FIGHT-101, a first-in-human study of potent and selective FGFR 1-3 inhibitor pemigatinib in pan-cancer patients with FGF/FGFR alterations and advanced malignancies

Subbiah, Vivek; Iannotti, Nicholas; Gutierrez, Martin; Smith, David C.; Féliz, Luis; Lihou, Christine; Tian, Chen; Silverman, Ian M.; Ji, Tao; Saleh, Mansoor N.

doi:10.1016/j.annonc.2022.02.001

Cited by 120 publications

(126 citation statements)

References 25 publications

Supporting

Mentioning

125

Contrasting

Order By: Relevance

“…Therefore, a minimal PBPK with advanced dissolution, absorption, and metabolism (ADAM) absorption model for pemigatinib that incorporates CYP3A4‐mediated metabolism derived from in vitro data and human absorption, distribution, metabolism, and excretion (ADME) data was then further developed, and the model was used to describe the clinical PK data from pemigatinib‐alone cohorts in the CYP3A4‐mediated DDI study 7 and the PK data from the dose groups of 6–20 mg in the phase I dose‐escalation and dose‐expansion study (NCT02393248). 6 The sensitivity analysis of the pemigatinib fraction of drug metabolized by CYP3A4 ( f mCYP3A4 ) on drug interaction with itraconazole ( CYP3A4‐mediated DDI study) suggested that CYP3A4 contributes ~55% of the metabolic clearance for pemigatinib. The verified pemigatinib model was then used to simulate the observed effect of itraconazole on pemigatinib PK and to confirm the contribution of CYP3A4 ( f mCYP3A4 = 55%) to pemigatinib metabolic clearance.…”

Section: Methodsmentioning

confidence: 99%

“… 6 The simulations were performed using an age range of 21–79 years (proportion of female volunteers: 0.5), matching the demographics of the phase I study (median age, 59.0 years [range, 21.0–83.0 years]; male, 39.1%; White, 89.1%; median BMI, 27.1 kg/m 2 [range, 17.6–49.0 kg/m 2 ]). 6 …”

Section: Methodsmentioning

confidence: 99%

“…], geometric mean [coefficient of variation percent] steady‐state [SS] AUC 0–24 h = 2620 nM · h [54%]; maximum plasma drug concentration [C max ] = 236 nM [56%]). 6 Data from in vitro studies have indicated that cytochrome P450 (CYP) 3A4 is the major isozyme responsible for the metabolism of pemigatinib. In addition, pemigatinib is an inhibitor of P‐gp, organic cation transporter‐2 (OCT2), and multidrug and toxin extrusion protein‐1 (MATE1).…”

Section: Introductionmentioning

confidence: 99%

“…Pemigatinib exhibited an approximately linear relationship for both C max and area under the concentration–time curve (AUC) following oral dosing over the dose range studied in the first‐in‐human dose‐escalation and cohort‐expansion study conducted in patients with cancer (1–20 mg). 6 Pemigatinib was rapidly absorbed with a terminal half‐life of ~15 h. The recommended dose is 13.5 mg q.d. on a 2‐weeks‐on/1‐week‐off therapy schedule and 13.5 mg q.d.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Evaluation of drug–drug interaction potential for pemigatinib using physiologically based pharmacokinetic modeling

Chen

Yeleswaram

2022

CPT Pharmacom & Syst Pharma

View full text Add to dashboard Cite

Pemigatinib is a potent inhibitor of fibroblast growth factor receptor being developed for oncology indications. It is primarily metabolized by cytochrome P450 (CYP) 3A4, and the ratio of estimated concentration over concentration required for 50% inhibition ratio for pemigatinib as an inhibitor of P‐glycoprotein (P‐gp), organic cation transporter‐2 (OCT2), and multidrug and toxin extrusion protein‐1 (MATE1) exceeds the cutoff values established in regulatory guidance. A Simcyp minimal physiologically based pharmacokinetic (PBPK) with advanced dissolution, absorption, and metabolism absorption model for pemigatinib was developed and validated using observed clinical pharmacokinetic (PK) data and itraconazole/rifampin drug–drug interaction (DDI) data. The model accurately predicted itraconazole DDI (approximate 90% area under the plasma drug concentration–time curve [AUC] and approximate 20% maximum plasma drug concentration [C max ] increase). The model underpredicted rifampin induction by 100% (approximate 6.7‐fold decrease in AUC and approximate 2.6‐fold decrease in C max in the DDI study), presumably reflecting non‐CYP3A4 mechanisms being impacted. The verified PBPK model was then used to predict the effect of other CYP3A4 inhibitors/inducers on pemigatinib PK and pemigatinib as an inhibitor of P‐gp or OCT2/MATE1 substrates. The worst‐case scenario DDI simulation for pemigatinib as an inhibitor of P‐gp or OCT2/MATE1 substrates showed only a modest DDI effect. The recommendation based on this simulation and clinical data is to reduce pemigatinib dose for coadministration with strong and moderate CYP3A4 inhibitors. No dose adjustment is required for weak CYP3A4 inhibitors. The coadministration of strong and moderate CYP3A4 inducers with pemigatinib should be avoided. PBPK modeling suggested no dose adjustment with P‐gp or OCT2/MATE1 substrates.

