Pralsetinib (Gavreto): A Comprehensive Monograph on a Selective RET Kinase Inhibitor

Executive Summary

Pralsetinib, marketed under the brand name Gavreto, is an orally administered, small-molecule, targeted antineoplastic agent. It represents a significant advancement in the field of precision oncology as a highly potent and selective inhibitor of the Rearranged during Transfection (RET) receptor tyrosine kinase. The development of pralsetinib was driven by the need to overcome the limitations of older, less specific multi-kinase inhibitors, which exhibited activity against RET but were often associated with substantial off-target toxicities. Pralsetinib's mechanism of action involves the direct inhibition of wild-type RET as well as oncogenic RET fusions and mutations that serve as key drivers in various solid tumors.

Clinical development, centered on the pivotal Phase 1/2 ARROW trial, has demonstrated profound and durable clinical responses in biomarker-selected patient populations. Pralsetinib has secured regulatory approval for the treatment of adult patients with metastatic RET fusion-positive non-small cell lung cancer (NSCLC) and for certain pediatric and adult patients with RET fusion-positive thyroid cancer. The efficacy data from the ARROW study underscore its transformative potential, with high overall response rates and prolonged durations of response, even in heavily pretreated patient populations.

The clinical application of pralsetinib requires a nuanced understanding of its distinct pharmacological profile. Its pharmacokinetics are characterized by a significant food effect on absorption, necessitating strict administration on an empty stomach to ensure consistent drug exposure. The safety profile is manageable but includes clinically important risks such as interstitial lung disease/pneumonitis, hypertension, hepatotoxicity, and hematologic toxicities. Furthermore, pralsetinib is a sensitive substrate of both the cytochrome P450 3A4 (CYP3A4) enzyme and the P-glycoprotein (P-gp) transporter, leading to a high potential for clinically significant drug-drug interactions that mandate careful medication management and, in many cases, specific dose adjustments. This monograph provides a comprehensive review of the chemical properties, pharmacology, clinical efficacy, regulatory history, and clinical management considerations for pralsetinib.

Drug Identification and Chemical Properties

Nomenclature and Identifiers

Pralsetinib is identified by a consistent set of generic, brand, and chemical names, as well as unique database and regulatory codes that ensure its precise identification across clinical, research, and commercial contexts.

• Generic Name: Pralsetinib [1]
• Brand Name: Gavreto [1]
• Code Names and Synonyms: BLU-667, CS 3009 [1]
• DrugBank ID: DB15822 [1]
• CAS Number: 2097132-94-8 [3]
• ChEMBL ID: CHEMBL4297597, CHEMBL4582651 [5]
• ATC Code: L01EX23 [1]

Physicochemical Characteristics

Pralsetinib is a synthetic small molecule classified as a tyrosine kinase inhibitor. Its specific chemical structure and properties define its interaction with its biological target and its pharmacokinetic behavior.

• Drug Type: Small Molecule [Query]
• Drug Class: Tyrosine Kinase Inhibitor; RET Inhibitor [1]
• Chemical Formula: C27​H32​FN9​O2​ [3]
• Molecular Weight: Approximately 533.6 g/mol [3]
• IUPAC Name: cis-N-{(1S)-1-[6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl]ethyl}-1-methoxy-4-{4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl}cyclohexane-1-carboxamide [3]
• SMILES Code: O=C([C@@]1(OC)CCC@@HCC1)NC
• InChI Key: GBLBJPZSROAGMF-RWYJCYHVSA-N
• Physical Appearance: A solid described as white to off-white
• Solubility: Soluble in dimethyl sulfoxide (DMSO); slightly soluble in methanol and water

Pharmacology and Mechanism of Action

The Role of the RET Proto-Oncogene in Oncology

The RET (Rearranged during Transfection) proto-oncogene encodes a transmembrane receptor tyrosine kinase that is essential for the normal development of the nervous and renal systems. In normal physiological conditions, RET signaling is tightly regulated. However, specific genetic alterations can transform the

RET gene into a potent oncogenic driver. These alterations primarily fall into two categories: gene fusions and activating point mutations.

