| On May 28, 2021, the U.S. Food and Drug Administration (FDA) approved LUMAKRAS (sotorasib) for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), as determined by an FDA-approved test, who have received at least one prior systemic therapy. This indication is approved under accelerated approval based on overall response rate (ORR) and duration of response (DOR). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). The approved recommended dosage of LUMAKRAS is 960 mg orally once daily. The tablet should be taken at the same time each day and swallowed whole. Additional information regarding dosage and administration as well as warnings and precautions about hepatotoxicity and interstitial lung disease (ILD)/pneumonitis can be found in the full prescribing information linked below. Mechanism of Action (MOA) and Pharmacokinetics (PK) MOA: Sotorasib is an inhibitor of KRAS G12C, a tumor-restricted, mutant-oncogenic form of the RAS GTPase, KRAS. General PK: Sotorasib exhibited non‑linear, time-dependent PK over the dose range of 180 mg to 960 mg (0.19 to 1 time the approved recommended dosage) once daily with similar systemic exposure (i.e., AUC0-24h and Cmax) across doses at steady-state due to saturable absorption. Sotorasib plasma concentrations reached steady state within 22 days. No accumulation was observed after repeat sotorasib dosages with a mean accumulation ratio of 0.56 (CV 59%). Absorption: The median time to sotorasib peak plasma concentration is 1 hour. Distribution: The sotorasib mean volume of distribution (Vd) at steady state is 211 L (CV 135%). In vitro, sotorasib plasma protein binding is 89%. Elimination: The sotorasib mean terminal half-life is 5 hours (SD 2). At 960 mg once daily, the sotorasib steady state apparent clearance is 26.2 L/hr (CV 76%). Metabolism: The main metabolic pathways of sotorasib are non‑enzymatic conjugation and oxidative metabolism with CYP3As. Excretion: After a single dose of radiolabeled sotorasib, 74% of the dose was recovered in feces (53% unchanged) and 6% (1% unchanged) in urine. Drug Interactions Acid‑Reducing Agents: Avoid co-administration of LUMAKRAS with proton pump inhibitors (PPIs), H2 receptor antagonists, and locally acting antacids. If co-administration cannot be avoided, administer LUMAKRAS 4 hours before or 10 hours after administration of a locally acting antacid. Concomitant use of LUMAKRAS with gastric acid-reducing agents decreased sotorasib concentrations, which may reduce the efficacy of sotorasib. Strong CYP3A4 Inducers: Avoid co-administration of LUMAKRAS with strong CYP3A4 inducers. Co-administration of LUMAKRAS with a strong CYP3A4 inducer decreased sotorasib, which may reduce the efficacy of sotorasib. CYP3A4 Substrates: Avoid co-administration of LUMAKRAS with CYP3A4 sensitive substrates for which minimal concentration changes may lead to therapeutic failures of the substrate. If co-administration cannot be avoided, increase the sensitive CYP3A4 substrate dosage in accordance with its prescribing information. Co-administration of LUMAKRAS with a CYP3A4 substrate decreased its plasma concentrations, which may reduce the efficacy of the substrate. P-glycoprotein (P-gp) Substrates: Avoid co-administration of LUMAKRAS with P-gp substrates, for which minimal concentration changes may lead to serious toxicities. If co-administration cannot be avoided, decrease the P-gp substrate dosage in accordance with its prescribing information. Co-administration of LUMAKRAS with a P-gp substrate (digoxin) increased digoxin plasma concentration, which may increase the adverse reactions of digoxin. Use in Specific Populations No clinically meaningful differences in the PK of sotorasib were observed based on age (28 to 86 years), sex, race (White, Black and Asian), body weight (36.8 to 157.9 kg), line of therapy, Eastern Cooperative Oncology Group Performance Status [ECOG PS (0,1)], mild and moderate renal impairment (eGFR ≥ 30 mL/min/1.73 m2), or mild hepatic impairment (AST or ALT < 2.5 × ULN or total bilirubin < 1.5 × ULN). The effect of severe renal impairment or moderate to severe hepatic impairment on sotorasib PK has not been studied. Efficacy and Safety Efficacy of LUMAKRAS was demonstrated in a subset of patients enrolled in a single‑arm, open‑label, multicenter trial. The major efficacy outcome measures were ORR and DOR as evaluated by Blinded Independent Central Review (BICR) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Additional information regarding the efficacy trial can be found in the full prescribing information linked below. The most common adverse reactions (≥ 20%) were diarrhea, musculoskeletal pain, nausea, fatigue, hepatotoxicity, and cough. The most common laboratory abnormalities (≥ 25%) were decreased lymphocytes, decreased hemoglobin, increased aspartate aminotransferase, increased alanine aminotransferase, decreased calcium, increased alkaline phosphatase, increased urine protein, and decreased sodium. | 
No comments:
Post a Comment