Osimertinib

Synthetic Routes and Reaction Conditions

The synthesis of osimertinib involves multiple steps, starting from commercially available starting materials. The key steps include the formation of the core structure, followed by the introduction of various functional groups. The synthetic route typically involves:

Formation of the Core Structure: The core structure of this compound is synthesized through a series of condensation and cyclization reactions.

Introduction of Functional Groups: Various functional groups, such as methoxy, dimethylamino, and indole groups, are introduced through nucleophilic substitution and coupling reactions.

Final Assembly: The final assembly involves the coupling of the core structure with the side chains to form the complete molecule.

Industrial Production Methods

Industrial production of this compound involves optimizing the synthetic route to ensure high yield and purity. The process typically includes:

Dry Granulation: The active pharmaceutical ingredient (API) is processed using dry granulation methods, such as roller compaction, to form tablets.

Optimization of Reaction Conditions: Parameters such as temperature, pressure, and pH are optimized to maximize yield and minimize impurities.

Metabolic Pathways and Biotransformation

Osimertinib undergoes hepatic metabolism via two primary routes:

• Oxidation : Primarily mediated by CYP3A4/5 enzymes, forming active metabolites AZ7550 and AZ5104 .
• Dealkylation : Produces AZ5104, which exhibits greater potency against wild-type EGFR than the parent compound .

Key Metabolites:

Deuteration at specific positions (e.g., this compound-d3) reduces AZ5104 formation due to kinetic isotope effects, confirming CYP3A’s role in demethylation .

Michael Addition Reaction in Plasma

This compound’s acrylamide group reacts with free cysteine in plasma via a Michael addition , leading to instability . This reaction is pH- and temperature-dependent:

The adducts disrupt quantification in pharmacokinetic studies, necessitating stabilization protocols .

Covalent Binding to EGFR

This compound forms an irreversible covalent bond with cysteine-797 in EGFR’s ATP-binding pocket via its acrylamide moiety . This interaction is critical for targeting T790M/L858R mutants selectively:

Structural studies show that mutations (e.g., C797S) abolish covalent binding, conferring resistance .

Species-Specific Metabolism

This compound’s metabolic pathways differ between humans and mice:

CYP1A1 induction further accelerates this compound clearance in humanized models .

Degradation Under Oxidative Conditions

In vitro studies reveal this compound’s susceptibility to oxidative degradation:

Stabilization requires storage at −70°C with antioxidants like ascorbic acid .

Synthetic Modifications and Deuterated Analogues

Deuteration at the methylene bridge (this compound-d3) alters metabolic kinetics:

This strategy mitigates AZ5104-related toxicity while maintaining efficacy .

Reaction with Glutathione

This compound’s acrylamide group reacts with glutathione (GSH) in vitro, forming a thioether adduct:

This reaction underscores its potential for off-target interactions .

pH-Dependent Solubility

This compound mesylate exhibits pH-dependent solubility, influencing formulation design:

Adjuvant Therapy Post-Surgery

Recent studies have highlighted the efficacy of osimertinib as an adjuvant therapy for patients with resected stage IB to IIIA NSCLC harboring EGFR mutations. The ADAURA trial demonstrated that patients receiving this compound after surgery had significantly improved disease-free survival (DFS) compared to those receiving placebo. Key findings from the trial include:

• Survival Rates : At five years, 88% of patients treated with this compound were alive compared to 78% in the placebo group .
• Disease Control : this compound reduced the risk of local and distant metastases and improved central nervous system DFS .

First-Line Treatment for Advanced NSCLC

This compound is also indicated as a first-line treatment for patients with advanced NSCLC who have activating EGFR mutations. Clinical trials have reported high overall response rates (ORR) and prolonged progression-free survival (PFS):

• Efficacy Metrics : A meta-analysis indicated an ORR of 79% and a disease control rate (DCR) of 97% in treatment-naïve patients .
• PFS Outcomes : The median PFS was reported at approximately 18.9 months for first-line this compound treatment .

Treatment for CNS Metastases

This compound has shown notable efficacy in patients with CNS metastases from NSCLC. Studies indicate that it penetrates the blood-brain barrier effectively, leading to significant tumor regression:

• CNS Response Rates : In trials such as AURA3, the confirmed CNS ORR was reported at 70%, significantly higher than traditional chemotherapy regimens .

Safety Profile

While this compound is generally well-tolerated, it is associated with specific adverse effects, including interstitial lung disease, skin reactions, and gastrointestinal issues. In the ADAURA trial, serious adverse events occurred in 16% of the this compound group compared to 12% in the placebo group . Monitoring for these effects is crucial during treatment.

