receiving pralsetinib and for 1 week after the final dose.1 Patients should be apprised of the potential hazard to the fetus if pralsetinib is used during pregnancy.1
Pralsetinib may cause fetal harm if administered to pregnant women based on its mechanism of action and animal findings.1
The manufacturer states that a pregnancy test should be performed prior to initiation of pralsetinib therapy in females of reproductive potential.1 Patients should be apprised of the potential hazard to the fetus if pralsetinib is used during pregnancy.1
It is not known whether pralsetinib or its metabolites are distributed into human milk.1 The effects of the drug on nursing infants or on the production of milk are unknown.1 Because of the potential for adverse reactions to pralsetinib in nursing infants, women should be advised not to breast-feed while receiving the drug and for 1 week after the final dose.1
Females and Males of Reproductive Potential
Verify pregnancy status in females of reproductive potential prior to initiating pralsetinib.1 Advise females of reproductive potential to use effective non-hormonal contraception during therapy and for 2 weeks after the last dose.1 Advise males with females partners of reproductive potential to use effective contraception during therapy and for 1 week after the last dose.1
Pralsetinib may impair fertility based on histopathological findings in reproductive tissues of male and female rats and a fertility study in which animals of both sexes were treated and mated to each other.1
Safety and efficacy of pralsetinib for the treatment of metastatic rearranged during transfection (RET) fusion-positive non-small cell lung cancer (NSCLC) have not been established in pediatric patients.1
Safety and efficacy of pralsetinib for the treatment of RET fusion-positive thyroid cancer in pediatric patients 12 years of age or older is supported by extrapolation of data from a clinical study evaluating pralsetinib in adults and additional pharmacokinetic data in pediatric patients 12 years of age or older demonstrating that age and body weight had no clinically meaningful effect on the pharmacokinetics of the drug.1 Systemic exposure of pralsetinib is expected to be similar between adults and pediatric patients aged 12 years and older.1 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.1
Skeletal (i.e., physeal dysplasia) and tooth abnormalities (i.e., fractures, dentin matrix alteration, ameloblast/odontoblast degeneration, necrosis) have been observed in immature animals receiving pralsetinib at exposure levels similar to human exposure at the 400 mg once daily dosage.1 The manufacturer recommends monitoring growth plates in adolescents with open growth plates.1 If growth plate abnormalities occur, interruption or discontinuance of therapy should be considered based on the severity of the abnormality and individual risk-benefit assessment.1
In the ARROW study, 31% of patients receiving pralsetinib 400 mg once daily were 65 years of age or older and 7% were 75 years of age or older.1 No differences in pharmacokinetics, safety, or efficacy were observed between geriatric patients and younger adults.1
Mild (total bilirubin concentrations not exceeding the upper limit of normal [ULN] with AST concentrations exceeding the ULN, or total bilirubin concentrations exceeding 1 to 1.5 times the ULN with any AST concentration), moderate (total bilirubin concentration exceeding 1.5 to 3 times the ULN and any AST concentration), or severe (total bilirubin concentration exceeding 3 times the ULN and any AST concentration) hepatic impairment did not have clinically important effects on the pharmacokinetics of pralsetinib; no dosage adjustment is necessary in patients with mild to severe hepatic impairment.1
Population pharmacokinetic analysis suggests that mild or moderate renal impairment (creatinine clearance 30-89 mL/minute) does not affect the exposure of pralsetinib.1
Pharmacokinetics of pralsetinib have not been studied in patients with severe renal impairment (creatinine clearance less than 15 mL/minute).1
