We report 9 patients with EGFR
mutant NSCLC with CNS (brain and/or leptomeningeal) metastases treated with pulsatile erlotinib weekly as a single agent. All developed CNS disease as part of progression following initiation of standard daily dosing of EGFR TKIs. We used RECIST for evaluating radiographic changes during therapy because, to our knowledge, no other response criteria are widely accepted for evaluation of brain metastases from solid tumors such as NSCLC. For example, the traditional Macdonald criteria18
and the newly published criteria of the Response Assessment in Neuro-Oncology working group19
are intended for evaluation of primary brain tumors (especially glioblastoma) rather than brain metastases.
By formal RECIST evaluation, response of CNS disease was observed in 44% (4/9) of patients. However, 2 of 3 patients with isolated leptomeningeal metastases (without coexistent parenchymal brain metastases) achieved clear partial radiographic responses (Fig. ). RECIST defines leptomeningeal metastases as “nontarget” lesions, and clear but incomplete responses, such as those we observed, are designated as “noncomplete response/nonprogressive disease” rather than either partial response or stable disease. Therefore, if the 2 patients with clearly improved leptomeningeal disease (Fig. ) were designated as partial responders, then the response rate would increase to 67% (6/9) (Table ). Increased corticosteroids did not account for responses.20
Although the median time to progression was only 2.7 months, the median overall survival was 12.0 months. In context, median survival after whole brain radiotherapy for brain metastases is 4.9 months.21
However, the natural history of EGFR
mutant disease is often more favorable than for EGFR
wild-type disease. For example, Eichler et al. reported median survival of 14.5 months from diagnosis of brain metastases from EGFR
mutant lung cancer.10
In addition, some of the responses we observed were not durable.
Moreover, all patients in our series had worsening CNS metastases during or following treatment with an EGFR TKI at standard dosing, which was not addressed in the Eichler series.10
Heon et al. reported median survival of approximately 5 months among patients with EGFR
mutant NSCLC following the development of new or worsening CNS metastases after conventional EGFR TKI therapy.8
In addition, all but 1 (89%, 8/9) of our patients had leptomeningeal metastases, which is generally considered more refractory to treatment than isolated parenchymal brain metastases, and this issue was not analyzed in detail in the Eichler10
We identified an EGFR TKI sensitizing mutation in all tested CNS tissue and acquired resistance mutations in none. Three patients had T790M in disease outside the CNS (cases 4, 8, and 9; Table ), including one without T790M in the CNS (case #4). Therefore, we did not address whether pulsatile therapy could overcome molecular resistance mechanisms in the CNS. However, the available data suggest it cannot. For example, no patient had a response outside the CNS, although only 1 (case #9) had both documented T790M and was re-evaluated systemically following pulsatile therapy. Best response in this case was progressive disease (Table ).
There are several limitations to our study, including the small size, the retrospective design, the difficulty of determining response of isolated leptomeningeal disease, and limited availability of tissue for molecular analysis in some cases.
However, our results suggest that pulsatile erlotinob at approximately 1500 mg per week is safe and has activity in patients with CNS disease from EGFR
mutant NSCLC even when systemic resistance has developed and been confirmed. Poor penetration of erlotinib when administered at standard low doses daily may explain in part the failure to achieve control of CNS metastases, rather than acquired resistance mutations such as T790M.8,11,12,22
A prospective trial is planned.
Conflict of interest statement. Consultant/Advisory Board: MolecularMD (W.P.), AstraZeneca (W.P.), Boehringer-Ingelheim (M.G.K.), Pfizer (M.G.K.), Roche/Genentech/OSI (V.A.M., A.B.L.), Eisai (A.B.L.), Enzon (A.B.L.), Merck/Schering Plough (J.L.C., A.B.L.), Bristol Myers-Squibb (W.P., A.B.L.), Symphony Evolution (W.P.); Campus Bio (A.B.L.) Cephalon (A.B.L.), ImClone (A.B.L.), GSK (A.B.L.); Rights to EGFR T790M testing were licensed on behalf of W.P. to MolecularMD by Memorial Sloan-Kettering Cancer Center. All other authors: None declared.