Pemigatinib shows antitumor activity in tumors with FGFR alterations

Based ondata from the Phase 2 FIGHT-207 trial (NCT 03822117), advanced/metastatic or unresectable solid tumors harboring activating FGFR mutations or fusions/rearrangements responded to pemigatinib; the agent demonstrated antitumor activity in patients with cholangiocarcinoma, central nervous system (CNS) tumors, gynecological tumors, and pancreatic cancer.

Specifically, pts with FGFR fusions or rearrangements (n=49 Cohort A) had an objective response rate (ORR) of 26.5% (95% Confidence interval ,15.0%-41.1%), disease control rate (DCR) was 65.3% (95% confidence interval ,50.4%-78.3%). Those carrying FGFR actionable single nucleotide variants (n=32 Cohort B) had an ORR of 9.4% (95% confidence interval, 2.0%-25.0%) and a DCR of 56.3% (95% confidence interval, 37.7%-73.6%). Patients with FGFR kinase domain mutations or variants of unknown significance (n=26 Cohort C) had an ORR of 3.8% (95% Confidence interval , 0.1%-19.6%), DCR is 34.6% (95% confidence interval : 17.2%-55.7%). Pemetinibis currently significantly active in cholangiocarcinoma with FGFR fusions, and significant activity is also seen in mutations in the extracellular ligand binding and transmembrane domains.

In the Phase 1/2 FIGHT-101 trial (NCT02393248), pemetinib, a selective, potent oral FGFR1-3 inhibitor, previously produced a manageable safety profile and pharmacodynamic and clinical activity in patients pretreated with FGF/FGFR-altered solid tumors. In August 2022, the U.S. Food and Drug Administration (FDA) approved pemetinib for the treatment of adults with FGFR1 rearranged relapsed or refractory myeloid/lymphoid tumors.

The open-label, single-armFIGHT-207 basket trial further evaluated pemetinibin unresectable or advanced disease/Role in patients with metastatic solid tumors with confirmed activating FGFR mutations or fusions/rearrangements. All patients in Cohorts A, B, and C received continuous 21-day cycles of pemetinib at 13.5 mg daily until they experienced disease progression or unacceptable toxicity. The primary endpoint of the trial was RECIST v1.1 confirmed ORR or response assessment by neuro-oncology criteria in Cohorts A and B. Secondary endpoints include progression-free survival (PFS), duration of response (DOR) and overall survival (OS) in Arms A and B, as well as safety in all arms.

At the time of data cutoff, all patients in all 3 cohorts had discontinued treatment. In Cohort A, reasons for discontinuation included disease progression (67.3%), physician decision (4.1%), adverse effects (AEs; 6.1%), patient discontinuation (6.1%), subject discontinuation from the study (8.2%), and other (8.2%). In Cohort B, reasons for discontinuation were disease progression (96.9%) and death (3.1%). Patients in Cohort C discontinued treatment due to disease progression (65.4%), AEs (11.5%), patient withdrawal (7.7%), sponsor discontinuation of the study (3.8%), death (7.7%), or other (3.9%).

Among all patients (N=111), the median age was 62.0 years (range, 25-84 years), and 55.9% of patients were female. The majority of patients (95.5%) had an ECOG performance status of 0 or 1. In addition, 55.9% of patients received 2 or more systemic therapies, and 44.1% received 0 or 1 systemic therapy. The most common tumor types in the overall population included cholangiocarcinoma (16.2%), gynecological (12.6%), central nervous system (11.7%), urothelial bladder (10.8%), pancreatic (7.2%), non-small cell lung cancer (6.3%), and breast cancer (5.4%).

Additional data from cohortA showed that the median DOR was 7.8 months (95% CI, 4.2-not estimable [NE]). The median PFS of these patients was 4.5 months (95% CI, 3.6-6.3), and the median OS was 17.5 months (95% CI, 7.8-NE). In Cohort B, patients experienced a median DOR of 6.9 months (95% CI, 4.0-NE), a median PFS of 3.7 months (95% CI, 2.1-4.5), and a median OS of 11.4 months (95.CI, 16.6-NE). The median PFS and median OS of patients in cohort C were 2.0 months (95% CI, 1.8-3.7) and 11.0 months (95% CI, 3.9-NE), respectively. Median hazard ratio data are not available.

Regarding safety, pemetinibThe toxicity profile of is consistent with previous studies. The most common treatment-emergent AEs included hyperphosphatemia (any grade, 83.8%; grade ≥3, 0.9%), stomatitis (53.2%; 9.0%, respectively), alopecia (40.5%; 0.9%), diarrhea (38.7%; 0.9%), and constipation (33.3%; 0.9%). Results from the translational analysis showed that responses were observed in all cohorts, including patients with FGFR alterations that were not previously considered actionable or previously uncharacterized FGFR alterations. Most responses were reported in patients with cholangiocarcinoma, central nervous system tumors, gynecological tumors, and pancreatic tumors with actionable FGFR alterations.

Additionally, tissue analysis revealed that co-alterations in BAP1 and TP53 were mutually exclusive in baseline archived tumor samples. BAP1 co-changes were significantly associated with response, and TP53 co-changes were associated with poor response. Among tissue-evaluable patients who achieved response in the overall population (n=15), 46.7% had BAP1 co-alterations and none had TP53 co-alterations. Among those with stable or progressive disease (n=57), 3.5% had BAP1 co-alterations and 40.4% had TP53 co-alterations. Pathway analysis using tissue and ctDNA showed that co-alterations in MAPK and PI3K pathway genes were associated with lack of response. At disease progression, the most common emergent pathogenic variants in ctDNA include FGFR2, TP53, PIK3CA, KRAS, NRAS, FGFR3, FGFR1, ARID1A, KIT, ATM, BRCA2, and HRAS.