Erlotinib 'dosing-to-rash': a phase II intrapatient dose escalation and pharmacologic study of erlotinib in previously treated advanced non-small cell lung cancer

• Published in: British journal of cancer 2011-09, Vol.105 (7), p.938-944
• Main Authors: Mita, A C, Papadopoulos, K, de Jonge, M J A, Schwartz, G, Verweij, J, Mita, M M, Ricart, A, Chu, Q S-C, Tolcher, A W, Wood, L, McCarthy, S, Hamilton, M, Iwata, K, Wacker, B, Witt, K, Rowinsky, E K
• Format: Article
• Language: English
• Subjects: 631/92/436/108; 631/92/436/1729; 631/92/436/2388; 692/699/67/1612/1350; Adenocarcinoma - drug therapy; Adenocarcinoma - pathology; Adult; Aged; Antineoplastic agents; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - pathology; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - pathology; Chemotherapy; Clinical Study; Drug Resistance; Epidemiology; Erlotinib Hydrochloride; Exanthema - chemically induced; Female; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - pathology; Male; Medical sciences; Middle Aged; Molecular Medicine; Oncology; Pharmacology. Drug treatments; Prognosis; Protein Kinase Inhibitors - pharmacokinetics; Protein Kinase Inhibitors - therapeutic use; Quinazolines - pharmacokinetics; Quinazolines - therapeutic use; Tissue Distribution; Tumors
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2011.332

Background: To evaluate the anticancer activity of erlotinib in patients with previously treated, advanced non-small cell lung cancer (NSCLC) whose dose is increased to that associated with a maximal level of tolerable skin toxicity (i.e., target rash (TR)); to characterise the pharmacokinetics (PK) and pharmacodynamics (PD) of higher doses of erlotinib. Methods: Patients initially received erlotinib 150 mg per day. The dose was successively increased in each patient to that associated with a TR. Anticancer activity was evaluated. Plasma, skin, and hair were sampled for PK and PD studies. Results: Erlotinib dose escalation to 200–475 mg per day was feasible in 38 (90%) of 42 patients. Twenty-four (57%) patients developed a TR, but 19 (79%) did so at 150 mg per day. Five (12%) patients, all of whom developed a TR, had a partial response. Median progression-free survival (PFS) was 2.3 months (95% CI: 1.61, 4.14); median PFS was 3.5 months and 1.9 months, respectively, for patients who did and did not experience a TR (hazard ratio, 0.51; P =0.051). Neither rash severity nor response correlated with erlotinib exposure. Conclusion: Intrapatient dose escalation of erlotinib does not appreciably increase the propensity to experience a maximal level of tolerable skin toxicity, or appear to increase the anticancer activity of erlotinib in NSCLC.