Abstract P4-12-24: Phase I trial of S-222611, a dual tyrosine kinase inhibitor of EGFR and HER2, with preliminary evidence of efficacy in patients (pts) with heavily-pretreated HER2-positive metastatic breast cancer
Authors: Baird RD , Cresti N , Beddowes E , Saggese M , Flynn M , Garcia Corbacho J , Gao F , Lemech C , Donaldson K , Posner J , Kawabata I , Forster M , Arkenau HT , Plummer R , Jodrell D , Spicer J 
Published: August 2014

Abstract
Background and rationale: S-222611 is a novel, oral, reversible inhibitor of EGFR, HER2 and HER4 with an improved preclinical profile compared with first-generation pan-HER inhibitors.
Research objectives: We conducted a phase I study to determine safety, maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (PD) and preliminary efficacy in pts with solid tumors expressing EGFR or HER2.
Patients and methods: Pts with advanced solid tumors and biopsies confirming EGFR and/or HER2 expression were treated with continuous daily oral doses of S-222611. The dose of S-222611 was escalated in cohorts of at least 3 pts from 100mg to 1600mg. PK profiles were obtained in all pts, and PD assays for pEGFR, pHER2 and pHER3 were performed on paired tumor biopsies in selected pts.
Results: A total of 50 pts have been treated to-date; age 25-80y; 20 female; 13 with HER2-positive metastatic breast cancer (HER2+ MBC). S-222611 was generally well tolerated with two dose-limiting toxicities in the dose-escalation phase: rash at 1200mg; diarrhea at 1600mg. MTD was not defined. Diarrhea was the most frequent toxicity, but was rarely worse than grade 1/2. Nausea, rash, anorexia and fatigue were also seen. Bilirubin rises with normal transaminases were observed. Plasma concentrations of S-222611 increased with dose up to 800mg, which was the dose selected for the expansion phase. Steady state values of Cmax and AUC0-24 at this dose were in the effective range of concentrations in mouse models. Average t½ of 33h was consistent with once daily dosing. Tumor responses were seen over the full dose range tested (100-1600mg), with four pts on treatment for &gt;12 months. Out of 13 HER2+ MBC pts, one clinical complete response (CR) was observed for &gt;12 months, and four partial responses (PRs) were also seen (2 confirmed, 2 unconfirmed), yielding an overall response rate of 38% in this small group (Table 1). All 5 responding patients had previously progressed on trastuzumab (T); 4 of them had also progressed on lapatinib (L); and one patient had progressed on T, L and T-DM1. Out of 6 breast patients with PD results available, the 3 pts with a decrease in pHER3 all responded, whereas the 3 pts with no change or increase in pHER3 all had disease progression.
Conclusion: S-222611 was well tolerated in doses up to 1600mg daily with diarrhea, nausea and rash being readily manageable. Significant antitumor activity has been observed in patients with heavily pre-treated HER2+ MBC, including those progressing on prior T, L and T-DM1. Rates of grade 3 diarrhea appear markedly lower than those reported for other second-generation pan-HER TKIs. The recommended phase 2 dose, based on PK and clinical activity, is 800mg/day.
Table 1. HER2+ MBC pts with tumor shrinkage after S-222611 treatmentPatient numberPrior progression on trastuzumab-based regimenPrior progression on lapatinib-based regimenBest responseMonths on treatment (at time of data lock)S01014YYclinical CR20.3m (ongoing)S03034YNconfirmed PR11.5m (ongoing)S04046YYconfirmed PR6.0m (ongoing)S01030YYunconfirmed PRwithdrawn at 3.7m with progressionS01047YYunconfirmed PR4.8m (ongoing)
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-12-24.