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Pemigatinib in previously treated solid tumors with activating FGFR1-FGFR3 alterations: phase 2 FIGHT-207 basket
Jordi Rodón1, Silvia Damian2, Muhammad Furqan3
1The University of Texas MD Anderson Cancer Center, Houston, TX, USA. jrodon@mdanderson.org.
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 .
Insights
Pemigatinib, an FGFR inhibitor, showed efficacy in advanced solid tumors with FGFR alterations. The study identified new therapeutic areas and resistance mechanisms for FGFR inhibition.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Fibroblast growth factor receptor (FGFR) alterations are key drivers of oncogenesis in various cancers.
- Targeting FGFR signaling represents a promising therapeutic strategy for FGFR-altered tumors.
Purpose of the Study:
- To evaluate the efficacy and safety of pemigatinib, a selective FGFR1-FGFR3 inhibitor, in patients with advanced solid tumors harboring FGFR alterations.
- To explore response rates, survival outcomes, and identify predictive biomarkers and resistance mechanisms.
Main Methods:
- Phase 2, open-label, single-arm, multicenter FIGHT-207 basket study.
- Patients with advanced solid tumors and specific FGFR alterations (fusions/rearrangements, activating non-kinase domain mutations, kinase domain mutations) were enrolled.
- Objective response rate (ORR), progression-free survival (PFS), duration of response (DoR), and overall survival (OS) were assessed.
Main Results:
- ORRs were 26.5% (cohort A: fusions/rearrangements), 9.4% (cohort B: activating non-kinase domain mutations), and 3.8% (cohort C: kinase domain mutations).
- Median PFS was 4.5 months (cohort A) and 3.7 months (cohort B). Median DoR was 7.8 months (A) and 6.9 months (B). Median OS was 17.5 months (A) and 11.4 months (B).
- Hyperphosphatemia and stomatitis were common adverse events. TP53 co-mutations correlated with lack of response, while BAP1 alterations predicted higher response rates.
Conclusions:
- Pemigatinib demonstrates clinical activity in FGFR-altered advanced solid tumors, particularly those with fusions/rearrangements.
- The study identified potential predictive markers (BAP1) and resistance mechanisms (gatekeeper/molecular brake mutations), expanding the scope of FGFR inhibition.
- Further investigation into novel therapeutic areas and drug failure mechanisms is warranted.
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