FIGHT-207: Anonymized Genomic Alterations and Clinical Responses

Background: FIGHT-207 was a phase 2 study of the FGFR1-FGFR3 inhibitor pemigatinib in patients with previously treated, locally advanced/metastatic or unresectable solid tumor malignancies harboring activating fibroblast growth factor receptor (FGFR) gene alterations. Population information: 107 patients were divided into 3 cohorts: FGFR1–FGFR3 fusions/rearrangements; n=49 Activating FGFR1–FGFR3 non-kinase domain single nucleotide variants (SNVs); n=32 FGFR1–FGFR3 kinase domain mutations or variants of unknown significance (VUS) with potential pathogenicity; n=26 Participants on study had tumors that were grouped into the following histologies based on ≥ 5 patients: Cholangiocarcinoma, gynecologic cancers (cervical, endometrial, uterine), central nervous system (glioblastoma, low-grade pediatric glioma, astrocytoma), pancreatic cancer, breast cancer, urothelial tract/bladder cancer, non-small cell lung cancer, and other (adrenal cancer, anal cancer, cancer of unknown primary origin, colorectal cancer, gastric/gastroesophageal cancer, gallbladder cancer, giant cell bone tumor, head and neck cancer, lung neuroendocrine cancer, nasopharyngeal cancer, ovarian cancer, prostate cancer, renal cell cancer, sarcoma, solitary fibrous tumor). Among the efficacy-evaluable participants, 99 had both independent review committee (IRC) central best overall response (BOR) and tissue NGS- data; 2 additional patients had Not Evaluable (NE) as central BOR Baseline tissue targeted NGS data (F1CDx, Foundation Medicine Inc.) of genomic alterations are reported for N=101 participants Baseline plasma targeted NGS analysis (PredicineCare, Predicine Inc.) of genomic data are reported for N=83 participants; data at disease-progression are reported for N=78 participants. Principal Findings: The FIGHT-207 study provided evidence of clinical benefit of pemigatinib in multiple histologies, explored the clinical actionability of various FGFR1-FGFR3 gene alterations, and leveraged the depth of translational data from targeted NGS analysis of baseline samples and plasma samples obtained at baseline and end of treatment to provide key insights into the biology of FGFR inhibition and the clinical utility of FGFR inhibitors. The FIGHT-207 article (pending in Nat.Med. NMED-A128973B) reports evidence suggesting clinical acquired resistance to FGFR inhibition via secondary FGFR mutations as well as emerging co-mutations in other oncogenic and tumor suppressor pathways. This study also provides evidence of acquired resistance to FGFR inhibition in multiple histologies beyond cholangiocarcinoma and urothelial cancers in a systemic correlative analysis of post-progression ctDNA in a trial. Data available through dbGaP: Anonymized information for 101 participants with both IRC central BOR evaluation (including 2 patients with NE as BOR) and tissue NGS data, including tumor histology, enrollable FGFR alteration, and outcome. Genomic alterations determined by baseline tissue NGS (F1CDx, Foundation Medicine Inc.) Genomic alterations determined by plasma NGS analysis (PredicineCare, Predicine Inc.) of ctDNA analysis at baseline (n=83) and at end of treatment/ disease progression (n=78) including genomic alterations that were not assessed to be Germline SNPs. ]]>
Reproduced from “Rodón J, Damian S, Furqan M, et al. Pemigatinib in previously treated solid tumors with activating FGFR1-FGFR3 alterations: phase 2 FIGHT-207 basket trial. Nat Med. 2024 May 6. Inclusion Criteria: Age ≥ 18 years old with a histologically or cytologically confirmed advanced/metastatic or surgically unresectable solid tumor and radiographically measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or Response Assessment in Neuro-Oncology (RANO) Documented FGFR1–FGFR3 mutation or fusion/rearrangement Disease progression after ≥ 1 line of prior systemic therapy; no therapy available likely to provide clinical benefit Eastern Cooperative Oncology Group performance status ≤ 2 Provision of a baseline tumor specimen Willingness to avoid pregnancy or fathering children Exclusion Criteria: Prior receipt of a selective FGFR inhibitor or concurrent administration or receipt of anticancer medications ≤ 28 days before first pemigatinib dose Candidacy for potentially curative surgery Clinically significant corneal or retinal disorder confirmed by ophthalmologic examination Current evidence of ectopic mineralization or calcification Radiation administered ≤ 2 weeks before the first dose of pemigatinib or inadequate recovery from radiation-related toxicities Untreated CNS metastases or CNS metastases that have progressed or additional malignancy requiring active treatment or is progressing, except for basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy Gastrointestinal disorders that could interfere with the absorption, metabolism, or excretion of pemigatinib Inability to swallow and retain oral medication Clinically significant or uncontrolled cardiac disease, except for patients with a pacemaker or well-controlled atrial fibrillation History or presence of clinically meaningful abnormal electrocardiogram Active chronic or current infectious disease requiring systemic antibiotic, antifungal, or antiviral treatment ≤ 2 weeks before enrollment Active Hepatitis B or Hepatitis C infections or HIV infection Use of potent cytochrome P450 3A4 (CYP3A4) inhibitors or inducers or moderate CYP3A4 inducers ≤ 14 days or ≤ 5 half-lives, whichever is longer, before the first dose of pemigatinib Known hypersensitivity or severe reaction to pemigatinib or its excipients Inadequate recovery from toxicity or complications from major surgery Pregnancy or breastfeeding Receipt of an investigational drug for any indication History of hypovitaminosis D requiring supraphysiologic doses to correct the deficiency Inability or unlikeliness of the patient to comply with the dose schedule and evaluations Any condition that in the investigator's opinion may interfere with the full participation in the study, pose a significant risk to the patient, or interfere with data interpretation Inability of the patient to provide informed consent Patients with laboratory values outside of normal ranges were also excluded: Nonpermitted hematology values were platelets ≤ 75 × 109/L, hemoglobin ≤ 9.0 g/dL, or absolute neutrophil count ≤ 1.5 × 109/L; Transfusions were allowed with a 2-week washout period Laboratory values suggesting hepatic dysfunction were alanine aminotransferase ≥ 3 × upper limit of normal (ULN); (> 5 × ULN for liver metastasis), aspartate aminotransferase ≥ 3 × ULN (> 5 × ULN for liver metastasis), total bilirubin ≥ 1.5 × ULN (≥ 2.5 × ULN if Gilbert's syndrome or liver metastasis), or alkaline phosphatase ≥ 3 × ULN Prohibited renal values were serum creatinine clearance ≤ 30 mL/minute based on the Cockcroft-Gault formula Patients with serum phosphate > ULN or serum calcium outside of normal range or serum albumin-corrected calcium outside of the normal range when serum albumin is outside of the normal range were also excluded ]]>