RET fusions, such as KIF5B-RET and CCDC6-RET, result from chromosomal rearrangements that join the kinase domain of RET to a partner gene. This leads to the expression of a chimeric protein with constitutive, ligand-independent kinase activity. Similarly, certain point mutations, such as the common

M918T mutation in medullary thyroid cancer, lock the kinase in a permanently "on" state. This aberrant and continuous activation of the RET kinase drives oncogenesis by promoting uncontrolled cell growth, proliferation, and survival through the dysregulation of critical downstream signaling cascades, including the MAPK/ERK and PI3K/AKT pathways. These alterations are the definitive oncogenic drivers in specific subsets of malignancies, including approximately 1-2% of non-small cell lung cancers (NSCLC), 10-20% of papillary thyroid cancers, and up to 90% of advanced medullary thyroid cancers (MTC).

Pralsetinib as a Highly Selective RET Kinase Inhibitor

Pralsetinib is a next-generation, orally available precision therapy designed to specifically inhibit the RET kinase. Its primary mechanism of action is the competitive inhibition of adenosine triphosphate (ATP) binding to the RET kinase domain. By occupying the ATP-binding site, pralsetinib prevents the autophosphorylation of the RET receptor, thereby blocking its activation and abrogating all downstream oncogenic signaling. The molecular basis for this potent inhibition has been elucidated through co-crystal structure analysis, which reveals that the aminopyrimidinyl and methylaminopyrazolyl moieties of pralsetinib form three critical hydrogen bonds with hinge residues Ala807 and Glu805 within the adenosine pocket of the RET kinase.

Potency Against Wild-Type, Fused, and Mutated RET Isoforms

A key feature of pralsetinib is its potent activity across a wide spectrum of RET alterations. It demonstrates sub-nanomolar inhibitory concentrations (IC50​) against wild-type RET, various oncogenic RET fusions (e.g., CCDC6-RET), and clinically relevant activating point mutations, including M918T. The reported IC50​ values for these targets are consistently in the range of 0.3–0.4 nM. Importantly, this potent activity extends to RET kinase domain mutations that can confer resistance to other kinase inhibitors, such as the "gatekeeper" mutations

V804L and V804M, against which pralsetinib also maintains an IC50​ of ~0.3-0.4 nM. This broad-spectrum potency against both primary oncogenic drivers and potential resistance mutations provides a strong therapeutic rationale for its use in

RET-altered cancers.

Comparative Selectivity and Off-Target Profile

The clinical utility of pralsetinib is fundamentally linked to its high degree of selectivity. It was rationally designed to overcome the limitations of older multi-kinase inhibitors (MKIs) like cabozantinib and vandetanib. While these older agents have activity against RET, they also inhibit numerous other kinases, such as vascular endothelial growth factor receptor 2 (VEGFR2), leading to a lack of specificity that is associated with substantial off-target toxicities. This engineered selectivity is a defining characteristic of pralsetinib and directly contributes to its improved therapeutic window. Preclinical kinase panel screening demonstrated that pralsetinib is at least 100-fold more selective for RET over 96% of 371 other kinases tested. Its inhibitory concentration against VEGFR2 (

IC50​ = 35 nM) is nearly two orders of magnitude weaker than its activity against RET, effectively minimizing the VEGFR2-mediated toxicities (e.g., severe hypertension, bleeding) that often limit the utility of older MKIs. This biochemical precision translates into a more tolerable clinical profile, allowing for sustained target inhibition at therapeutic doses.

The development and approval of pralsetinib, alongside its contemporary selpercatinib, marks a strategic maturation in oncology drug development. Its entire clinical pathway was predicated on a "biomarker-first" approach, where patient eligibility was determined not by cancer histology alone but by the presence of a specific molecular driver. The pivotal ARROW trial exclusively enrolled patients with documented RET gene alterations, and the subsequent regulatory approvals are strictly limited to these biomarker-defined populations, with treatment contingent upon confirmation by an FDA-approved diagnostic test. This paradigm stands in contrast to historical approaches and exemplifies the advancement of precision oncology, where therapies are developed for a specific molecular vulnerability. This has had profound effects on the field, establishing comprehensive genomic testing as a standard of care in relevant cancers and reshaping the design of clinical trials to focus on molecularly-defined cohorts.

Pharmacokinetics: Absorption, Distribution, Metabolism, and Excretion (ADME)

The clinical use of pralsetinib is governed by its distinct pharmacokinetic properties, particularly its absorption characteristics and metabolic pathways, which have significant implications for dosing and drug-drug interaction management.

