Abstract CT113: Preliminary data on a phase 1b, first-in-human study of the allosteric extracellular FGFR2 inhibitor alofanib in patients with refractory metastatic gastric cancer
Authors: Tsimafeyeu Ilya , Statsenko Galina , Mochalova Anastasia , Trenina Natalia , Kurakin Vyacheslav , Besova Natalia , Novoselova Kristina , Abramova Natalia , Obarevich Ekaterina , Kashanova Alina , Suetina Margarita , Moiseyenko Vladimir , Byakhov Mikhail , Artamonova Elena , Vladimirova Liubov , Tjulandin Sergei 
Published: July 2021

Abstract
Fibroblast growth factor receptor 2 (FGFR2) is associated with an unfavorable prognosis in patients with gastric cancer. Acquired mutations in FGFR2 develop resistance to multikinase inhibitors. Besides, resistance to monoclonal antibodies depends on the type of FGFR2 isoforms IIIc or IIIb expressed by cancer cells. Alofanib (RPT835) is a small molecule, allosteric inhibitor that binds to the non-active site of FGFR2 extracellular domain. RPT835GC1B (NCT04071184) is an ongoing Phase 1b open-label study evaluating the safety and preliminary efficacy of alofanib in patients with metastatic gastric adenocarcinoma pretreated with ≥ 1 previous lines of therapy. The standard dose-escalation part (design 3+3) aims to establish the maximum tolerated dose (MTD) or recommended phase 2 dose (R2PD) as a primary endpoint. The first part of the study includes a 28-day period when alofanib is administered daily intravenously for 5-days followed by a 2-day interval (rest). There are five dose levels: 50, 100, 165, 250, and 350 mg/m2. Secondary endpoints include pharmacokinetic (PK) parameters, rate of adverse events, progression-free survival (PFS), overall survival (OS), and objective response rate. All patients received alofanib until disease progression or unacceptable toxicity. As of data cutoff on December 30, 2020, 13 patients have been enrolled in the trial. Patients were predominantly male (85%), 54% had 2 and more metastatic sites, including liver metastases (54%), and were heavily pretreated (60% received previous 3-6 lines of therapy). To date, all enrolled patients have been studied for safety and have not experienced any dose-limiting toxicities (DLTs) within the 28-day DLT-assessment window. Grade 3 or higher drug related adverse events have included raised ALT/AST at 50 mg/m2, diarrhea at 165 mg/m2, and hyponatremia at 350 mg/m2. 93% of patients had any grade adverse events. Most common Grade 1-2 adverse events included fatigue, diarrhea, nausea, anemia, thrombocytopenia, increased alkaline phosphatase, and reactions immediately after intravenous injections (facial flushing, dizziness, weakness, sweating, and sinus tachycardia). Grade 1 hyperphosphatemia was founded in 25% of cases. One patient discontinued treatment due to drug related Grade 3 uncontrolled diarrhea. Alofanib has demonstrated evidence of biologic activity in 12 patients in the first 4 dose levels evaluated to date. Disease control rate was 75% (1 durable partial response (13 months) at 50 mg/m2 and 8 stable diseases at 50-250 mg/m2). After a median follow-up of 4.5 months, the median PFS and OS was not reached. In conclusion, dosing up to 350 mg/m2 of alofanib was well tolerated, DLT and MTD were not reached. The early biologic activity of alofanib in the late-line treatment of metastatic gastric cancer is encouraging. In addition to the above, any updated safety, PK, and efficacy data will be presented at the time of the AACR meeting.
Citation Format: Ilya Tsimafeyeu, Galina Statsenko, Anastasia Mochalova, Natalia Trenina, Vyacheslav Kurakin, Natalia Besova, Kristina Novoselova, Natalia Abramova, Ekaterina Obarevich, Alina Kashanova, Margarita Suetina, Vladimir Moiseyenko, Mikhail Byakhov, Elena Artamonova, Liubov Vladimirova, Sergei Tjulandin. Preliminary data on a phase 1b, first-in-human study of the allosteric extracellular FGFR2 inhibitor alofanib in patients with refractory metastatic gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT113.