Activity of erlotinib when dosed below the maximum tolerated dose for EGFR‐mutant lung cancer: Implications for targeted therapy development

Abstract

Background Erlotinib is a standard first-line therapy for metastatic non-small-cell lung cancers (NSCLC) with epidermal growth factor receptor (EGFR) mutations. The recommended dose of 150mg daily is the maximum tolerated dose (MTD). Little clinical data is available regarding its efficacy at doses less than MTD. Methods An institutional database was queried for patients with advanced NSCLC positive for EGFR L858R mutations or exon 19 deletions treated with erlotinib. Treatment course, including erlotinib dose at initiation of treatment, at four months into therapy, and at disease progression, was studied retrospectively. Progression-free survival (PFS) was compared between patients taking MTD (150mg) and reduced-dose (≤100mg) erlotinib. Results 198 eligible patients were identified. Thirty-one (16%) were initiated on reduced-dose erlotinib; they were older (p=0.001) with a lower performance status (p=0.01) compared to those initiated at MTD. Response rate to reduced-dose erlotinib was 77%. Median PFS of patients initiated on reduced-dose erlotinib was 9.6 months versus 11.4 months for those initiated at MTD, a difference that was not statistically significant (HR 0.81, 95% CI: 0.54-1.21, p=0.30). There was a non-significant trend towards higher rates of progression within the CNS with reduced-dose erlotinib. Conclusions At doses below MTD, erlotinib treatment results in a high response rate and prolonged median PFS. Review of the literature indicates that 15 out of 30 small molecule inhibitors approved or in late-stage development for cancer therapy have recommended doses below MTD. When the toxicities of MTD dosing are a concern, investigation of small molecule inhibitors at doses below MTD is warranted.

Afatinib Therapy for Brain Metastases Aggravated by a Reduction in the Dose of Erlotinib Due to the Development of Hepatotoxicity

“…The superiority of erlotinib over gefitinib is attributable to the lower maximum tolerable dose (MTD) of gefitinib, which is one-third of that of erlotinib ( 17 , 18 ). However, reduced-dose of erlotinib has been reported to exacerbate BM ( 19 ). In fact, in the present case, CNS progression was observed one month after we reduced the dosage to 50 mg every other day, despite the fact that the extracranial disease remained stable.…”

Efficacy and Tolerability of Erlotinib 100 mg/d vs. Gefitinib 250 mg/d in EGFR-Mutated Advanced Non-small Cell Lung Cancer (E100VG250): An Open-Label, Randomized, Phase 2 Study

“…Preclinical models and phase-1 pharmacokinetic data suggested that erlotinib 25 mg/d led to similar antitumor effect compared with gefitinib 250 mg/d (12,13). Retrospective studies also supported this notion by showing similar PFS between patients treated with reduced-dose erlotinib (≤ 100 mg/d) and those with standard dose (14). Post-hoc analyses that might be subjected to survival bias found a correlation between dose reduction of EGFR TKIs and better treatment outcomes (15,16).…”

Optimized Dosing: The Next Step in Precision Medicine in Non-Small-Cell Lung Cancer

“…However, as shown in Table 1, in the current dosing regimens of both drugs, no relationship between plasma exposure and response has been found [21][22][23][24]. Interestingly, lower doses of erlotinib and gefitinib (25-100 mg once daily [QD] and 250 mg on alternating days, respectively) were noninferior to the approved dose of erlotinib 150 mg QD and gefitinib 250 mg QD [24][25][26][27][28][29]. Unfortunately, no exposure-response analyses were performed in these patients.…”