GAVRETO Capsule Ref.[10176] Active ingredients: Pralsetinib

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

Cardiac Electrophysiology

The QT interval prolongation potential of GAVRETO was assessed in 34 patients with RET fusion-positive solid tumors administered at the recommended dosage. No large mean increase in QTc (>20 ms) was detected in the study.

At 400 mg 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 2830 (52.5%) ng/mL and 43900 (60.2%) 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 <2-fold after once-daily repeated oral administration.

Absorption

The median time to peak concentration (T_max) ranged from 2 to 4 hours following single doses of pralsetinib 60 mg to 600 mg.

Food Effect

Following administration of a single dose of 400 mg GAVRETO with a high-fat meal, (approximately 800 to 1000 calories with 50 to 60% of calories from fat), the mean (90% CI) C_max of pralsetinib was increased by 104% (65%, 153%), the mean (90% CI) AUC_0-INF was increased by 122% (96%,152%), and the median T_max was delayed from 4 to 8.5 hours, compared to the fasted state.

Distribution

The mean (CV%) apparent volume of distribution (Vd/F) of pralsetinib is 228 L (75%). Protein binding of pralsetinib is 97.1% and is independent of concentration. The blood-to-plasma ratio is 0.6 to 0.7.

Elimination

The mean (±standard deviation) plasma elimination half-life (T_½) of pralsetinib 14.7 hours (6.5) following single doses and 22.2 hours (13.5) following multiple doses of pralsetinib. The mean (CV%) apparent oral clearance (CL/F) of pralsetinib is 9.1 L/h (60%) at steady state.

Metabolism

Pralsetinib is primarily metabolized by CYP3A4 and to a lesser extent by CYP2D6 and CYP1A2, in vitro. Following a single oral dose of approximately 310 mg of radiolabeled pralsetinib to healthy subjects, pralsetinib metabolites from oxidation (M531, M453, M549b) and glucuronidation (M709) were detected as 5% or less.

Excretion

Approximately 73% (66% as unchanged) of the total administered radioactive dose [¹⁴C] pralsetinib was recovered in feces and 6% (4.8% as unchanged) was recovered in urine.

Specific Populations

No clinically significant differences in the PK of pralsetinib were observed based on age (18 to 87 years), sex, race (256 White, 2 Black, or 147 Asian), and body weight (29.5 to 149 kg). Mild and moderate renal impairment (CLcr 30-89 mL/min) had no effect on the exposure of pralsetinib. Pralsetinib has not been studied in patients with severe renal impairment (CLcr <15 mL/min).

Patients with Hepatic Impairment

Mild hepatic impairment (total bilirubin ≤1.0 × ULN and AST > ULN, or total bilirubin >1.0 to 1.5 × ULN and any AST) had no effect on the PK of pralsetinib. Pralsetinib has not been studied in patients with moderate (total bilirubin >1.5 to 3.0 × ULN and any AST) or severe (total bilirubin >3.0 ULN and any AST) hepatic impairment.

Drug Interaction Studies

Clinical Studies and Model-Informed Approaches

Combined P-gp and Strong CYP3A Inhibitors: Coadministration of itraconazole 200 mg once daily with a single GAVRETO 200 mg dose increased pralsetinib C_max by 84% and AUC_0-INF by 251%.

Strong CYP3A Inducers: Coadministration of rifampin 600 mg once daily with a single GAVRETO 400 mg dose decreased pralsetinib C_max by 30% and AUC_0-INF by 68%.

Mild CYP3A Inducers: No clinically significant differences in the PK of pralsetinib were identified when GAVRETO was coadministered with mild CYP3A inducers.

Acid-Reducing Agents: No clinically significant differences in the PK of pralsetinib were observed when coadministered with gastric acid reducing agents.

In Vitro Studies

Cytochrome P450 (CYP) Enzymes: Pralsetinib is a time-dependent inhibitor of CYP3A4/5 and; an inhibitor of CYP2C8, CYP2C9, and CYP3A4/5, but not an inhibitor of CYP1A2, CYP2B6, CYP2C19 or CYP2D6 at clinically relevant concentrations.

Pralsetinib is an inducer of CYP2C8, CYP2C9, and CYP3A4/5 but not an inducer of CYP1A2, CYP2B6, or CYP2C19 at clinically relevant concentrations.

