In a dedicated fertility study, male and female rats received afatinib daily by the oral administration at doses of 4, 6, or 8 mg/kg. In males at doses of 6 mg/kg (approximately equal to the exposure by AUC in patients at the recommended human dose of 40 mg daily) or greater, there was an increase in the incidence of low or no sperm count, though overall fertility was not affected; decreases in sperm count were supported by findings of increased apoptosis in the testes and atrophy in the seminal vesicles and the prostate in general toxicology studies. In females at the high dose of 8 mg/kg (approximately 0.63 times the exposure by AUC in patients at the recommended human dose of 40 mg daily), there was a mild decrease in the number of corpora lutea along with a mild increase in post-implantation loss due to early resorptions. In a 4-week general toxicology study, female rats had decreases in ovarian weights at all dose levels; organ weight had not fully recovered by the end of a 2-week recovery period.

14  CLINICAL STUDIES
Non-small Cell Lung Cancer (NSCLC)

Study 1 The efficacy and safety of GILOTRIF in the first-line treatment of 345 patients with EGFR mutation-positive, metastatic (Stage IV and Stage IIIb with pleural and/or pericardial effusion as classified by the American Joint Commission on Cancer [AJCC, 6th edition]) NSCLC were established in a randomized, multicenter, open-label trial (Study 1). Patients were randomized (2:1) to receive GILOTRIF 40 mg orally once daily (n=230) or up to 6 cycles of pemetrexed/cisplatin (n=115). Randomization was stratified according to EGFR mutation status (exon 19 deletion vs exon 21 L858R vs other) and race (Asian vs non-Asian). The major efficacy outcome was progression-free survival (PFS) as assessed by an independent review committee (IRC). Other efficacy outcomes included objective response rate (ORR) and overall survival (OS). EGFR mutation status was prospectively determined for screening and enrollment of patients by a clinical trial assay (CTA). Tumor samples from 264 patients (178 randomized to GILOTRIF and 86 patients randomized to chemotherapy) were tested retrospectively by the companion diagnostic therascreen ® EGFR RGQ PCR Kit, which is FDA-approved for selection of patients for GILOTRIF treatment.

Among the patients randomized, 65% were female, the median age was 61 years, the baseline ECOG performance status was 0 (39%) or 1 (61%), 26% were Caucasian and 72% were Asian. The majority of the patients had a tumor sample with an EGFR mutation categorized by the CTA as either exon 19 deletion (49%) or exon 21 L858R substitution (40%), while the remaining 11% had other mutations.

A statistically significant improvement in PFS as determined by the IRC was demonstrated for patients randomized to GILOTRIF compared with those randomized to chemotherapy. See Table 3 and Figure 1. There was no statistically significant difference for overall survival between the treatment arms at the interim analysis conducted at 84% of the planned events for the final analysis.

Table 3: Efficacy Results of Study 1
GILOTRIF(N=230)  Pemetrexed/Cisplatin(N=115) 
Progression-free Survival 
Number of Deaths or Progressions, N (%) 152 (66.1%) 69 (60.0%)
          Median Progression-free Survival (months) 11.1 6.9
Q