Oral Bioavailability and Absorption Dynamics

Pralsetinib is administered orally as a hard capsule and is rapidly absorbed, with the median time to reach maximum plasma concentration (Tmax​) occurring 2 to 4 hours after administration under fasting conditions.

A critical aspect of its absorption profile is a pronounced food effect. When administered with a high-fat meal, the bioavailability of pralsetinib increases substantially, with the mean maximum concentration (Cmax​) increasing by 104% and the mean total exposure (Area Under the Curve, AUC) increasing by 122%. This interaction also delays absorption, with the median

Tmax​ shifting from 4 hours to 8.5 hours. To mitigate the risk of unpredictable overexposure and associated toxicity, and to ensure consistent pharmacokinetics, pralsetinib must be administered in a fasted state. The prescribing information strictly mandates that the drug be taken on an empty stomach, with no food consumed for at least 2 hours before and at least 1 hour after the dose. This demanding administration schedule can present a significant adherence challenge for patients, particularly those experiencing cancer-related symptoms like nausea or fatigue. Inconsistent adherence to the fasting requirement could lead to dangerous fluctuations in drug exposure, potentially compromising either safety or efficacy. This underscores the need for thorough patient education and support to manage this regimen in real-world clinical practice.

Distribution

Once absorbed, pralsetinib distributes extensively throughout the body. It is highly bound to human plasma proteins (~97.1%), a property that is independent of drug concentration. The large apparent volume of distribution (

Vd​) of 228–303 L indicates that the drug is not confined to the vascular compartment and partitions extensively into peripheral tissues. Evidence also suggests that pralsetinib crosses the blood-brain barrier, a clinically important feature given its demonstrated efficacy in patients with central nervous system (CNS) metastases.

Metabolic Pathways and Cytochrome P450 System Interplay

Pralsetinib is primarily cleared via hepatic metabolism.

In vitro studies have identified the cytochrome P450 (CYP) enzyme system as the main pathway, with CYP3A4 being the principal enzyme responsible for its metabolism. The enzymes CYP2D6 and CYP1A2 play minor roles. In addition to being a CYP3A4 substrate, pralsetinib is also a substrate of the critical efflux transporter P-glycoprotein (P-gp).

This dual-substrate nature for both a major metabolic enzyme and a key efflux transporter creates a high-risk pharmacokinetic profile that is highly susceptible to drug-drug interactions (DDIs). Many commonly used medications are potent inhibitors or inducers of CYP3A4 and/or P-gp, and the frequent overlap between these pathways makes pralsetinib particularly vulnerable. Clinical DDI studies have confirmed this vulnerability: co-administration with itraconazole (a strong CYP3A and P-gp inhibitor) increased pralsetinib exposure by 3.5-fold, while the strong CYP3A inducer rifampin decreased exposure by 68%. Such large variations in drug exposure are clinically unacceptable, as they can lead to severe toxicity or a complete loss of therapeutic effect. Consequently, this dual-substrate vulnerability is the direct reason for the complex and highly prescriptive dose modification guidelines found in the drug's labeling, making comprehensive medication reconciliation and pharmacist consultation essential components of safe pralsetinib therapy.

Elimination and Half-Life

The elimination of pralsetinib and its metabolites occurs predominantly through the hepatobiliary system. A human mass balance study demonstrated that after a single oral dose, 73% of the radioactivity was recovered in the feces (with 66% as unchanged pralsetinib), while only 6% was recovered in the urine (5% as unchanged drug). The mean apparent oral clearance (

CL/F) at steady state is approximately 9.1 L/h. The mean plasma elimination half-life (

t1/2​) is approximately 15 to 22 hours following multiple doses, which supports a once-daily dosing regimen.

Clinical Efficacy in RET-Altered Malignancies

Overview of the Pivotal ARROW Clinical Trial Program

The clinical efficacy and safety of pralsetinib were established in the multicenter, open-label, multi-cohort Phase 1/2 ARROW trial (NCT03037385). This first-in-human study was designed to evaluate pralsetinib in patients with advanced solid tumors harboring

RET gene alterations. The Phase 2 dose-expansion portion of the trial, which forms the basis of its regulatory approvals, investigated the recommended dose of 400 mg once daily. The primary efficacy endpoints were Overall Response Rate (ORR) and Duration of Response (DoR), as assessed by a Blinded Independent Central Review (BIRC) using RECIST v1.1 criteria.