Case Study 1: Early-Stage NSCLC

A patient diagnosed with stage IIIB NSCLC underwent surgical resection followed by adjuvant treatment with this compound. Post-treatment imaging showed no evidence of recurrence after two years, supporting the drug's role in preventing relapse in early-stage disease.

Case Study 2: Advanced NSCLC with CNS Metastasis

Another patient with advanced NSCLC and confirmed T790M mutation received this compound after progression on first-line therapy. The patient experienced a significant reduction in tumor size within three months, illustrating this compound's effectiveness against CNS lesions.

Osimertinib exerts its effects by irreversibly binding to mutant forms of the EGFR, including T790M, L858R, and exon 19 deletion mutations . This binding inhibits the tyrosine kinase activity of the receptor, preventing downstream signaling pathways that promote cell proliferation and survival . This compound also has the ability to cross the blood-brain barrier, making it effective in treating brain metastases .

Similar Compounds

Gefitinib: A first-generation EGFR TKI used in the treatment of NSCLC.

Erlotinib: Another first-generation EGFR TKI with similar limitations as gefitinib.

Afatinib: A second-generation EGFR TKI that is more potent but associated with higher toxicity.

Dacomitinib: Another second-generation EGFR TKI with broader activity but increased side effects.

Uniqueness of Osimertinib

This compound is unique in its ability to selectively target both sensitizing and resistance mutations in the EGFR gene while sparing wild-type EGFR, reducing toxicity . It has shown superior efficacy in treating NSCLC with T790M mutations and has a favorable safety profile compared to earlier generations of EGFR TKIs .

Osimertinib, also known as AZD9291 or Tagrisso, is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that has shown significant efficacy in treating non-small cell lung cancer (NSCLC), particularly in patients with specific EGFR mutations. This article explores the biological activity of this compound, highlighting its mechanisms of action, clinical effectiveness, and safety profile based on diverse research findings.

This compound selectively targets and irreversibly binds to the EGFR kinase domain, specifically at the cysteine residue at codon 797 (C797), through covalent bond formation. This mechanism results in potent inhibition of both sensitizing mutations (such as exon 19 deletions and L858R) and the T790M resistance mutation. In vitro studies have demonstrated that this compound exhibits a significantly lower IC50 against mutant EGFR compared to wild-type EGFR, indicating its high selectivity:

• IC50 Values :
  • Exon 19 deletion: 8–17 nmol/L
  • L858R/T790M: 5–11 nmol/L
  • Wild-type EGFR: 461–650 nmol/L .

Pharmacokinetics and Metabolism

This compound is metabolized into two primary active metabolites: AZ5104 and AZ7550. Both metabolites retain significant inhibitory activity against EGFR mutations. Notably, AZ5104 is more potent against exon 19 deletions and T790M mutations than this compound itself. This compound also demonstrates superior blood-brain barrier penetration compared to other EGFR TKIs, which is critical for treating patients with CNS metastases .

Clinical Efficacy

This compound has been evaluated across multiple clinical trials, demonstrating robust efficacy in various patient populations with NSCLC:

Key Clinical Findings

• AURA Trials :
  • AURA3 trial showed an overall response rate (ORR) of 63.3% with a disease control rate (DCR) of 93.3% among patients previously treated with other EGFR TKIs.
  • Median progression-free survival (mPFS) was reported at 10.41 months , with median overall survival (mOS) reaching 31.37 months .
• UNICORN Study :
  • In a cohort of previously untreated patients with uncommon EGFR mutations, this compound achieved an ORR of 55% and mPFS of 9.4 months .
• ARTICUNO Study :
  • This study confirmed this compound's activity in patients with uncommon EGFR mutations, reporting an intracranial ORR of 58% , emphasizing its efficacy even in the presence of brain metastases .

Table: Summary of Clinical Outcomes

Safety Profile

This compound is generally well-tolerated, with a low incidence of serious adverse effects. The most common side effects include diarrhea, rash, and dry skin, which are manageable and typically do not lead to treatment discontinuation. Notably, the incidence of hyperglycemia is less than 1%, attributed to its selective action on EGFR without significant off-target effects on insulin receptors .

Case Studies

Several case studies highlight the real-world effectiveness of this compound:

• A patient cohort from a multicenter study demonstrated sustained tumor shrinkage after starting this compound therapy, confirming its effectiveness in advanced stages of NSCLC.
• Another case series reported that patients with CNS metastases experienced significant improvements in both neurological symptoms and tumor size following treatment with this compound.