The most common adverse reactions (≥25%) were musculoskeletal pain, constipation, hypertension, diarrhea, fatigue, edema, pyrexia, and cough.1 The most common grade 3 or 4 laboratory abnormalities (≥2%) were decreased lymphocytes, decreased neutrophils, decreased phosphate, decreased hemoglobin, decreased leukocytes, decreased sodium, decreased calcium (corrected), increased ALT/AST concentrations, decreased platelets, increased alkaline phosphatase, increased or decreased potassium, and increased bilirubin.1
Pralsetinib is metabolized principally by CYP3A4 and to a lesser extent by CYP isoenzymes 2D6 and 1A2.1 In vitro studies indicate that pralsetinib is a substrate and inhibitor of P-gp and breast cancer resistance protein (BCRP).1 Pralsetinib is also an inhibitor of organic anion transporting peptide (OATP) 1B1, OATP1B3, organic anion transporter (OAT)1, multidrug and toxin extrusion (MATE)1, MATE2-K, and bile salt efflux pump (BSEP).1 Pralsetinib is not an inhibitor of organic cation transporter (OCT) 1, OCT2, and OAT1A3.1
In vitro studies indicate that pralsetinib is a time-dependent inhibitor of CYP3A and an inhibitor of CYP isoenzymes 2C8, 2C9, and 3A.1 Pralsetinib is an inducer of CYP isoenzymes 2C8, 2C9, and 3A.1 Pralsetinib does not inhibit CYP isoenzymes 1A2, 2B6, 2C19, or 2D6 and does not induce 1A2, 2B6, or 2C19.1
Drugs Affecting or Affected by Hepatic Microsomal Enzymes
Strong or Moderate CYP3A Inhibitors and/or P-gp Inhibitors
Concomitant use of pralsetinib with a strong or moderate CYP3A inhibitor and/or P-gp inhibitor may result in increased pralsetinib exposure and increased risk or severity of adverse reactions to pralsetinib.1 When the combined P-gp and strong CYP3A inhibitor itraconazole (200 mg once daily) was administered concomitantly with pralsetinib (single 200-mg dose), AUC and peak plasma concentration of pralsetinib increased by 3.5- and 1.8-fold, respectively.1
Avoid concomitant use of pralsetinib with a strong or moderate CYP3A inhibitor and/or P-gp inhibitor.1 If concomitant use with a strong or moderate CYP3A and/or P-gp inhibitor cannot be avoided, reduce the dose of pralsetinib as described in Table 3.1 When concomitant use of the P-gp and/or CYP3A inhibitor is discontinued, the pralsetinib dosage should be returned (after 3-5 elimination half-lives) to the dosage used prior to initiation of the P-gp and/or CYP3A inhibitor.1
Strong or Moderate CYP3A Inducers
Concomitant use of pralsetinib and strong or moderate inducers of CYP3A may result in decreased pralsetinib exposure and decreased efficacy of pralsetinib.1 When the strong CYP3A inducer rifampin (600 mg once daily) was administered concomitantly with pralsetinib (single 400-mg dose), AUC and peak plasma concentration of pralsetinib decreased by 68 and 30%, respectively.1
Avoid concomitant use of pralsetinib with strong or moderate CYP3A inducers.1 If concomitant use with strong or moderate CYP3A inducers cannot be avoided, increase the dose of pralsetinib as described in Table 4, starting on day 7 of concomitant use.1 After the moderate or strong CYP3A inducer has been discontinued for at least 14 days, the pralsetinib dosage should be returned to the dosage used prior to initiation of the moderate or strong CYP3A inducer.1
Drugs Affecting Gastric Acidity
Although aqueous solubility of pralsetinib is pH dependent, with higher pH resulting in lower solubility, concomitant administration of pralsetinib with drugs that reduce gastric acidity such as proton-pump inhibitors, antacids, and histamine H2-receptor antagonists do not have a clinically meaningful effect on pharmacokinetics of pralsetinib.2 When esomeprazole (40 mg once daily for 6 days) was administered concomitantly with pralsetinib (single 400-mg dose), no clinically significant differences in pharmacokinetics of pralsetinib were observed.1, 2
No dosage adjustment is necessary when pralsetinib is administered concomitantly with drugs affecting gastric acidity.2
