Pemigatinib in previously treated solid tumors with activating FGFR1-FGFR3 alterations: phase 2 FIGHT-207 basket trial

Abstract

Fibroblast growth factor receptor (FGFR) alterations drive oncogenesis in multiple tumor types. Here we studied pemigatinib, a selective, potent, oral FGFR1-FGFR3 inhibitor, in the phase 2 FIGHT-207 basket study of FGFR-altered advanced solid tumors. Primary end points were objective response rate (ORR) in cohorts A (fusions/rearrangements, n = 49) and B (activating non-kinase domain mutations, n = 32). Secondary end points were progression-free survival, duration of response and overall survival in cohorts A and B, and safety. Exploratory end points included ORR of cohort C (kinase domain mutations, potentially pathogenic variants of unknown significance, n = 26) and analysis of co-alterations associated with resistance and response. ORRs for cohorts A, B and C were 26.5% (13/49), 9.4% (3/32) and 3.8% (1/26), respectively. Tumors with no approved FGFR inhibitors or those with alterations not previously confirmed to be sensitive to FGFR inhibition had objective responses. In cohorts A and B, the median progression-free survival was 4.5 and 3.7 months, median duration of response was 7.8 and 6.9 months and median overall survival was 17.5 and 11.4 months, respectively. Safety was consistent with previous reports. The most common any-grade treatment-emergent adverse events were hyperphosphatemia (84%) and stomatitis (53%). TP53 co-mutations were associated with lack of response and BAP1 alterations with higher response rates. FGFR1-FGFR3 gatekeeper and molecular brake mutations led to acquired resistance. New therapeutic areas for FGFR inhibition and drug failure mechanisms were identified across tumor types. ClinicalTrials.gov identifier: NCT03822117 .

Fig. 1. Patient disposition and samples for genomic analysis.

a, Patient disposition. b, Samples for genomic analysis. The primary reason for treatment discontinuation is shown for each patient. *FoundationOne, FMI. ^†The four patients originally misassigned to cohort C based on local test uncertainty were analyzed here with the relevant set of gene alterations in cohorts A and B. EOT, end of treatment; FMI, Foundation Medicine, Inc.

Fig. 2. Best percent change from baseline by FGFR co-alteration subgroup.

Best percent change from baseline by RECIST or RANO for all evaluable patients with tissue NGS report and reported best change in lesion size: FGFR fusions/rearrangements (n = 48); FGFR actionable SNVs (n = 32); FGFR kinase domain mutations or VUS (n = 20). Best OR and PFS by IRC indicated where evaluable. Patients are arranged by FGFR alteration type. Bars are colored by major tumor histologies. Dashed lines indicate a criterion for partial response (change from baseline in target lesion size ≥30%). Tumors are grouped into the following histologies based on ≥5 patients: Cholangiocarcinoma, gynecologic cancers (cervical, endometrial and uterine), CNS (glioblastoma, low-grade pediatric glioma and 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 and solitary fibrous tumor). Genomic analysis is included for all reportable samples and included NGS analysis of tumor tissues and ctDNA at baseline, and of ctDNA at time of progression (gray boxes indicate no report).

Fig. 3. Best percent change from baseline by tumor type.

Best percent change from baseline by RECIST or RANO (denoted by +) for all evaluable patients with tissue NGS report and reported best change in lesion size; BOR and PFS by IRC indicated where evaluable. Patients are arranged by major tumor histologies as previously described. Bars are colored by FGFR alteration type. Dashed lines indicate a criterion for partial response (change from baseline in target lesion size ≥30%; top) and clinical benefit (PFS ≥ 6 months; bottom). Tumors are grouped into the following histologies based on ≥5 patients: Cholangiocarcinoma, gynecologic cancers (cervical, endometrial and uterine), CNS (glioblastoma, low-grade pediatric glioma and 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 and solitary fibrous tumor).

Fig. 4. Compilation of FGFR1–FGFR3 SNVs and associated clinical responses to FGFR inhibitors.

Clinical response data for patients with alternative FGFR1–FGFR3 SNVs treated with pemigatinib (FIGHT-101 (n = 9), FIGHT-201 (n = 154), FIGHT-202 (n = 5), FIGHT-207 (n = 53)), futibatinib (n = 6), infigratinib (n = 5)^,, Debio1347 (n = 5)^, or RLY-4008 (n = 14) are compiled by site of mutation with indicated rates of BOR. For cases with multiple FGFR co-mutations, additional mutations are noted in parentheses. Ig, immunoglobulin.

Extended Data Fig. 1. (A) DOR and (B) PFS Based on IRC Assessment per RECIST v1.1 or RANO and (C) OS (Efficacy-Evaluable Population).

DOR, duration of response; IRC, independent review committee; NE, not estimable; OS, overall survival; PFS, progression-free survival; RANO, Response Assessment in Neuro-Oncology; RECIST, Response Evaluation Criteria in Solid Tumors.

Extended Data Fig. 2. Genes With Most Frequent Emergent Pathogenic or Resistance Variants at Progression by ctDNA.

Genes with pathogenic or known resistance variants detected by ctDNA at progression but not at baseline are plotted by number of emergent variants. ctDNA, circulating tumor DNA.

Extended Data Fig. 3. Across-Indication Analysis of Baseline Co-alterations.

Analysis of tumor tissue samples includes all evaluable patients from cohorts A, B, and C and central tissue next-generation sequencing (Foundation Medicine, Inc.) reporting. Known or likely pathogenic somatic gene alterations occurring in ≥2% of patients are shown. Patients are arranged by best percent change from baseline per RECIST or RANO. BOR, best overall response; cnv, copy number variation; CR, complete response; FGFR, fibroblast growth factor receptor; IRC, independent review committee; NA, not applicable; NE, not evaluable; PChg, percent change from baseline; PD, progressive disease; PR, partial response; SD, stable disease; snv, single-nucleotide variant.