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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.

Esophageal cancer is the sixth most common cause of cancer-related death worldwide. Esophageal adenocarcinoma is the most common subtype of esophageal cancer in the United States, and its incidence has risen dramatically in the last few decades. Modern endoscopic and surgical techniques have significantly improved morbidity and mortality rates of patients undergoing treatment for esophageal cancer. However, most cases are diagnosed at a late stage when the prognosis is poor, emphasizing the need for an effective screening strategy. This clinical overview focuses on screening, multidisciplinary evaluation, and treatment of early esophageal adenocarcinoma.

Targeted therapies in biliary tract cancer (BTC) are emerging as options for patients not who do not respond to first-line treatment. Agents acting on tumor-specific oncogenes in BTC may target fibroblast growth factor receptor 2 (FGFR2), isocitrate dehydrogenase (IDH), B-raf kinase (BRAF), and human epidermal growth factor receptor 2 (HER-2). Additionally, given the heterogeneous genetic landscape of advanced BTCs, many harbor genetic aberrations that are common among solid tumors, including RET fusions, tropomyosin receptor kinase (TRK) fusions, and high tumor mutational burden (TMB). This review aims to provide updates on the evolving array of therapeutics available, and to summarize promising works on the horizon.

The outcomes of endoscopic submucosal dissection (ESD) for T1b esophageal cancer (EC) and its recurrence rates remain unclear in the West. Using a multicenter cohort, we evaluated technical outcomes and recurrence rates of ESD in the treatment of pathologically staged T1b EC.We included patients who underwent ESD of T1b EC at 7 academic tertiary referral centers in the United States (n = 6) and Brazil (n = 1). We analyzed demographic, procedural, and histopathologic characteristics and follow-up data. Time-to-event analysis was performed to evaluate recurrence rates.Sixty-six patients with pathologically staged T1b EC after ESD were included in the study. A preprocedure staging EUS was available in 54 patients and was Tis/T1a in 27 patients (50%) and T1b in 27 patients (50%). En-bloc resection rate was 92.4% (61/66) and R0 resection rate was 54.5% (36/66). Forty-nine of 66 patients (74.2%) did not undergo surgery immediately after resection and went on to surveillance. Ten patients had ESD resection within the curative criteria, and no recurrences were seen in a 13-month (range, 3-18.5) follow-up period in these patients. Ten of 39 patients (25.6%) with noncurative resections had residual/recurrent disease. Of the 10 patients with noncurative resection, local recurrence alone was seen in 5 patients (12.8%) and metastatic recurrence in 5 patients (12.8%). On univariate analysis, R1 resection had a higher risk of recurrent disease (hazard ratio, 6.25; 95% confidence interval, 1.29-30.36; P = .023).EUS staging of T1b EC has poor accuracy, and a staging ESD should be considered in these patients. ESD R0 resection rates were low in T1b EC, and R1 resection was associated with recurrent disease. Patients with noncurative ESD resection of T1b EC who cannot undergo surgery should be surveyed closely, because recurrent disease was seen in 25% of these patients.

Background: The 5-year survival rate for metastatic pancreatic cancer is ~3%, indicating an urgent need for novel therapies. Combination therapy with modified FOLFIRINOX (leucovorin, irinotecan, 5-fluorouracil, and oxaliplatin) and immunotherapy has been proposed for first-line metastatic pancreatic cancer to improve tolerability and clinical efficacy, respectively (NCCN, Pancreatic. 2021; Vonderheide, Annu. Rev. Med. 2020). The present study evaluates the safety, pharmacokinetics, and preliminary antitumor activity of modified FOLFIRINOX + giloralimab (CD40 agonist) with or without budigalimab (anti-PD-1) in patients with untreated metastatic pancreatic cancer. Methods: Multicenter, randomized phase 1b/2 study (NCT04807972) in patients (18-75 years) with untreated metastatic pancreatic cancer. The phase 1b (dose escalation) examines the safety dose level of giloralimab in a triplet of modified FOLFIRINOX + giloralimab + budigalimab using a Bayesian optimal interval [BOIN] design. BOIN design is utilized to guide giloralimab escalation decisions. In phase 2 (dose expansion), patients are randomized 1:1:1 to receive treatment with modified FOLFIRINOX (cohort A), modified FOLFIRINOX + giloralimab (cohort B), or modified FOLFIRINOX + giloralimab + budigalimab (cohort C). Randomization is stratified according to Eastern Cooperative Oncology Group performance status. Primary objectives are to assess the safety and tolerability of modified FOLFIRINOX + giloralimab + budigalimab (phase 1b) and to evaluate overall survival in patients treated with modified FOLFIRINOX + giloralimab with or without budigalimab (versus those receiving modified FOLFIRINOX alone; phase 2). Secondary objectives include characterizing the pharmacokinetics of giloralimab and budigalimab in combination with modified FOLFIRINOX, assessing the efficacy of modified FOLFIRINOX + giloralimab with or without budigalimab, and evaluating the safety/tolerability of modified FOLFIRINOX + giloralimab with or without budigalimab. Patients will receive giloralimab and budigalimab intravenously in combination with modified FOLFIRINOX in a 28-day cycle. Dose-limiting toxicities are assessed during the first cycle of dosing. Adverse events are evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events. Blood samples for pharmacokinetic analysis are collected at designated time points throughout the study. Responses are assessed by Response Evaluation Criteria in Solid Tumors version 1.1. Survival outcomes are described using the Kaplan-Meier method. Approximately 129 patients are planned to be included. Enrollment started in June 2021, with 7 patients enrolled as of November 2021. Citation Format: Dung T. Le, Marcia Cruz-Correa, David L. Bajor, Rocio Garcia-Carbonero, Marion Harris, Roberto Pazo-Cid, Hedy Kindler, Nelson Yee, Suneel Kamath, Maulik Patel, Hua Fang, William Henner, Patrick Hardesty, Martha Blaney, Michael McDevitt, Talia Golan. Phase 1b/2 study of giloralimab in combination with modified FOLFIRINOX with or without budigalimab in patients with untreated metastatic pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT246.

Early esophageal cancer involves the mucosal and submucosal layers of the esophagus. Early esophageal cancer is a heterogeneous group, and achieving optimal outcomes requires a multidisciplinary approach to align patients to their optimal treatment. Although organ-sparing endoscopic resection has become the preferred management option for superficial esophageal cancer, it is not adequate in all tumors, such as high-risk lesions with poorly differentiated pathology, lymphovascular invasion, or deep submucosal invasion. In such high-risk lesions, surgery, chemotherapy, and/or radiation may be required. In this article, we present our multidisciplinary approach to early esophageal cancer.

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.