EORTC 24051: Unexpected side effects of a phase I study of TPF induction chemotherapy (IC) followed by chemoradiation (CRT) with lapatinib (LAP), a dual EGFR/ErbB2 inhibitor, in patients with locally advanced larynx and hypopharynx squamous cell carcinoma (LA-LxHxSCC)

Abstract

6017 Background: CRT is considered a standard approach for LA-LxHxSCC. TPF IC regimen seems to improve outcome in locally advanced head and neck SCC. The addition of LAP was investigated in combination with a sequential therapeutic approach (IC→ CRT). Methods: Eligible tumors were SCCHN: T3-T4 larynx (Lx), T2-T4 hypopharynx (Hx) N0–3 M0. The objective of this trial is to determine MTD, DLT and recommended dose of LAP when administered with TPF IC (docetaxel (T) 75mg/m2 (60 mg/m2 for the first cycle) d1, CDDP 75mg/m2 d1, 5FU 750mg/m2/d continuous infusion d1-d5 q3weeks) followed by CRT (weekly carboplatin AUC 1.5 and RT 70Gy in 7 weeks; 2Gy/fx). LAP is administered concomitantly with IC (escalating dose 500–1500mg po daily) and during CRT (1,500 mg daily). Results: Seven male patients were included; tumor sites: LX (n = 3) / Hx: (n = 4), median age 59 years (range: 47–79), WHO PS 0–1, no severe or uncontrolled comorbidity. Three pts were included in the first cohort, at dose level 1 (LAP 500 mg daily plus TPF IC). Renal toxicity was observed among these 3 pts (grade 4 [n = 1], grade 2 [n=1] and grade 1 [n=1]), with 1 DLT, leading to treatment interruption in this group. This nephrotoxicity was reversible after stopping lapatinib and hydration of the patients. As LAP plus cisplatinum plus RT was feasible in another study, a second cohort was conducted in 4 pts, receiving LAP at the same dosage, and docetaxel (T) was only introduced from cycle 2 of IC to see what is the role of T in the observed side effect. Two DLTs were observed among this second cohort of subjects: one pt presented a grade 2 renal toxicity, grade 3 diarrhea and dehydration and a second pt presented a grade 3 anorexia and grade 3 stomatitis. Based on the occurrence of 3 DLTs at the first dose level of LAP, patient recruitment was closed. Despite these safety issues, all patients recovered and were treated off-study. They will receive follow-up as foreseen by the protocol. Conclusions: These data suggest that LAP should not be combined with TPF IC regimen for LA-LxHxSCC due to prohibited toxicity. [Table: see text]