A phase I, dose-escalation trial of continuous and pulsed-dose afatinib (A) combined with pemetrexed (P) in patients (pts) with advanced solid tumors: Final analysis.

2523 Background: A is an irreversible ErbB Family Blocker that has shown additive effects when combined with P in EGFR-mutant NSCLC cell lines. This Ph I trial assessed the MTD, safety and PK of continuous and pulsed-dose A + P in pts with advanced solid tumors. Methods: In a3+3 dose-escalation design, IV P (500 mg/m2) was administered on day (d) 1 of each 21-d cycle combined with either continuous oral A qd (Schedule A; SA) on d1–21 (d2–21 in Cycle 1) or pulsed-dose oral A qd (Schedule B; SB) on d1–6 of each 21-d cycle. In SA, A starting dose was 30 mg, escalated to maximum of 50 mg. Once the MTD was reached in SA, A was administered at a starting dose of 50 mg in SB. Pts received up to 6 cycles of P with the option for A monotherapy thereafter. P and steady state A PK were analyzed by intra-individual comparison in SA only for possible drug–drug interaction. Results: 53 pts were treated (SA: n=23, median age 58 yrs; ECOG 0/1/2 [30%/65%/4%]; SB: n=30, median age 62 yrs, ECOG 0/1/2 [27%/70%/3%]). MTD of A in SA was 30 mg; 8 pts had dose-limiting toxicities (DLTs) in Cycle 1 (40 mg: 2/3 pts; 30 mg; 6/19 pts). 30-mg cohort included 19 evaluable pts; 1 pt was replaced during expansion (incomplete PK collection) and had a DLT. MTD of A in SB was 50 mg; 11 pts had DLTs in Cycle 1 (70 mg: 4/5 pts; 60 mg: 6/17 pts; 50 mg: 1/6 pts). Most frequent drug-related AEs in SA were diarrhea (91%), stomatitis (65%) and rash (61%) and in SB were diarrhea (83%), rash (83%) and fatigue (80%); most were Grade 1/2. 6 pts in SA and 8 pts in SB completed 6 treatment cycles; 1 pt in each schedule remain on treatment. Best response in SA was 1 confirmed partial response (CPR; NSCLC, prior sequential chemotherapies and erlotinib) and 6 pts with stable disease (SD). In SB, best response was 1 CPR (bladder cancer, prior sequential chemotherapies) and 10 pts with SD. No clinically relevant PK interactions between A and P were observed. Conclusions: Continuous or pulsed-dose A combined with P exhibited a manageable safety profile. No clinically relevant PK interactions were seen in SA. Continuous dose A 30 mg/d with P 500 mg/m2 (d1 of each 21d cycle) is the recommended dose for further Ph II studies. No apparent safety or dose advantage was observed in SB. Clinical trial information: NCT01169675.

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