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Evaluation of drug–drug interaction potential for pemigatinib using physiologically based pharmacokinetic modeling

Chen

Yeleswaram

2022

CPT Pharmacom & Syst Pharma

View full text Add to dashboard Cite

show abstract

“…Pemigatinib, a selective pan-fibroblast growth factor receptor (FGFR) inhibitor now US Food and Drug Administration-approved for use in locally advanced or metastatic cholangiocarcinoma with an FGFR2 fusion or rearrangement, continues to be investigated in various neoplasms. [8][9][10][11][12][13][14][15][16][17] This pan-FGFR inhibitor is a smallmolecule kinase inhibitor that exerts its main effects in FGFR1, FGFR2, and FGFR3 and a minor effect on FGFR4 with a half maximal inhibitory concentration (IC50) of , 2 nM. [17][18][19] In vitro preclinical data using cancer cell lines, including those from lung, gastric, endometrial, bladder, and hematologic malignancies, showed that pemigatinib can effectively inhibit phosphorylation of FGFR1-3, which decreased downstream signaling and cell viability.…”

Section: Discussionmentioning

confidence: 99%

Activity of Pemigatinib in Pilocytic Astrocytoma andFGFR1^N546KMutation

Capone

Ketonen

Weathers

et al. 2022

JCO Precision Oncology

Self Cite

View full text Add to dashboard Cite

First-Line Genomic Profiling in Previously Untreated Advanced Solid Tumors for Identification of Targeted Therapy Opportunities

et al. 2023

View full text Add to dashboard Cite

IMPORTANCEPrecision oncology using comprehensive genomic profiling (CGP) by next-generation sequencing is aimed at companion diagnosis and genomic profiling. The clinical utility of CGP before the standard of care (SOC) is still not resolved, and more evidence is needed.OBJECTIVETo investigate the clinical utility of next-generation CGP (FoundationOne CDx [F1CDx]) in patients with previously untreated metastatic or recurrent solid tumors.DESIGN, Setting, and ParticipantsThis multicenter, prospective, observational cohort study enrolled patients with previously untreated advanced solid tumors between May 18, 2021, and February 16, 2022, with follow-up through August 16, 2022. The study was conducted at 6 hospitals in Japan. Eligible patients were aged 20 years or older and had Eastern Cooperative Oncology Group performance status of 0 to 1 with previously untreated metastatic or recurrent cancers in the gastrointestinal or biliary tract; pancreas, lung, breast, uterus, or ovary; and malignant melanoma.EXPOSUREComprehensive genomic profiling testing before SOC for advanced solid tumors.MAIN OUTCOMES AND MEASURESProportion of patients with actionable or druggable genomic alterations and molecular-based recommended therapy (MBRT).RESULTSA total of 183 patients met the inclusion criteria and 180 patients (92 men [51.1%]) with a median age of 64 years (range, 23-88 years) subsequently underwent CGP (lung [n = 28], colon/small intestine [n = 27], pancreas [n = 27], breast [n = 25], biliary tract [n = 20], gastric [n = 19], uterus [n = 12], esophagus [n = 10], ovary [n = 6], and skin melanoma [n = 6]). Data from 172 patients were available for end point analyses. Actionable alterations were found in 172 patients (100.0%; 95% CI, 97.9%-100.0%) and druggable alternations were identified in 109 patients (63.4%; 95% CI, 55.7%-70.6%). The molecular tumor board identified MBRT for 105 patients (61.0%; 95% CI, 53.3%-68.4%). Genomic alterations included in the companion diagnostics list of the CGP test were found in 49 patients (28.5%; 95% CI, 21.9%-35.9%) in a tumor-agnostic setting. After a median follow-up of 7.9 months (range, 0.5-13.2 months), 34 patients (19.8%; 95% CI, 14.1%-26.5%) received MBRT.CONCLUSIONS AND RELEVANCEThe findings of this study suggest that CGP testing before SOC for patients with advanced solid tumors may be clinically beneficial to guide the subsequent anticancer therapies, including molecularly matched treatments.

show abstract

FIGHT-101, a first-in-human study of potent and selective FGFR 1-3 inhibitor pemigatinib in pan-cancer patients with FGF/FGFR alterations and advanced malignancies

Cited by 120 publications

References 25 publications

Evaluation of drug–drug interaction potential for pemigatinib using physiologically based pharmacokinetic modeling

Evaluation of drug–drug interaction potential for pemigatinib using physiologically based pharmacokinetic modeling

Activity of Pemigatinib in Pilocytic Astrocytoma andFGFR1^N546KMutation

First-Line Genomic Profiling in Previously Untreated Advanced Solid Tumors for Identification of Targeted Therapy Opportunities

Contact Info

Product

Resources

About

FIGHT-101, a first-in-human study of potent and selective FGFR 1-3 inhibitor pemigatinib in pan-cancer patients with FGF/FGFR alterations and advanced malignancies

Cited by 120 publications

References 25 publications

Evaluation of drug–drug interaction potential for pemigatinib using physiologically based pharmacokinetic modeling

Evaluation of drug–drug interaction potential for pemigatinib using physiologically based pharmacokinetic modeling

Activity of Pemigatinib in Pilocytic Astrocytoma andFGFR1N546KMutation

First-Line Genomic Profiling in Previously Untreated Advanced Solid Tumors for Identification of Targeted Therapy Opportunities

Contact Info

Product

Resources

About

Activity of Pemigatinib in Pilocytic Astrocytoma andFGFR1^N546KMutation