Abstract P4-21-08: A phase I/II of S-222611, a reversible EGFR and HER2 inhibitor, combined with trastuzumab +/- chemotherapy in patients with HER2-positive metastatic breast cancer
Authors: Rafii S , Macpherson I , Baird R , Saggese M , Spiliopoulou P , Kumar S , Italiano A , Bonneterre J , Campone M , Cresti N , Posner J , Takeda Y , Arimura A , Spicer J 
Published: March 2017

Abstract
Background: S-222611, an oral, reversible EGFR and HER2 inhibitor, has been shown to be well-tolerated as monotherapy at a dose of 800mg daily with good anti-tumor activity in patients previously treated with other anti-HER2-based regimens. This study evaluated the tolerability and safety of daily oral administration of S-222611 (S) in combination with trastuzumab (T), trastuzumab + vinorelbine (T+V) and trastzumab + capecitabine (T+C) in HER2-positive (HER2+) metastatic breast cancer (MBC) with or without brain metastases.
Methods: This study was performed as a 3+3 dose escalation followed by expansion to examine the tolerability and safety of S in combination with T, T+V and T+C in Arms A, B and C, respectively. S was administered orally once daily, starting at a dose of 400mg in Arm A, and 200mg in Arms B and C. The dosing of T was 8mg/kg loading followed by 6mg/kg or fixed dose of 600mg subcutaneously every 21 days as recommended. V was administered at 60mg/m2 orally on Day 1 and 8 of a 21-day cycle, and C 1000mg/m2 orally daily for 14 days followed by a 7-day rest period. All patients had HER2+ MBC and were required to have progressed following at least one prior line of anti-HER2 therapy. Prior treatments with V and C were permitted. Anti-diarrhea prophylaxis with loperamide was not required.
Results: A total of 45 patients were enrolled. All patients had received prior anti-tumor regimens including T (n=45), T-DM1 (n=26), pertuzumab (n=9) and lapatinib (n=12). The clinically recommended doses of S at which most adverse events were manageable,were determined as:600mg in Arm A, 200mg in Arm B and 400mg in Arm C. Dose limiting toxicities included Grade 3 diarrhea for Arm A; and Grade 4 neutropenia, Grade 3 Hypokalemia and Hypophosphatemia for Arm B. As of 13 May 2016, treatment is ongoing in 2 patients. No other Grade 4 AEs related to S-222611 have been observed. Grade 3 bilirubin elevation was observed in 5/45 patients, probably due to transporter (UGT1A1) inhibition, while no G3/4 liver dysfunction was reported. RECIST partial responses (PR) were observed in 6 of 9 patients in Arm A and 5 of 9 patients in Arm C, at respective clinically recommended doses. Nine of 45 patients had brain metastases; 4 of these patients showed RECIST PR including an intracranial tumor response in one patient (400mg in Arm C) who had prior treatments with paclitaxel, T+C, T-DM1 and V after diagnosis of BM.
Conclusions: The clinically recommended doses of S-222611 combined with T, T +V and T+C were determined for further clinical studies. Clinical benefit (PR and SD &gt;6 month) was seen with each combination even in heavily pre-treated HER2+ MBC patients.
Summary of the safety and efficacy of S-222611 (S) combination. Dose (mg)nDLT (1st cycle)G3 Diarrhea during study (N of patients)RECIST tumor response, PR n/ SD ≥6M nORR n (%)CBR n (%)Arm A: S + T4005010/10/5 (0%)1/5 (20%)Arm A: S + T6009036/06/9 (67%)6/9 (67%)Arm A: S + T8007141/11/7 (14%)2/7 (29%)Arm B: S + T + V2005020/40/5 (0%)4/5 (80%)Arm B: S + T + V4002211/01/2 (50%)1/2 (50%)Arm C: S + T + C2004010/10/4 (0%)1/4 (25%)Arm C: S + T + C4009025/05/9 (56%)5/9 (56%)Arm C: S + T + C6004022/12/4 (50%)3/4 (75%)
Citation Format: Rafii S, Macpherson I, Baird R, Saggese M, Spiliopoulou P, Kumar S, Italiano A, Bonneterre J, Campone M, Cresti N, Posner J, Takeda Y, Arimura A, Spicer J. A phase I/II of S-222611, a reversible EGFR and HER2 inhibitor, combined with trastuzumab +/- chemotherapy in patients with HER2-positive metastatic breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-21-08.