Pralsetinib, an inhibitor of multiple receptor tyrosine kinases, including wild-type and mutated rearranged during transfection ( RET ) isoforms, is an antineoplastic agent.1, 2 RET is a receptor tyrosine kinase (RTK) involved in the initiation of various cascades of intracellular signaling events (i.e., MAPK, PI3K, JAK-STAT, Pka, Pkc signal transduction pathways), which leads to cell proliferation critical to development of the enteric nervous system and kidney and contributes to the maintenance of neural, neuroendocrine, and hematopoietic and male germ cell tissues postnatally.16 Genomic aberrations in RET have been implicated in the pathogenesis of several human cancers.16 Chromosomal rearrangements involving in-frame fusions of RET with various partners or point or insertion-deletion (indel) mutations in RET can result in constitutively activated chimeric RET fusion proteins that can act as oncogenic drivers by promoting cell proliferation of tumor cell lines.16, 17 Pralsetinib has demonstrated antitumor activity in cultured cells and animal models with RET fusions and mutations including KIF5B-RET , CCDC6-RET , RET-M918T , RET-C634W , V804E , V804L , and V804M .1, 2, 4 In addition, pralsetinib prolonged survival in mice implanted intracranially with tumor models expressing KIF5B-RET or CCDC6-RET .1 In cellular assays, pralsetinib inhibited RET at approximately 14-, 40-, and 12-fold lower concentrations than VEGFR2, FGFR2, and JAK2, respectively.1
In vitro, pralsetinib is 8- to 28-fold more potent against wild-type RET compared to cabozantinib and vandetanib.5 Selectivity of drug against RET also is 88-fold higher compared to other multikinase inhibitors.5
Following oral administration, peak plasma concentrations of pralsetinib are achieved in a median of 2-4 hours.1 Administration of pralsetinib with a high-fat meal increased peak plasma concentration or AUC of the drug by 2- or 2.2-fold, respectively; median time to peak concentration was delayed by 4.5 hours compared to the fasting state.1 Pralsetinib is 97% bound to plasma proteins, independent of pralsetinib concentration.1 Pralsetinib is metabolized principally by CYP3A4 and to a lesser extent by CYP2D6 and CYP1A2.1 Oxidation and glucuronidation are minor pathways (metabolites detected as ≤5%).1 Following oral administration of a single dose of radiolabeled pralsetinib, 73% of the dose is eliminated in feces (66% as unchanged drug) and 6% of the dose is eliminated in urine (4.8% as unchanged drug).1 The mean plasma elimination half-life of pralsetinib is 16 hours following a single dose and 20 hours following multiple doses.1 Age (19-87 years), sex, race/ethnicity, body weight, and mild to moderate renal impairment (creatinine clearance 30-89 mL/minute) do not have clinically important effects on the pharmacokinetics of pralsetinib.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Distribution of pralsetinib is restricted.13 Contact manufacturer for additional information.13
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Capsule | 100 mg | Rigel Pharmaceuticals |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions March 10, 2026. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Rigel Pharmaceuticals, Inc. Gavreto® (pralsetinib) capsules prescribing information. South San Francisco, CA; 2025 Dec.
2. Food and Drug Administration. Center for Drug Evaluation and Research. Application number: 213721Orig1s000: Multi-discipline review. From FDA website. [Web]
3. Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. [Web]
4. Li AY, McCusker MG, Russo A et al. RET fusions in solid tumors. Cancer Treat Rev . 2019; 81:101911. [PubMed 31715421]
5. Cascetta P, Sforza V, Manzo A et al. RET Inhibitors in Non-Small-Cell Lung Cancer. Cancers (Basel) . 2021; 13 [PubMed 34503226]
6. Gainor JF, Curigliano G, Kim DW et al. Pralsetinib for RET fusion-positive non-small-cell lung cancer (ARROW): a multi-cohort, open-label, phase 1/2 study. Lancet Oncol . 2021; 22:959-969. [PubMed 34118197]
8. Besse B, Felip E, Kim ES et al. AcceleRET Lung: A Phase 3 Study of First-Line Pralsetinib in Patients with RET-Fusion+ Advanced/ Metastatic NSCLC. International Association for the Study of Lung Cancer (IASLC) poster presentations 12. Poster. No. 87.02.
9. Subbiah V, Hu MI, Wirth LJ et al. Pralsetinib for patients with advanced or metastatic RET-altered thyroid cancer (ARROW): a multi-cohort, open-label, registrational, phase 1/2 study. Lancet Diabetes Endocrinol . 2021; 9:491-501. [PubMed 34118198]
12. Santoro M, Moccia M, Federico G et al. RET Gene Fusions in Malignancies of the Thyroid and Other Tissues. Genes (Basel) . 2020; 11 [PubMed 32326537]
13. Genentech. Gavreto® distribution. From Genentech for US Healthcare Providers website. [Web]
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