http://www.tlcr.org/article/view/819/1407
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Neratinib
Neratinib (HKI-272), an irreversible HER family inhibitor targeting EGFR/HER-1, HER-2 and HER-4, was initially tested in a phase I trial of 72 patients with advanced ErbB2 or ErbB1/EGFR IHC positive tumors (58). Maximum tolerated dose (MTD) was determined to be 320 mg and the most common related adverse event at this dose was diarrhea. Strikingly, a long-lasting disease control (defined as stable disease for >24 weeks) was observed in 43% of refractory NSCLC patients.
A large non-randomized phase II tria l explored the activity of neratinib in three different cohorts of advanced pretreated NSCLC patients (60). Arm A included patients with activating EGFR mutation (N=91), arm B included EGFR wild-type patients (N=48) while arm C included EGFR TKI-naïve patients selected for adenocarcinoma histology and smoking history (N=28). Subjects in arms A and B had to have received at least 12 weeks of prior erlotinib/gefitinib treatment. In the overall population (N=158), the activity was lower than expected, with only 2% of responders (RR 3.4% arm A; 0% arm B; 0% arm C). Interestingly, the three responding patients harbored the rare G719X point mutation in exon 18, maybe suggesting that neratinib could be less effective in presence of classical EGFR mutations; on the contrary, the presence of T790M mutation did not seem guarantee any benefit from such treatment. Median PFS was 15.3 weeks in the entire cohort, without significant difference between the three arms (15.3, 16.1 and 9.3 weeks in arm A, B and C respectively). Nevertheless, in the first 39 patients receiving neratinib at the dose of 320 mg daily the occurrence of grade 3 diarrhea was unacceptably high (50%); as a consequence, a dose reduction to 240 mg was required in order to improve tolerability with the hypothetical disadvantage of negatively affect response. Anyway, this major limitation led to dissipate the interest to further explore neratinib in NSCLC.
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