Jen, Kai Yu

Abstract Background: Oncogenic alterations (gene amplification, mutation, and fusion/rearrangements) of fibroblast growth factor receptor 2 (FGFR2) are rare and occur at varying frequencies across solid tumor types and have become critical therapeutic targets in drug development. First generation FGFR pan-kinase inhibitors non-selectively inhibit FGFR1-4 and are associated with dose limiting toxicities and narrow therapeutic windows. Off-isoform toxicity (FGFR1-hyperphosphatemia; FGFR4-diarrhea) and on-target acquired resistance have led to limited efficacy, which is primarily seen in FGFR2-fusion+ intrahepatic cholangiocarcinoma. Therapies that selectively target FGFR2 remain an unmet need in advanced breast cancer as well as other solid tumor types. RLY-4008 is a novel, oral FGFR2 inhibitor designed to overcome the limitations of pan-FGFR inhibitors (FGFRi) by potently and selectively targeting primary oncogenic FGFR2 alterations and acquired resistance mutations. RLY-4008 is > 200-fold selective over FGFR1, > 80- and > 5000-fold selective over FGFR3 and FGFR4 respectively. Here we describe a phase 1/2 study to investigate the safety and antitumor activity in advanced FGFR2 altered cancers, including breast cancer. Methods: ReFocus is a phase 1/2 open label global study evaluating the safety and efficacy of RLY-4008 (NCT04526106) in adult patients with advanced unresectable and/or metastatic cancers harboring an FGFR2 alteration. Key eligibility criteria include: documented FGFR2 alteration in blood or tissue per local assessment, ECOG performance status of 0-1, disease that is refractory or not adequately responding to standard therapy, has no available standard therapy, or patient is intolerant of, or declined standard therapy (including pan-FGFRi), and measurable or evaluable disease per RECIST 1.1. FGFR2 alteration will be confirmed retrospectively by central laboratory assessment. Part 1 dose escalation employed the Bayesian Optimal Interval (BOIN) design to determine the MTD/RP2D of RLY-4008. Part 2 dose expansion is presently enrolling patients at the RP2D of RLY-4008 and includes 5 cohorts comprised of patients with: 1. FGFR2 fusion+ cholangiocarcinoma previously treated with an FGFRi; 2. FGFR2 fusion+ cholangiocarcinoma not previously treated with an FGFRi; 3. FGFR2 fusion+ solid tumors; 4. FGFR2 mutation+ solid tumors and 5. FGFR2 amplified solid tumors. Solid tumors in cohorts 3, 4 and 5 will have a focus in breast cancer. The primary endpoint is objective response rate (ORR); key secondary endpoints include: duration of response, safety and tolerability, correlation of FGFR2 genotype by central tissue assessment with antitumor response, characterization of PK profile, and quality of life. US enrollment began September 2020 and has expanded into Europe and Asia. Clinical trial information: NCT04526106. Citation Format: Suneel Kamath, David Tai, Irene Moreno, Hani Babiker, Zhaohui Jin, Changhoon Yoo, Fabien Ricard, Kai Yu Jen, Jim Coward, Jia Liu, Frans Opdam, Michael Millward, Mariano Ponz-Sarvise, Jeffrey Yachnin, Richard Kim, Joon Oh Park, Vivek Subbiah, Alison M. Schram. ReFocus: A Phase 1/2 Study of the Highly Selective FGFR2 Inhibitor, RLY-4008, in Patients with Advanced Solid Tumors Including Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT3-24-01.

