The NCCN Oncology Research Program (ORP) strives to improve the quality of life for patients and reduce cancer-related deaths by advancing cancer therapies through research. Since the program‘s establishment in 1999, the NCCN ORP has brought millions of dollars in research grants to investigators at NCCN Member Institutions. Research grants are provided to NCCN through collaborations with pharmaceutical and biotechnology companies; these grants are in turn used to support scientifically meritorious cancer research efforts.

NCCN ORP studies typically explore new avenues of clinical investigation and seek answers to important cancer-related questions. All studies are approved and funded through a scientific peer-review process and are overseen by the ORP.

This feature highlights an NCCN study funded through the grant mechanism.

A Phase II Study of Futibatinib and Pembrolizumab in Metastatic Microsatellite Stable Endometrial Carcinoma

Principal Investigator: Siqing Fu, MD, PhD

Condition: Endometrial carcinoma

Institution: The University of Texas MD Anderson Cancer Center

Fibroblast growth factor receptor (FGFR) gene aberrations occur in a wide variety of cancers, including FGFR2 mutations such as D101Y, S252W, P253R, A314D, A315T, S373C, Y376C, C383R, N550K, and K660E, in approximately 10% to 16% of endometrial cancer. In addition to its driving mechanisms in tumorigenesis and metastases via activation of many intracellular signaling pathways, activation of FGFR kinases induces an immunosuppressive tumor microenvironment and enhances PD-L1 expression, providing a promising strategy to combine an FGFR inhibitor with immune checkpoint blockade. Preclinical research and pilot clinical studies support that treatment with an FGFR inhibitor in combination with anti–PD-(L)1 therapy demonstrates synergistic antitumor activity in both FGFR wild-type and aberrant malignancies. It is noted that the combination of lenvatinib and pembrolizumab has been approved for the treatment of advanced microsatellite stable (MSS) endometrial carcinoma regardless of FGFR status. However, the fact that a significant portion of patients (70%) cannot tolerate the treatment and require drug interruptions for treatment-related toxicity urges us to develop less toxic, more effective therapeutic regimens. Therefore, we propose this pilot phase II study to explore the combination therapy of futibatinib and pembrolizumab in patients with metastatic MSS endometrial carcinoma to provide a well-tolerated regimen while the durable antitumor efficacy remains.

Primary Objectives:

• • Evaluate the objective response rate (ORR) of futibatinib and pembrolizumab in patients with metastatic MSS endometrial carcinoma

• • Evaluate the safety and tolerability of futibatinib and pembrolizumab in patients with metastatic MSS endometrial carcinoma

Primary Endpoints:

• • Complete responses (CRs) and partial responses (PRs) according to RECIST version 1.1

• • Adverse events (AEs; via clinical manifestations and laboratory tests) and serious AEs according to the NCI’s CTCAE version 5.0

Exploratory Objectives:

• • Assess patient-reported outcomes (PROs)

• • Assess survival

• • Assess changes of blood cytokines and chemokines

• • Assess circulating free DNA

• • Assess tumor potential biomarkers

• • Explore potential biomarkers predicting major clinical outcomes

Exploratory Endpoints:

• • Self-reported symptomatic AEs using PRO version of the CTCAE (PRO-CTCAE) and the 2-level version of EQ-5D (EQ-5D-3L) for the initial 6 weeks of therapy and at the end of each cycle thereafter

• • Progression-free survival (PFS), defined as the time from treatment initiation to the occurrence of disease progression or death from any cause, whichever occurs first, and overall survival (OS), defined as the time from treatment initiation to death from any cause

• • Cytokine and chemokine measurement using multiplex ELISA at baseline, prior to day 1 of cycle 2 (C2D1), and end of therapy or prior to day 1 of cycle 13 (C13D1) if still on therapy

• • Multiple immunohistochemistry on tumor specimens at baseline (all), prior to C2D1 (patients with stage II disease), and at relapse in patients with either documented stable disease for ≥6 months, CR, or PR

• • Next-generation sequencing (NGS) on circulating DNA at baseline, prior to C2D1, and end of therapy or prior to C13D1 if still on therapy

• • NGS on tumor specimens for targeted exome panel including FGFR1–4 genetic aberrations to reveal potential biomarkers at baseline (all), prior to C2D1, and at relapse in patients with either documented stable disease ≥6 months, CR, or PR

• Fisher exact or log rank test to relate potential biomarkers with ORR, PFS, OS, PROs, and toxicity

Contact: Siqing Fu, MD, PhD   •   713-792-4318   • siqingfu@mdanderson.org

Coordinator: Sneha Alexander   •   SAlexander6@mdanderson.org

ClinicalTrials.gov Identifier: NCT05036681