High-dose, pulsatile erlotinib after progression on standard dose erlotinib in EGFR-mutated NSCLC patients

Standard dose and schedule for erlotinib is 150 mg daily. However, different
dosing schedules have been evaluated, in which pulsatile doses up to 2000 mg
have been evaluated tolerable and with acceptable toxicity profile. This
weekly, high-dosing schedule has been described in several case reports as
therapeutic option for patients with leptomeningeal metastases. One group
retrospectively analysed a series of 9 patients.

Toxicity of high-dose, pulsatile erlotinib
Known side effects of erlotinib in the standard, daily 150 mg dosing schedule
comprise rash, diarrhoea, fatigue, nausea and/or emesis, stomatitis, weight
loss, dehydration, pneumonitis and elevated liver values. Side effects of the
higher-dose, weekly schedule are similar to the daily, standard dosing
schedule. One study evaluated erlotinib in doses of 1200 mg, 1600 mg and 2000
mg. The dosing schedule of 1600 mg showed three grade 2 toxicities; one patient
with grade 2 diarrhoea, one patient with grade 2 fatigue and one patient with
grade 2 nausea and/or emesis. Nine patients reported grade 1 toxicities, of
which most reported rash and diarrhoea.

Rationale
Since there are no other therapeutic options for patients with leptomeningeal
metastases from EGFR-mutated NSCLC and toxicity of the high-dose pulsatile
dosing schedule seems acceptable, we have treated several patients from our
department with this schedule. One patient treated with this schedule caught
our special attention. It was a female patient of 51 years old with
EGFR-mutated NSCLC who had been treated with EGFR-TKI*s since 2007, including
erlotinib in combination with sorafenib, single agent erlotinib and afatinib in
combination with cetuximab. After progression on the latter regimen she was
treated with 2 cycles of cisplatin and pemetrexed. A CT-scan showed disease
stabilisation of the intrathoracic disease but she developed leptomeningeal
metasases. It was decided to treat her with erlotinib 1500 mg once weekly and
maintain cytotoxic chemotherapy. Surprisingly after 3 weekly doses of the high
dose erlotinib regimen there was significant decrease of the intrathoracic
disease. Also, her neurological symptoms improved dramatically.
Although the molecular background of the tumor of this patient is unknown,
approximately 50% of patients with an activating EGFR mutation harbour
secondary mutations in particular the T790M mutation. The net result of this
mutation is an increase in affinity of the EGF receptor for ATP thereby
restoring signal transduction through this pathway. Since erlotinib is a
competitive inhibitor of EGF signalling, in theory higher dose of the drug
might restore sensitivity for the drug in this (common) situation.
We would like to evaluate prospectively whether this high-dose, weekly schedule
of erlotinib shows activity in EGFR-mutated NSCLC patients that have developed
systemic progression of disease. Since toxicity of this higher dose of
erlotinib has been reported to be acceptable, we think that it is justified to
evaluate this relatively simple dosing schedule in this group of patients.

see whether this treatment schedule is effective in EGFR-mutated NSCLC patients
who have developed progression after treatment with EGFR-TKI monotherapy in
standard dose before

Single-arm, open-label phase II study

erlotinib 1500 mg once every week

Risks include side-effects of the treatment schedule.