Abstract INTRODUCTION: Oncogenic FGFR2 alterations (fusions/rearrangements, amplifications, mutations) are key drivers in cholangiocarcinoma (CCA) and multiple solid tumors. Current pan-FGFR inhibitor (FGFRi) therapy is limited by off-isoform toxicity and acquired FGFR2 kinase domain resistance mutations. RLY-4008 is a highly selective and potent oral inhibitor designed to target both FGFR2 driver and resistance mutations. We initiated a first-in-human study in advanced solid tumors patients (pts) to define the safety, pharmacokinetics (PK) and efficacy of RLY-4008 (NCT04526106). METHODS: Adult pts received RLY-4008 QD or BID on a 4-week cycle following a BOIN escalation design. Adverse events (AEs), PK, ctDNA and anti-tumor activity (RECIST 1.1) were assessed. RESULTS: As of 16AUG21, 45 pts (35 CCA; 10 other) have been treated with RLY-4008 at total daily doses of 30-200 mg (18 pts BID; 27 pts QD). 44 pts had oncogenic FGFR2 alterations (26 fusions/13 mutations/5 amplifications). The median number of prior anti-neoplastic therapies was 3 (range 1-15). 94% (33/35) of CCA pts had prior chemotherapy and 69% (24/35) had prior FGFRi. 56% (9/16) CCA pts with prior FGFRi and evaluable ctDNA had ≥1 FGFR2 resistance mutation at baseline, most commonly at positions 549 (8/9), 617 (3/9), or 564 (2/9). RLY-4008 had rapid absorption (Tmax 1-7h), half-life to support QD dosing (18-34 h), dose-dependent exposure (AUC; Cmax) and predicted FGFR2 occupancy >85% across dose levels. The MTD has not been defined, and QD dose exploration continues to select the optimal biologically efficacious dose. AEs occurring in >20% of pts include stomatitis (49%), palmar-plantar erythrodysesthesia (PPE, 38%), dry mouth (29%), and nail toxicities (22%), majority of which were ≤Gr 2. 6 pts had Gr 1-2 retinopathy, which resolved in all cases. 5 AEs were considered dose limiting toxicities: 4 in BID (rash/PPE/mucositis/hyperbilirubinemia) and 1 in QD (retinopathy). No Gr 4/5 drug-related AEs were seen. 25 pts remain on treatment (range 1-37 weeks). RLY-4008 showed broad anti-tumor activity across dose levels and FGFR2 alterations with radiographic tumor reductions of ≥10% in 59% pts (19/32; -11% to -83%). Activity was seen in FGFRi-naïve, FGFR2-fusion+ CCA with PRs in 50% of pts (3/6, 2 confirmed and 1 pending confirmation; -56% to -83%). Activity was also seen in FGFRi pre-treated FGFR2-fusion+ CCA pts (N=16) with 16 SD, including 9 pts with tumor reduction ≥10% (from -12% to -35%). Of the FGFRi pre-treated FGFR2-fusion+ CCA patients with detectable FGFR2 resistance mutations in ctDNA at baseline, 78% (7/9) were undetectable at C2D1. CONCLUSION: RLY-4008 demonstrates promising safety, tolerability, and clinical activity in FGFR2-altered solid tumor pts, including those who progressed on prior FGFRi therapy. Consistent with the FGFR2-selective mechanism, minimal off-isoform toxicity (FGFR1-hyperphosphatemia; FGFR4-diarrhea) was seen. These encouraging data validate selective targeting of FGFR2 and suggest that RLY-4008 has potential to overcome resistance to FGFRi. Citation Format: Lipika Goyal, Mitesh Borad, Vivek Subbiah, Amit Mahipal, Suneel Kamath, Kabir Mody, Robin Katie Kelley, Richard Kim, Vaibhav Sahai, Anthony El-Khoueiry, Efrat Dotan, Oleg Schmidt-Kittler, Jinshan Shen, Kai Yu Jen, Alicia Deary, Wei Guo, Mahesh Padval, Cori Ann J. Sherwin, Charles Ferte, Beni Wolf, Alison M. Schram. First results of RLY-4008, a potent and highly selective FGFR2 inhibitor in a first-in-human study in patients with FGFR2-altered cholangiocarcinoma and multiple solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P02-02.

TPS4165 Background: Oncogenic activation of FGFR2 via genomic rearrangement, gene amplification, or point mutation in advanced solid tumors provides the opportunity for rapid clinical development of highly selective FGFR2 inhibitors using a precision oncology approach to deliver clinical benefit to genomically-defined patient (pt) populations. Unfortunately, this opportunity remains largely unrealized as current, non-selective small molecule inhibitors (pan-FGFRi) suffer from off-isoform toxicity (FGFR1-hyperphosphatemia; FGFR4-diarrhea) and on-target acquired resistance leading to only modest efficacy primarily limited to FGFR2-fusion+ intrahepatic cholangiocarcinoma (ICC). RLY-4008 is a novel, oral FGFR2 inhibitor designed to overcome the limitations of pan-FGFRi by potently and selectively targeting primary oncogenic FGFR2 alterations and acquired resistance mutations. We initiated a first-in-human (FIH) precision oncology study of RLY-4008 in advanced solid tumor pts with FGFR2 alterations with primary objectives to define the maximum tolerated dose/recommended phase 2 dose (MTD/RP2D) and adverse event (AE) profile of RLY-4008 and key secondary objectives to assess FGFR2 genotype in blood and tumor tissue, pharmacokinetics (PK), and anti-tumor activity. Methods: This is a global, multi-center, FIH dose escalation/expansion study of RLY-4008 (NCT04526106) in adult pts who have unresectable or metastatic solid tumors with FGFR2 alteration per local assessment, ECOG performance status 0-2, measurable or evaluable disease per RECIST 1.1, and who are refractory, intolerant, or declined standard therapy including pan-FGFRi. FGFR2 alteration will be confirmed retrospectively by central laboratory assessment. For the dose escalation (Ñ50), RLY-4008 is administered QD/BID on a continuous schedule with 4-week cycles according to a Bayesian Optimal Interval design that allows accelerated dose titration, additional accrual to dose levels declared tolerable, and exploration of alternative schedules if warranted. The MTD is determined via logistic regression of the dose limiting toxicity rate across all dose levels and an RP2D less than the MTD may be considered based on observed AEs, PK, and anti-tumor activity. Following dose escalation, the dose expansion (Ñ75) will treat pts with RLY-4008 at the MTD/RP2D and includes 5 groups with any prior therapy (except group 2): 1. FGFR2 fusion+ ICC pts; 2. FGFR2 fusion+ ICC pts with no prior FGFRi; 3. FGFR2 fusion+ pts with other solid tumors; 4. FGFR2-mutation+ solid tumor pts and 5. FGFR2-amplified solid tumor pts. The primary endpoints are MTD/RP2D and AE profile; key secondary endpoints are FGFR2 genotype in blood and tumor tissue, PK parameters; overall response rate, and duration of response per RECIST 1.1. US enrollment began SEP2020 and Europe/Asia start-up is underway. Clinical trial information: NCT04526106.