Abstract PO4-05-09: Phase I study of the FGFR inhibitor rogaratinib, fulvestrant and palbociclib in advanced hormone receptor-positive (HR+) breast cancer (BC) with FGFR1/2 amplification and/or overexpression (FGFR1/2+)
Authors: Martínez-Jáñez Noelia , Pernas Sonia , García-Sáenz José Ángel , Murillo Serafin Morales , Bermejo Begoña , Guerra Juan A , Mouron Silvana , Quintela-Fandino Miguel 
Published: May 2024

Abstract
Background: Novel therapies are needed upon progression to first-line CDK4/6 inhibitor (CDK4/6i) plus aromatase inhibitor (AI) in advanced HR+ BC. One frequent alteration driving resistance to CDKi plus AI is FGFR1/2 amplification or overexpression. In preclinical FGFR1/2+ HR+ BC models, combined CDK4/6, ER and FGFR blockade was more effective than single- or double combinations (Breast Cancer Res; 23:21-37; 2021). Rogaratinib (ROGA) is a selective FGFR1-4 kinase inhibitor with significant activity in FGFR-aberrant tumors. We aimed to study the tolerability and preliminary efficacy of ROGA added to fulvestrant (FUL) and palbociclib (PAL) in patients (pts) with FGFR1/2+ HR+ BC progressing on first-line CDK4/6i plus AI.
Methods: ROGABREAST (NCT04483505) was a single-arm, prospective, multicentric, open-label, phase I dose-escalation trial following a classic 3+3 schedule. Pts were pre-screened for FGFR1/2 amplification and/or overexpression by FISH and RNAScope. Women &gt;18 year-old with advanced HR+ BC progressing on first-line CDI4/6i plus AI, and adequate organ function were included. Pts received ROGA monotherapy q12 hours in day 1. In day 2, pts continued ROGA and started FUL (500 ug IM) plus PAL (100 mg/day on days 1-21). FUL was repeated in day +15. Cycle 1 was 29 days-long and followed by 28-day cycles (continuous ROGA q12 hours days 1-28, FUL 500 ug day 1, and PAL 100mg/d days 1-21). Level 1 was ROGA 400 mg/bid and escalated 200 mg/bid increments. FUL dose was not modified. PAL was allowed to escalate intrapatient to 125 mg/d after cycle 2 in pts experiencing ≤ grade 1 tolerable side effects as the greatest toxicity in cycle 1. PK and PD (FGF23 and phosphate levels) profiles were obtained in days +1 and +15. DLT-assessment period was cycle 1-2.
Results: from 12/2020 to 5/2022, 67 pts were screened; 29 were FGFR1/2+ (22 and 5 RNAscope-positive for FGFR1 and FGFR2; 17 and 3 FISH-positive for FGFR1 and FGFR2). Nine pts entered the study. Six were enrolled in level 1, where 1 DLT (grade 3 diarrhea) occurred, and 3 in level 2 (600 mg ROGA bid; no DLTs). Grade 3 hyperphosphatemia, adequately controlled with diet and chelants (33% of the patients) and grade 2 non-tolerable dactylitis/onycholysis (11%) were the most frequent severe toxicities after the DLT period. Other toxicities were mild and well-tolerated (grade 1-2 diarrhea and hyperphosphatemia occurred in 66 and 44% of the pts, respectively). Median PFS was 113 days and 44% of the pts had a PFS &gt; 180 days, with no apparent relationship with FGFR1 or 2 status, or mutations found via WES. The trial was terminated after completion of level 2 due to rogaratinib development discontinuation.
Conclusions: Triple FGFR1/2, CDK4/6 and ER blockade appears safe at standard drug dosages and shows promising clinical activity in second-line HR+ FGFR1/2+ BC patients progressing on CDK4/6i plus AI.
Citation Format: Noelia Martínez-Jáñez, Sonia Pernas, José Ángel García-Sáenz, Serafin Morales Murillo, Begoña Bermejo, Juan A Guerra, Silvana Mouron, Miguel Quintela-Fandino. Phase I study of the FGFR inhibitor rogaratinib, fulvestrant and palbociclib in advanced hormone receptor-positive (HR+) breast cancer (BC) with FGFR1/2 amplification and/or overexpression (FGFR1/2+) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-05-09.