Preliminary activity and safety results from a phase I clinical trial of PF-00299804, an irreversible pan-HER inhibitor, in patients (pts) with NSCLC.

8027 Background: PF-00299804 (PF) is an orally bioavailable, potent, irreversible small molecule inhibitor of HER1, HER2, and HER4. HER1 overexpression/aberrant function is widely observed in NSCLC and HER1 mutations are implicated in mechanisms of tumorigenesis and are associated with sensitivity to EGFR inhibitors gefitinib (G) and erlotinib (E). Results in pts with refractory NSCLC enriched for HER gene amplification, HER1/HER2 mutation, or wild type (WT) KRAS, within the phase I study are reported.,NSCLC pts (n=42) received PF 16 mg (n=1), 30 mg (n=2), 45 mg, the MTD (n=33) or 60 mg (n=6) QD either continuously or for 2 weeks of a 3- week cycle. NSCLC pts were included in both the dose-escalation phase and at MTD, when additional NSCLC pts with HER1 mutant or KRAS WT tumors were recruited.,44 pts with NSCLC have been enrolled to date (29 evaluable for response). Baseline characteristics were: median age 57 yrs (range 26-77), prior EGFR inhibitors 94% (E n=21, G n=6, E + G n=3; cetuximab n=1), prior chemotherapy 79% (median no. of regimens 2; range 0-6), never smokers (48%), ex-smokers (45%) and current smokers (6%). Mutational status was known in part for 30 pts: HER1 mutant/WT: 23/7; KRAS WT/unknown: 17/13. The median duration of therapy was 2 mths (range 1- 6).23 pts received PF 45 mg QD for which the safety profile is as follows: G3: fatigue, DVT, nausea, acne, hypokalemia, diarrhea, hypoxia, and decreased appetite; G4: dyspnea, pulmonary embolism, and pain. The most frequently reported AEs (any grade) were diarrhea (78%) and rash (65%). Among 29 pts evaluable for tumor response, 2 PRs (RECIST) were noted and an additional 8 pts reported SD (clinical benefit rate 34%). Of the 2 PRs, one pt received PF 16 mg QD escalated to 30 mg QD and had previously received 6 lines of chemotherapy and G (6 months); the second received PF 45 mg QD, had previously received 3 lines of chemotherapy and E (4 months), and had a EGFR exon 20 insertion (D770delinsGI) mutation. Both PRs were durable (>200 days).,PF-00299804 45 mg QD is well tolerated. Encouraging activity was seen in heavily pre-treated NSCLC pts, including 2 PRs after failure of prior treatment with reversible EGFR inhibitors. Phase II studies in refractory NSCLC pts are underway. [Table: see text].