Transporter Systems: Pralsetinib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), but not a substrate of bile salt efflux pump (BSEP), organic cation transporter [OCT]1, OCT2, organic anion transporting polypeptide [OATP]1B1, OATP1B3, multidrug and toxin extrusion [MATE]1, MATE2-K, organic anion transporter [OAT]1, or OAT3.

Pralsetinib is an inhibitor of P-gp, BCRP, OATP1B1, OATP1B3, OAT1, MATE1, MATE2-K, and BSEP, but not an inhibitor of OCT1, OCT2, and OAT1A3 at clinically relevant concentrations

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 2.5-3.6 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 at 5 mg/kg (approximately 0.3 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 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 0.9 times the human exposure based on AUC at the clinical dose of 400 mg.

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 ≥1.1 times and ≥2.6 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 2.4-3.5 times and ≥0.11 times, respectively, the human exposure based on AUC at the clinical dose of 400 mg.

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 114 patients in the efficacy population(s) described in this section, samples from 59% 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 400mg orally once daily until disease progression or unacceptable toxicity.

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

Metastatic RET Fusion-Positive NSCLC Previously Treated with Platinum Chemotherapy

Efficacy was evaluated in 87 patients with RET fusion-positive NSCLC with measurable disease who were previously treated with platinum chemotherapy enrolled into a cohort of ARROW.

The median age was 60 years (range: 28 to 85); 49% were female, 53% were White, 35% were Asian, 6% were Hispanic/Latino. ECOG performance status was 0-1 (94%) or 2 (6%), 99% of patients had metastatic disease, and 43% had either a history of or current CNS metastasis. Patients received a median of 2 prior systemic therapies (range 1–6); 45% had prior anti-PD-1/PD-L1 therapy and 25% had prior kinase inhibitors. A total of 52% of the patients received prior radiation therapy. RET fusions were detected in 77% of patients using NGS (45% tumor samples; 26% blood or plasma samples, 6% unknown), 21% using FISH, and 2% using other methods. The most common RET fusion partners were KIF5B (75%) and CCDC6 (17%).

Efficacy results for RET fusion-positive NSCLC patients who received prior platinum-based chemotherapy are summarized in Table 6

Table 6. Efficacy Results in ARROW (Metastatic RET Fusion-Positive NSCLC Previously Treated with Platinum Chemotherapy):

NE = not estimable
* Confirmed overall response rate assessed by BICR
^† Calculated using the proportion of responders with an observed duration of response at least 6 months or greater

For the 39 patients who received an anti-PD-1 or anti-PD-L1 therapy, either sequentially or concurrently with platinum-based chemotherapy, an exploratory subgroup analysis of ORR was 59% (95% CI: 42, 74) and the median DOR was not reached (95% CI: 11.3, NE).

Among the 87 patients with RET-fusion positive NSCLC, 8 had measurable CNS metastases at baseline as assessed by BICR. No patients received radiation therapy (RT) to the brain within 2 months prior to study entry. Responses in intracranial lesions were observed in 4 of these 8 patients including 2 patients with a CNS complete response; 75% of responders had a DOR of ≥6 months.

Treatment-naïve RET Fusion-Positive NSCLC

Efficacy was evaluated in 27 patients with treatment-naïve RET fusion-positive NSCLC with measurable disease enrolled into ARROW.

The median age was 65 years (range 30 to 87); 52% were female, 59% were White, 33% were Asian, and 4% were Hispanic or Latino. ECOG performance status was 0-1 for 96% of the patients and all patients (100%) had metastatic disease 37% had either history of or current CNS metastasis. RET-fusions were detected in 67% of patients using NGS (41% tumor samples; 22% blood or plasma; 4% unknown) and 33% using FISH. The most common RET fusion partners were KIF5B (70%) and CCD6 (11%).

Efficacy results for treatment-naïve RET fusion-positive NSCLC are summarized in Table 7.

Table 7. Efficacy Results for ARROW (Treatment-Naïve Metastatic RET Fusion-Positive NSCLC:

NE = not estimable
* Confirmed overall response rate assessed by BICR
^† Calculated using the proportion of responders with an observed duration of response at least 6 months or greater