Low-Dose Erlotinib Shows Promise in Elderly, Frail Patients with EGFR+ NSCLC

A phase II study indicated that low-dose erlotinib (Tarceva) appears to be safe and effective in elderly or frail patients with EGFR mutation-positive non-small cell lung cancer.

A multicenter phase II trial published in JAMA Oncology indicated that low-dose erlotinib (Tarceva) appears to be safe and effective in elderly or frail patients with EGFR mutation-positive non-small cell lung cancer (NSCLC) and could be a valid treatment option. 

However, more research on the dosing strategy of target-based drugs is warranted according to the researchers, especially in frail patients in the real-world setting. 

“With the increased number of elderly and frail patients with cancer, more patients would receive benefit from this value-based treatment to enhance risk-benefit and cost-benefit ratios,” the authors wrote. “In fact, our low-dose erlotinib therapy could substantially reduce the treatment cost.” 

In this single-arm phase II trial, frail patients were enrolled from 21 Japanese institutions after meeting the inclusion critera. Those who were eligible for the study were chemotherapy-naive patients with EGFR-activating mutation-positive NSCLC who were considered frail based on age, the Charlson Comorbidity Index, and Eastern Cooperative Oncology Group performance status. 

The primary endpoint was objective response rate (ORR) at a dose of 50 mg per day, as confirmed by an independent review committee. Additionally, the study evaluated the pharmacokinetics of low-dose erlotinib and influence of ABCB1 gene polymorphisms. 

Initially, patients were administered 50 mg of erlotinib per day for 4 weeks; this was modified based on response or adverse events. Moreover, dose increase was permitted for patients with stable disease after 4 weeks. 

In total, 80 patients were enrolled in the study. An independent review committee confirmed a significant ORR of 60.0% (90% CI, 50.2%-69.2%). The disease control rate was 90.0% (90% CI, 82.7%-94.9%), median progression-free survival was 9.3 months (95% CI, 7.2-11.4 months), and median overall survival was 26.2 months (95% CI, 21.9-30.4 months). 

Mild adverse events (AEs) were observed in some individuals, with few participants exhibiting grade 3 or higher AEs. However, low-dose erlotinib treatment was temporarily suspended for 10 patients due to AEs. 5 of 80 patients (6%) had their dose reduced to 25 mg because of oral mucositis, paronychia, erythema multiforme, diarrhea, and anorexia. Even further, 2 patients discontinued treatment due to AEs (cutaneous ulcer and bone infection, and oral mucositis, respectively). Notably though, there were no cases of interstitial lung disease or treatment-related deaths. 

The median erlotinib plasma concentration was measured at 685 ng/mL (range, 153 to 1,950). Ultimately, 73 patients discontinued study treatment because of disease progression (n = 60), death (n = 3), AEs (n = 4), and patient requests (n = 6). No clear association was observed between the pharmacokinetics of low-dose erlotinib and the treatment outcome. 

“The results of our pharmacokinetics analysis showed that the median trough plasma concentration of erlotinib exceeded the effective level even after administration at a low dose,” the authors wrote. “No association was found between trough erlotinib concentration and diarrhea, whereas rash tended to be associated with erlotinib concentration. Furthermore, plasma concentrations of low-dose erlotinib in frail patients were higher than those in the phase I trial and tended to be higher in patients with [performance status; PS] of 3 or 4.”

Of note, the results of the FLAURA randomized clinical trial demonstrated that osimertinib (Tagrisso) was superior to first-generation TKIs, including erlotinib. Therefore, the results of this study have only limited influence on the standard of care. 

However, the FLAURA trial only enrolled good-risk patients, therefore the results cannot automatically be applied to real-world frail patient populations. More large-scale studies are necessary according to the researchers. 


Miyamoto S, Azama K, Ishii H, et al. Low-Dose Erlotinib Treatment in Elderly or Frail Patients With EGFR Mutation-Positive Non-Small Cell Lung Cancer. JAMA Oncology. doi:10.1001/jamaoncol.2020.1250.