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| Ref Type | Journal Article | ||||||||||||
| PMID | (38986210) | ||||||||||||
| Authors | Saleh M, Barve M, Subbiah V, Papadopoulos KP, Morgensztern D, Mettu NB, Roychowdhury S, Spanggaard I, Veronese ML, Tian C, Silverman IM, Gutierrez M | ||||||||||||
| Title | Open-label, dose-escalation FIGHT-101 study of pemigatinib combined with targeted therapy, chemotherapy, or immunotherapy in patients with advanced malignancies. | ||||||||||||
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| Abstract Text | Pemigatinib is an oral, potent, selective fibroblast growth factor receptor (FGFR) 1-3 inhibitor. FIGHT-101, a three-part, open-label, first-in-human, phase I/II study (NCT02393248), evaluated pemigatinib in patients with advanced solid tumors. In parts 1 and 2, pemigatinib monotherapy had a manageable safety profile and antitumor activity in FGFR-altered tumors. Part 3 (pemigatinib combination therapies) results are presented here.Patients received 9, 13.5, or 20 mg oral once-daily pemigatinib on continuous or intermittent schedules with gemcitabine and cisplatin (pemi/gem/cis), docetaxel (pemi/doc), trastuzumab (pemi/tras), pembrolizumab (pemi/pembro), or retifanlimab (pemi/reti) irrespective of whether the tumor was confirmed as FGFR altered. Primary endpoints were safety and pharmacodynamics. Secondary endpoints were investigator-assessed tumor objective response rates (ORRs) and pharmacokinetics (PK).Of 65 enrolled patients (pemi/gem/cis, n = 8; pemi/doc, n = 7; pemi/tras, n = 6; pemi/pembro, n = 26; pemi/reti, n = 18), all discontinued. Treatment-emergent adverse events (TEAEs) were generally consistent with individual drug AEs. Serious and grade ≥3 TEAEs occurred in 0%-85.7% and 33.3%-100.0% of patients across treatment groups, respectively. All pemigatinib combinations demonstrated steady-state PK comparable to monotherapy. Pharmacodynamic effects in all pemigatinib combinations, except pemi/gem/cis, were consistent with monotherapy. Less inhibition of FGFR2α phosphorylation was observed with this combination. ORRs (95% confidence interval) were 37.5% [8.5% to 75.5% (pemi/gem/cis)], 14.3% [0.4% to 57.9% (pemi/doc)], 0% (pemi/tras), 26.9% [11.6% to 47.8% (pemi/pembro)], and 11.1% [1.4% to 34.7% (pemi/reti)]. All groups had instances of tumor shrinkage. ORRs in assessable patients with FGFR rearrangements and mutations were 50% and 33%, respectively.Pemigatinib combination therapy showed no unexpected toxicities. PK and pharmacodynamics were mostly consistent with pemigatinib monotherapy. Pemi/gem/cis (37.5%) and pemi/pembro (26.9%) had the highest ORR; most responders had FGFR alterations. | ||||||||||||
| Molecular Profile | Treatment Approach |
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| Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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| Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
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| Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
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| Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
|---|---|---|---|---|---|
| FGFR1 | M532T | missense | unknown | FGFR1 M532T lies within the protein kinase domain of the Fgfr1 protein (UniProt.org). M532T has been identified in the scientific literature (PMID: 38986210, PMID: 36446043), but has not been biochemically characterized and therefore, its effect on Fgfr1 protein function is unknown (PubMed, Aug 2024). |
| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
|---|---|---|---|---|---|---|---|
| FGFR3 Y373C | transitional cell carcinoma | predicted - sensitive | Pembrolizumab + Pemigatinib | Case Reports/Case Series | Actionable | In a Phase I trial (FIGHT-101), treatment with the combination of Pemazyre (pemigatinib) and Keytruda (pembrolizumab) demonstrated safety in patients with advanced solid tumors and resulted in an objective response rate of 26.9% (7/26, all partial responses), including a partial response with a duration of response of 4.2 months in a patient with urothelial cancer harboring FGFR3 Y373C (PMID: 38986210; NCT02393248). | 38986210 |
| FGFR1 M532T | transitional cell carcinoma | predicted - sensitive | Pembrolizumab + Pemigatinib | Case Reports/Case Series | Actionable | In a Phase I trial (FIGHT-101), treatment with the combination of Pemazyre (pemigatinib) and Keytruda (pembrolizumab) demonstrated safety in patients with advanced solid tumors and resulted in an objective response rate of 26.9% (7/26, all partial responses), including a partial response with a duration of response of 6.5 months in a patient with urothelial cancer harboring FGFR1 M532T (PMID: 38986210; NCT02393248). | 38986210 |
| FGFR3 S249C | bladder urothelial carcinoma | predicted - sensitive | Pembrolizumab + Pemigatinib | Case Reports/Case Series | Actionable | In a Phase I trial (FIGHT-101), treatment with the combination of Pemazyre (pemigatinib) and Keytruda (pembrolizumab) demonstrated safety in patients with advanced solid tumors and resulted in an objective response rate of 26.9% (7/26, all partial responses), including a partial response with a duration of response of 50.3 months in a patient with urothelial bladder cancer harboring FGFR3 S249C (PMID: 38986210; NCT02393248). | 38986210 |