erated dose of neratinib was determined to be 30 mg. Of 4 evaluable patients with NSCLC, stable disease (SD)  4 weeks was observed in six (43%). Eight partial responses (PRs) and one patient with SD were also reported among 4 evaluable patients with breast cancer. Grade 3 treatment- emergent and treatment-related adverse events (AEs) included diarrhea (3%), fatigue (8%), vomiting (7%), dehydration (6%), nausea (4%), asthenia (%), and anorexia (%); no grade 4 toxicities were reported. A phase II trial [6] of 7 patients with advanced NSCLC who progressed following erlotinib or gefitinib studied three subgroups of patients with tumors thought likely to benefit from neratinib: arm A, EGFR mutation (n  9); arm B, wildtype EGFR (n  48); and arm C, EGFR TKI naive but with SKI-606 adenocarcinoma and a light smoking history (n8). Patients initially received neratinib at a dose of 30 mg/day, but the dose was decreased to 40 mg/day because of dose delays and reductions associated with diarrhea.

Of 58 evaluable patients, three (.9%) had an objective response and 4 (9%) had SD for six or more cycles, resulting in an objective RR of 3.4% for arm A and 0% for arms B and C. The median PFS intervals were 5.3 weeks overall and 5.3, 6., and 9.3 weeks in arms A, B, and C, respectively. The overall RRs observed in patients with an EGFR SKI-606 Bosutinib mutation (all 9 patients in arm A and  of 8 patients in arm C) were disappointing. However, three of four patients with an exon 8 G79X EGFR point mutation experienced a PR and the fourth had SD 40 weeks; among these patients, the median PFS interval was 5.7 weeks (90% CI, 5.6 –57.0 weeks).

Therefore, neratinib provided benefit in this small subgroup of patients with exon 8 G79X mutant EGFR tumors that had become refractory to reversible TKIs. Despite preclinical data suggesting a role for neratinib in overcoming resistance mediated by T790M [53], no patients with a known T790M mutation responded. Based on these results, neratinib is no longer in development for NSCLC  although it is being investigated in HER  breast cancer PF0099804, an irreversible HER family inhibitor that targets EGFR/HER-, HER-3, and HER-4 [63] (Table ), has demonstrated preclinical activity in gefitinib-resistant NSCLC models both in vitro and in vivo [64]. In a phase I trial in patients with advanced SKI-606 SRC inhibitor solid tumors, PF0099804 (0.5– 60 mg/day) was administered on two dosing schedules (once daily continuously, n  ; intermittently, n  0) [63].

In total,  patients were enrolled, with 47% of tumors being NSCLCs. Dose-limiting toxicities observed at the 60-mg/day dose were stomatitis, palmar–plantar erythema, and dehydration (n   for each, all grade 3). The maximum-tolerated dose was established at 45 mg/day. Four patients, each with NSCLC previously treated with erlotinib and/or gefitinib had a PR, and an additional 8 patients with NSCLC had SD 6 weeks. Interestingly, of five evaluable patients with an exon 0 mutation (typically erlotinib/gefitinib resistant), one patient had a PR and two patients had SD. Four patients with documented T790M mutations did not respond to PF0099804. The most common nonhematologic AE occurring in 5% of patients on both dosing schedules was diarrhea. PF0099804 has been evaluated in clinical trials in patients with NSCLC following treatment with a first-generation EGFR TKI. In a phase I trial [65], PF0099804 was evaluated in 44 NSCLC patients, most of whom had received prior EGFR inhibitors (94%) and prior chemotherapy (79%). Of 9 evaluable patients, two had PRs and eight had SD, resulting in a clinical benefit rate of 34%. Both patients who achieved a PR had previously received three or more lines of chemotherapy and either erlotinib or gefitinib. The most frequently reported AEs of any grade were diarrhea (78%) and rash (65%). Based on these results, trials of PF0099804 in patients with NSCLC refractory to chemotherapy and first-genera