Efficacy in RET Fusion-Positive Non-Small Cell Lung Cancer (NSCLC)

The ARROW trial demonstrated robust and durable anti-tumor activity in both treatment-naïve and previously treated patients with metastatic RET fusion-positive NSCLC.

Treatment-Naïve Patient Cohort

In patients who had not received prior systemic therapy for metastatic disease, pralsetinib showed high rates of response.

• Overall Response Rate (ORR): Across different analyses of the ARROW trial, the ORR in this population ranged from 70% to 79%. An analysis of 107 patients reported an ORR of 78% (95% CI: 68%, 85%), which included a complete response (CR) rate of 7%. Another analysis of 75 patients found an ORR of 72% (95% CI: 60%, 82%) with a 5% CR rate.
• Duration of Response (DoR): Responses were durable. The median DoR in the cohort of 107 patients was 13.4 months (95% CI: 9.4, 23.1). A separate analysis noted that 54% of responses were ongoing at 12 months.

Platinum-Pretreated Patient Cohort

Pralsetinib demonstrated remarkable efficacy in patients whose disease had progressed following standard-of-care platinum-based chemotherapy.

• Overall Response Rate (ORR): In this heavily pretreated population, the ORR was consistently high. An analysis of 87 patients showed an ORR of 57% (95% CI: 46%, 68%) with a CR rate of 5.7%. A larger analysis of 130 patients reported an ORR of 63% (95% CI: 54%, 71%).
• Duration of Response (DoR): The durability of response in this setting was exceptional and a key finding of the trial. In the cohort of 130 patients, the median DoR was 38.8 months (95% CI: 14.8, not estimable). An earlier analysis had already shown that 80% of responding patients had responses lasting 6 months or longer.

This profound and durable activity in patients who have already failed standard chemotherapy establishes selective RET inhibition as a new standard of care. Historically, outcomes for this patient population are poor. The ability of pralsetinib to induce a response in approximately 60% of these patients with a median duration of over three years is transformative. It demonstrates that the therapy remains highly effective by precisely targeting the central oncogenic driver, even after the cancer has proven refractory to broader-acting cytotoxic agents.

Efficacy in RET-Altered Thyroid Cancers

Pralsetinib also showed significant clinical activity in patients with advanced or metastatic RET-altered thyroid cancers.

RET-Mutant Medullary Thyroid Cancer (MTC)

• Previously Treated Cohort: In a cohort of 55 patients previously treated with the MKIs cabozantinib and/or vandetanib, pralsetinib achieved an ORR of 60% (95% CI: 46%, 73%). Of those who responded, 79% had responses lasting at least 6 months. The high response rate in patients who had already received other RET-active agents further underscores the superior potency and selectivity of pralsetinib.
• Treatment-Naïve Cohort: In 29 patients with no prior systemic therapy, the ORR was 66% (95% CI: 46%, 82%), with 84% of responses lasting at least 6 months.

RET Fusion-Positive Differentiated Thyroid Cancer (DTC)

In a smaller cohort of 9 patients with RET fusion-positive thyroid cancer who were refractory to radioactive iodine therapy, pralsetinib demonstrated a striking ORR of 89% (95% CI: 52%, 100%). All responding patients had responses lasting 6 months or longer.

The consistent, high-level efficacy of pralsetinib across different tumor histologies (lung adenocarcinoma, medullary thyroid carcinoma, papillary thyroid carcinoma) and regardless of the specific RET fusion partner (e.g., KIF5B vs. CCDC6) highlights a core principle of modern precision medicine. The clinical benefit is derived from inhibiting the specific RET oncoprotein, which serves as the cancer's central vulnerability, irrespective of the tissue environment in which the tumor arose. This provides a strong "tumor-agnostic" rationale for the investigation of pralsetinib in other solid tumors harboring

RET alterations, as is being explored in ongoing basket trials.

