NERATINIB ACTIVE ONLY AGAINST A SPECIFIC EGFR MUTATION NSCLC

NEW YORK (Reuters Health) Jun 15 - Neratinib, an irreversible pan-ErbB receptor tyrosine kinase inhibitor (TKI), shows low activity at tolerable doses in patients with advanced non-small-cell lung cancer (NSCLC), according to an online report in the May 17th Journal of Clinical Oncology.

"In its current formulation, neratinib is hard to give in doses that may affect lung cancer patients," Dr. Lecia V. Sequist from Massachusetts General Hospital Cancer Center and Dana-Farber Cancer Center, Boston, told Reuters Health in an email. "It is possible that patients with the G719X mutation may benefit preferentially."

In light of an earlier phase I study that showed activity in several heavily pretreated patients with NSCLC and breast cancer, Dr. Sequist and colleagues investigated the response rate to neratinib in specific groups of NSCLC patients in an open-label phase II study of 167 patients with advanced NSCLC.

Ninety-one patients with prior EGFR TKI treatment showed EGFR mutations (arm A), 48 patients with prior EGFR TKI treatment showed no mutations (arm B), and 28 patients were TKI na�ve but had clinical characteristics favorable for response to TKI (arm C).

The starting dose of neratinib was initially 320 mg/d, but this was reduced to 240 mg/d after severe diarrhea developed in 50% of patients, requiring dose reductions in 36%. Even after the reduction in starting dose, grade 3 diarrhea occurred in 25% of patients and prompted dose reductions in 16%.

Response rates were only 3.4% among patients with prior EGFR TKI treatment who showed EGFR mutations (arm A), and all 3 of these patients had an exon 18 G719X point mutation.

The G719X mutation comprises less than 5% of EGFR mutations, the researchers say, and has been associated with sensitivity to other TKIs, including gefitinib and erlotinib.

The response rate was 0% in the arms B and C, but stable disease was observed in 40 patients (50%) in arm A, 29 (64%) in arm B, and 8 (32%) in arm C.

None of the patients with the common EGFR T790M mutation responded to neratinib, nor did any patient with EGFR FISH positivity who were EGFR wild-type or any harboring a KRAS mutation.

"Future studies with neratinib in NSCLC will focus on attempting to modify the dose and/or schedule to mitigate diarrhea and allow for achievement of higher biologic doses," the investigators conclude.

"One of the main messages for readers from this trial is the advantages gained by collecting tumor material from 100% of participating research subjects -- it really gives you the power to see activity in minority molecular subgroups," Dr. Sequist said. "As a field, we need to strive for more designs that require tissue."

The study was funded by Wyeth, which was acquired by Pfizer in October 2009. Four of the 13 authors were employed by Pfizer, and one author had received research funding from Pfizer.

http://jco.ascopubs.org/cgi/content/abstract/JCO.2009.27.9414v1

J Clin Oncol 17 May 2010.