Phase I/II Study of Erlotinib to Determine the Optimal Dose in Patients With Non‐Small Cell Lung Cancer Harboring Only EGFR Mutations

The recommended daily dose of erlotinib was determined for patients with all types of non‐small cell lung cancer (NSCLC). We determined the optimal dose (OD) in patients with NSCLC harboring only epidermal growth factor receptor (EGFR) sensitizing mutations. EGFR‐tyrosine kinase inhibitor‐naïve patients with sensitizing mutations were eligible. Clinical OD was determined in a phase I/II study based on the continual re‐assessment method (CRM) of both disease control and dose‐limiting toxicity, defined as any toxicity of grade 2 (G2) or higher within 8 weeks. We also determined the pharmacologic OD via a pharmacokinetic (PK) study. Thirty‐eight patients were enrolled. Clinical OD was 25 mg/day by the CRM. Median progression‐free survival (mPFS) was 9.3 months. In receiver operating characteristic (ROC) analysis of mPFS, the trough concentration ( Cminss) was ≥ 0.30 μg/mL. The area under the curve (AUC) and Cminss were predicted via population PK (PopPK) or a bootstrap of 100 iterations (PopPK₁₀₀). TOX20 was defined as < 20% duration of any toxicity ≥ G2 during the PFS period. In ROC analysis of mPFS and TOX20 in the PopPK₁₀₀ study, Cminss was ≥ 0.17 and < 0.32 μg/mL, respectively. In ROC analysis of mPFS and TOX20 in the PopPK₁₀₀ study, Cminss was ≥ 0.15 and < 0.31 μg/mL, AUC was ≥ 14.4 and < 14.5 μg/mL•hour, and the dosage was ≥ 58.4 and < 58.8 mg/day, respectively. Clinical and pharmacologic ODs were 25 by CRM and 50–60 mg/day by PK, respectively. The proposed starting OD is 50–60 mg/day, with personalized adjustment of 0.15–0.31 μg/mL based on Cminss as determined by PopPK monitoring.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

☑ The recommended daily dose of erlotinib was determined for patients with all types of non‐small cell lung cancer (NSCLC). Many patients suffer severe and long‐term adverse events related to treatment despite tumors harboring sensitizing mutations.

• WHAT QUESTION DID THIS STUDY ADDRESS?

☑ What is the optimal dose of erlotinib for patients with NSCLC harboring sensitizing mutations?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

☑ In terms of therapy with a reduced dose of erlotinib, modest benefit was achieved when all patients received the same reduced dose, but greater benefit is obtained if each patient receives a personalized optimal dose via population pharmacokinetic monitoring based on interpatient variations.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ The method can be adapted to determine the optimal dose of molecular targeting agents other than erlotinib. The most benefit for patients is realized if their tumors are treated with a personalized optimal dose of molecular targeting agent, balancing toxicity and efficacy to adjust to interpatient differences.

Five epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitors (TKIs) are currently available for use in clinical practice. ¹ All of these EGFR‐TKIs improve progression‐free survival (PFS) compared with standard chemotherapy as first‐line treatment for patients with non‐small cell lung cancer (NSCLC) harboring sensitizing EGFR mutations. ² , ³ Erlotinib is a first‐generation EGFR‐TKI with a recommended once‐daily oral dose of 150 mg. This dose was intended to target all types of EGFR (i.e., wild type and any EGFR mutations) based on dose‐escalation experiments in a phase I study of cytotoxic agents ⁴ and is the maximum tolerated dose. EGFR‐tyrosine kinase sensitizing mutations include exon 19 deletions (E19DEL) and a point mutation in exon 21 (L858R); thus, erlotinib exhibits excellent efficacy in patients with NSCLC harboring these sensitizing mutations. ⁵ At a 150 mg/day dose, the mean trough steady‐state concentration ( Cminss) of erlotinib is > 2.5 µM. ⁴ However, several basic research studies reported a 50% growth inhibitory concentration in NSCLC cell lines harboring sensitizing mutations of < 0.1 µM. ⁶ , ⁷ , ⁸ It is, therefore, likely that erlotinib can be given at doses < 150 mg/day while maintaining clinical efficacy.A postmarketing surveillance study of erlotinib in Japan involving 3,488 patients ⁹ reported the following rates of adverse events (AEs) of grade 2 (G2) or higher; eruptions = 38.8%, paronychia = 3.4%, diarrhea = 7.1%, hepatic disorders = 5.4%, and interstitial lung disease = 3.7%. About 90% of the patients were given 150 mg/day of erlotinib during treatment in this surveillance study. Because 55.1% of the patients had a history of gefitinib treatment and patients with all types of EGFR were eligible for this study, median PFS was only 64 days (95% confidence interval (CI) 60–68 days). Several AEs induced by erlotinib persisted during treatment. Long‐term, persistent AEs, even of low grade, can restrict patients’ normal activities and adversely affect their quality of life (QOL). ¹⁰ In interpatient dose escalation, the degree of AEs became more and more severe depending on increasing the daily dose of erlotinib from 25 to 200 mg/day. ⁴ During long‐term treatment, reduced toxicity can lead to improved QOL. It is, therefore, likely that reducing the required dose of erlotinib would have beneficial toxicity and QOL effects.The purpose of the present two‐phase study was to determine the optimal dose (OD) of erlotinib in patients with NSCLC harboring only sensitizing mutations. The first phase determined the minimum effective dose (MED) and OD of erlotinib in the target patient population, and the second phase determined the clinical and pharmacologic ODs. The study’s overall goal was to facilitate personalized dosing of erlotinib with the objective of balancing toxicity and efficacy.