Indication	Patient Line of Therapy	N	Overall Response Rate (ORR) (95% CI)	Complete Response (CR)	Median Duration of Response (DoR) (95% CI)
NSCLC, RET Fusion+	Treatment-Naïve	107	78% (68, 85)	7%	13.4 months (9.4, 23.1)
NSCLC, RET Fusion+	Platinum-Pretreated	130	63% (54, 71)	6%	38.8 months (14.8, NE)
MTC, RET-Mutant	Treatment-Naïve	29	66% (46, 82)	N/A	Not Reached
MTC, RET-Mutant	Pretreated (Cabozantinib/Vandetanib)	55	60% (46, 73)	N/A	Not Reached
Thyroid Cancer, RET Fusion+	RAI-Refractory	9	89% (52, 100)	N/A	Not Reached
Data compiled from multiple analyses of the ARROW trial. N/A = Not Available; NE = Not Estimable; RAI = Radioactive Iodine.

Regulatory Landscape and Market Access

The regulatory journey of pralsetinib has been characterized by rapid approvals through expedited pathways, reflecting the high unmet need and compelling efficacy data for RET-altered cancers. However, its history also reveals the post-approval challenges faced by targeted therapies for rare indications.

U.S. Food and Drug Administration (FDA) Approval History

The FDA utilized multiple expedited programs to accelerate patient access to pralsetinib, including Priority Review, Breakthrough Therapy Designation, Orphan Drug Designation, and the Real-Time Oncology Review (RTOR) pilot program. This deployment of a full suite of regulatory tools demonstrates the FDA's commitment to flexibility and speed for highly effective targeted therapies. It signals an evolution in the regulatory framework to match the pace of scientific discovery, prioritizing rapid patient access based on strong surrogate endpoints like ORR, with the requirement for subsequent confirmation.

• September 4, 2020: Pralsetinib received its first FDA approval under the Accelerated Approval pathway for the treatment of adult patients with metastatic RET fusion-positive NSCLC.
• December 1, 2020: The FDA granted a second Accelerated Approval for two thyroid cancer indications: adult and pediatric patients (12 years and older) with advanced or metastatic RET-mutant MTC requiring systemic therapy, and those with advanced or metastatic RET fusion-positive thyroid cancer refractory to radioactive iodine.
• August 9, 2023: Based on additional data from the ARROW trial confirming the durability of response, the FDA converted the NSCLC indication from Accelerated to Regular (full) Approval.
• July 10, 2023 (Indication Withdrawal): The manufacturer voluntarily withdrew the U.S. indication for RET-mutant MTC. This decision was not based on new safety or efficacy concerns but on the inability to fulfill the post-marketing requirement of a confirmatory clinical trial, a common challenge in rare diseases where patient accrual for large randomized studies is difficult.

European Medicines Agency (EMA) and Other Regions

• November 19, 2021: The European Commission granted a Conditional Marketing Authorisation for pralsetinib as a monotherapy for adults with RET fusion-positive advanced NSCLC who had not previously been treated with a RET inhibitor.
• November 3, 2022: The company withdrew its application to extend the European indication to include thyroid cancer, citing a change in strategy.
• October 24, 2024 (Marketing Authorisation Withdrawal): The marketing authorisation for Gavreto in the European Union was fully withdrawn at the request of the holder for commercial reasons.

The divergent regulatory outcomes in the U.S. and Europe, particularly the withdrawals, highlight that strong initial efficacy data and expedited approvals do not guarantee sustained market access. The logistical and financial burdens of conducting confirmatory trials for rare mutations, combined with commercial viability assessments in a competitive landscape, can lead to a drug being removed from the market in certain regions, thereby limiting treatment options for patients despite the drug's proven clinical benefit.

Dosing, Administration, and Patient Management

Recommended Dosing Regimen

The recommended dosage of pralsetinib is 400 mg administered orally once daily for all approved indications in adults and pediatric patients aged 12 years and older.

• Administration: Due to the significant food effect, pralsetinib must be taken on an empty stomach. Patients should not eat for at least 2 hours before and at least 1 hour after taking the capsule. The capsules should be swallowed whole and not crushed, opened, or chewed.
• Management of Missed or Vomited Doses: If a dose is missed, it can be taken as soon as remembered on the same day. Patients should resume their normal schedule the following day. If vomiting occurs after a dose, an additional dose should not be taken; the patient should wait for the next scheduled dose.

Management of Adverse Reactions: Dose Modifications and Interruptions

A structured, stepwise dose reduction protocol is essential for managing treatment-related toxicities.

• Dose Reduction Levels:
• First Reduction: 300 mg once daily
• Second Reduction: 200 mg once daily
• Third Reduction: 100 mg once daily
• Permanent Discontinuation: Pralsetinib should be permanently discontinued in patients who are unable to tolerate a dose of 100 mg once daily.