Basic Research Questions

Q. What experimental methodologies are critical for elucidating osimertinib's mechanism of action and selectivity for EGFR mutations?

• Methodological Answer : Use crystallographic studies to analyze binding affinities to wild-type EGFR vs. T790M/L858R mutants . Combine kinase inhibition assays (e.g., ADP-Glo™ Kinase Assay) to quantify IC₅₀ values across EGFR variants. Validate selectivity via cell viability assays in isogenic cell lines (e.g., PC-9 with EGFR exon 19 deletions vs. H1975 with T790M mutations) .

Q. How can researchers design robust clinical trials to evaluate this compound's efficacy in EGFR-mutant NSCLC?

• Methodological Answer : Adopt randomized controlled trials (RCTs) with progression-free survival (PFS) and overall survival (OS) as primary endpoints. Stratify cohorts by mutation subtype (e.g., exon 19 del vs. L858R) and prior treatment history. Use RECIST 1.1 criteria for tumor response assessment and Kaplan-Meier analysis for survival curves . Include crossover arms to address ethical concerns in placebo groups .

Q. What statistical approaches are recommended for analyzing this compound's safety profile in heterogeneous patient populations?

• Methodological Answer : Apply Cox proportional hazards models to correlate adverse events (e.g., interstitial lung disease) with baseline covariates (age, smoking history). Use Fisher’s exact test to compare grade ≥3 adverse event rates between this compound and comparator TKIs. Pooled analysis of phase III trials (e.g., FLAURA, AURA3) can enhance statistical power .

Advanced Research Questions

Q. How can researchers resolve contradictions in this compound's reported efficacy across different ethnic subgroups?

• Methodological Answer : Conduct meta-regression analyses to assess ethnicity as a covariable. Use genome-wide association studies (GWAS) to identify pharmacogenetic variants (e.g., CYP3A4 polymorphisms) affecting drug metabolism. Collaborate with international consortia (e.g., LC-SCRUM-Asia) to harmonize data collection and reduce confounding .

Q. What preclinical models best recapitulate this compound resistance mechanisms, and how should they be validated?

• Methodological Answer : Develop patient-derived xenograft (PDX) models from this compound-resistant NSCLC biopsies. Perform whole-exome sequencing to identify resistance drivers (e.g., MET amplification, C797S mutations). Validate findings using CRISPR-Cas9 knock-in/knockout models and orthogonal assays (e.g., Western blot for bypass pathway activation) .

Q. Which methodologies are optimal for investigating this compound's synergism with immune checkpoint inhibitors (ICIs)?

• Methodological Answer : Use syngeneic mouse models (e.g., MC38 tumors with EGFR mutations) to assess tumor-infiltrating lymphocyte (TIL) populations post-treatment. Combine RNA-seq and multiplex immunohistochemistry (IHC) to profile PD-L1 expression and T-cell exhaustion markers. Phase Ib/II trials should employ Simon’s two-stage designs to evaluate dose-limiting toxicities .

Q. How can researchers address discrepancies in this compound's CNS penetration data across pharmacokinetic studies?

• Methodological Answer : Standardize cerebrospinal fluid (CSF) sampling protocols (timing relative to dosing, LC-MS/MS quantification). Compare blood-brain barrier (BBB) penetration in genetically engineered mouse models (GEMMs) vs. non-human primates. Use PET imaging with ¹¹C-labeled this compound to quantify real-time brain distribution .

Methodological and Data Analysis Questions

Q. What strategies mitigate bias when analyzing retrospective real-world evidence (RWE) on this compound?

• Methodological Answer : Apply propensity score matching to balance confounders (e.g., ECOG performance status, prior therapies). Use sensitivity analyses to test robustness against unmeasured variables. Adhere to STROBE guidelines for RWE reporting .

Q. How should researchers design studies to identify predictive biomarkers for this compound response?

• Methodological Answer : Integrate multi-omics data (ctDNA sequencing, proteomics) from baseline tumor biopsies. Use machine learning (e.g., random forest models) to prioritize biomarkers. Validate candidates in independent cohorts via IHC (e.g., EGFR phosphorylation status) or droplet digital PCR (ddPCR) .

Q. What frameworks guide the formulation of clinically relevant research questions for this compound combination therapies?

• Methodological Answer : Adopt the PICO framework:
• P opulation: EGFR-mutant NSCLC patients with acquired resistance.
• I ntervention: this compound + MET inhibitor (e.g., savolitinib).
• C omparator: this compound monotherapy.
• O utcome: PFS, ORR, and incidence of resistance mutations.
  Ensure feasibility using FINER criteria (Feasible, Interesting, Novel, Ethical, Relevant) .