Specific, guideline-driven actions are required for managing the most clinically significant adverse reactions.

Adverse Reaction	Severity (Grade)	Recommended Action
Interstitial Lung Disease (ILD) / Pneumonitis	Grade 1 or 2	Withhold until resolution; resume at a reduced dose.
	Grade 3 or 4, or recurrent	Permanently discontinue.
Hypertension	Grade 3 (persistent despite optimal therapy)	Withhold until controlled; resume at a reduced dose.
	Grade 4	Permanently discontinue.
Hepatotoxicity (Elevated AST/ALT)	Grade 3 or 4	Withhold; monitor weekly until resolution to ≤ Grade 1. Resume at a reduced dose.
	Recurrent Grade ≥3	Permanently discontinue.
Hemorrhagic Events	Grade 3 or 4	Withhold until recovery to ≤ Grade 1.
	Severe or life-threatening	Permanently discontinue.
Guidelines compiled from prescribing information.

Comprehensive Safety Profile

Overview of Adverse Reactions from Clinical Trials

The safety profile of pralsetinib has been well-characterized in the ARROW trial. Treatment-related adverse events (AEs) are common and frequently lead to dose modifications. In clinical trials, approximately 60% of patients required a dose interruption due to an AE, 36% required a dose reduction, and 15% permanently discontinued treatment due to toxicity.

Warnings and Precautions

The prescribing information for pralsetinib includes several important warnings for serious or life-threatening risks that require careful monitoring and management.

• Interstitial Lung Disease (ILD)/Pneumonitis: This is a serious and potentially fatal risk. ILD/pneumonitis occurred in 10-12% of patients, with 3.3% experiencing Grade 3-4 events and 0.2% experiencing a fatal reaction. Any new or worsening respiratory symptoms (e.g., cough, dyspnea, fever) warrant immediate investigation and interruption of therapy.
• Hypertension: High blood pressure is a common AE, occurring in up to 35% of patients, with Grade 3 hypertension observed in 18%. Blood pressure must be well-controlled prior to starting pralsetinib and should be monitored weekly for the first month, then monthly thereafter.
• Hepatotoxicity: Liver enzyme elevations are frequent. Increased aspartate aminotransferase (AST) occurred in 49% of patients (7% Grade 3-4) and increased alanine aminotransferase (ALT) occurred in 37% (4.8% Grade 3-4). Liver function tests should be monitored every 2 weeks for the first 3 months of treatment, then monthly.
• Hemorrhagic Events: Serious, including fatal, hemorrhagic events can occur. Grade 3 or higher events were reported in 2.5% of patients. Pralsetinib should be permanently discontinued for severe or life-threatening hemorrhage.
• Tumor Lysis Syndrome (TLS): Cases of TLS have been reported, particularly in patients with MTC. Patients with a high tumor burden or rapidly growing tumors are at increased risk and should be monitored closely and receive appropriate prophylaxis, including hydration.
• Risk of Impaired Wound Healing: Pralsetinib has the potential to inhibit VEGF signaling pathways, which can interfere with wound healing. Therapy should be withheld for at least 5 days prior to elective surgery and not resumed for at least 2 weeks post-operatively.
• Embryo-Fetal Toxicity: Pralsetinib can cause fetal harm. Females of reproductive potential must use effective non-hormonal contraception during treatment and for 2 weeks after the final dose. Males with female partners of reproductive potential must use effective contraception during treatment and for 1 week after the final dose.

Common Adverse Reactions and Laboratory Abnormalities

The safety profile of pralsetinib is distinct and predictable. While both pralsetinib and the other selective RET inhibitor, selpercatinib, are highly effective, their toxicity profiles differ. Pralsetinib is more commonly associated with hematologic adverse events, whereas selpercatinib is noted for a higher incidence of gastrointestinal side effects. This differentiation in their "toxicology signatures" is a critical factor in clinical decision-making. For a patient with poor bone marrow reserve, the risk of neutropenia with pralsetinib might favor the use of selpercatinib. Conversely, for a patient with pre-existing gastrointestinal issues, pralsetinib may be the preferred agent. This allows for a personalized therapeutic choice based not on efficacy, but on tailoring the specific safety profile to an individual patient's comorbidities.

Adverse Reaction	All Grades (%)	Grade 3-4 (%)
Clinical Adverse Reactions (≥25%)
Musculoskeletal Pain	32-44	2.5
Constipation	35-45	0.7-1.0
Hypertension	28-38	14-18
Diarrhea	24-30	2.5-3.2
Fatigue	35-42	2.3-2.5
Edema	20-44	0
Pyrexia (Fever)	20-29	0-0.7
Cough	23-36	0.4-0.5
Laboratory Abnormalities
Decreased Lymphocytes	52	20
Increased AST	49	7
Increased ALT	37	4.8
Decreased Hemoglobin	N/A	≥2
Decreased Neutrophils	N/A	≥2
Decreased Phosphate	N/A	≥2
Data compiled from prescribing information and clinical trial reports.

Clinically Significant Drug-Drug Interactions

The management of drug-drug interactions (DDIs) is a critical component of pralsetinib therapy due to its metabolism by CYP3A4 and transport by P-gp.

Impact of CYP3A and P-glycoprotein (P-gp) Modulators

• Inhibitors: Co-administration of pralsetinib with drugs that are combined P-gp and strong CYP3A inhibitors (e.g., itraconazole, ketoconazole, clarithromycin) should be avoided. This combination can dramatically increase pralsetinib exposure (AUC increased by 251% with itraconazole) and the risk of toxicity. If co-administration is unavoidable, a dose reduction of pralsetinib is mandatory. Similar precautions apply to strong or moderate CYP3A inhibitors and P-gp inhibitors alone, which also increase pralsetinib concentrations.
• Inducers: Co-administration with strong CYP3A inducers (e.g., rifampin, carbamazepine, phenytoin, St. John's Wort) should be avoided. These agents can significantly decrease pralsetinib exposure (AUC decreased by 68% with rifampin), leading to a potential loss of efficacy. If co-administration is necessary, a dose increase of pralsetinib is required.

Recommended Dose Adjustments for Co-administered Agents

The high sensitivity of pralsetinib to these interactions necessitates specific, prescriptive dose adjustments. The following table provides a simplified guide based on the prescribing information.

Interacting Drug Class	Current Pralsetinib Dose	Recommended Adjusted Pralsetinib Dose
Combined P-gp and Strong CYP3A Inhibitors	400 mg or 300 mg daily	Reduce to 200 mg daily
	200 mg daily	Reduce to 100 mg daily
Strong or Moderate CYP3A Inducers	400 mg daily	Increase to 800 mg daily (strong) or 600 mg daily (moderate)
	300 mg daily	Increase to 600 mg daily (strong) or 500 mg daily (moderate)
	200 mg daily	Increase to 400 mg daily (strong) or 300 mg daily (moderate)
Dose adjustments should be made according to full prescribing information. After the interacting drug is discontinued, the pralsetinib dose should be returned to the original level after an appropriate washout period.

Conclusion and Future Directions

Pralsetinib (Gavreto) has firmly established itself as a cornerstone of therapy for patients with RET-altered malignancies. As a second-generation, highly selective RET kinase inhibitor, it has produced transformative clinical outcomes, including high and exceptionally durable responses in patients with RET fusion-positive NSCLC and RET-altered thyroid cancers. Its success is a testament to the power of precision oncology, where treatment is guided by the specific molecular drivers of a patient's cancer.

The effective and safe use of pralsetinib in clinical practice, however, demands a sophisticated level of clinical management. Prescribers and pharmacists must be acutely aware of its unique pharmacological characteristics, including the critical need for administration in a fasted state to avoid dangerous variability in exposure, a distinct safety profile characterized by risks of ILD, hypertension, and hematologic toxicities, and a high susceptibility to clinically significant drug-drug interactions that require vigilant medication review and proactive dose adjustments.

The future of pralsetinib will be further defined by ongoing research. The Phase 3 AcceleRET Lung study (NCT04222972), which is comparing pralsetinib directly against standard-of-care platinum-based chemotherapy in the first-line setting for RET fusion-positive NSCLC, is a critical confirmatory trial that will clarify its ultimate position in the treatment algorithm. Ultimately, the continued success of pralsetinib and the broader field of targeted therapy depends on the continued expansion and integration of routine, comprehensive genomic testing into standard oncology care. Only through the systematic identification of patients with these relatively rare but highly actionable

RET alterations can the full benefit of this potent and precise therapy be realized.

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