Pemigatinib administered orally once daily.

Pemigatinib

Incyte Medical Monitor

The purpose of this study is to evaluate the efficacy and safety of pemigatinib in participants with previously treated locally advanced/metastatic or surgically unresectable solid tumors harboring activating FGFR mutations or translocations.

Participants will be assigned to 1 of 2 cohorts (Cohort A: FGFR1-3 in-frame fusions or FGFR2 intron 17 rearrangements; Cohort B: Known/predicted activating point mutations in FGFR1-3 \[excluding kinase domain\]) but there is no difference in the treatment regimen between the cohorts.

Efficacy and Safety of Pemigatinib in Participants With Solid Tumors With FGFR Mutations or Translocations (FIGHT-208)

A Phase 2, Open-Label, Single-Arm, Multicenter Study to Evaluate the Efficacy and Safety of Pemigatinib in Participants With Previously Treated Locally Advanced/Metastatic or Surgically Unresectable Solid Tumors Harboring Activating FGFR Mutations or Translocations (FIGHT-208)

Incyte shares data with qualified external researchers after a research proposal is submitted. These requests are reviewed and approved by a review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

The trial data availability is according to the criteria and process described on https://www.incyte.com/our-company/compliance-and-transparency

Defined as the proportion of participants in each cohort who achieve a complete response (CR) or partial response (PR) based on Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)

Defined as the time from first dose until progressive disease (per RECIST v1.1 or Response Assessment in Neuro-Oncology \[RANO\]) or death (whichever is first) in each cohort.

Defined as the time from the date of first assessment of CR or PR until the date of the first progressive disease (per RECIST v1.1 or RANO) or death (whichever is first) in each cohort.

Defined as the proportion of participants who achieved best overall response of CR, PR, or stable disease per RECIST v1.1 or RANO.

Defined as the time from first dose of study drug to death of any cause in each cohort.

Adverse events reported for the first time or worsening of a pre-existing event after first dose of study drug/treatment.

Incyte Corporation

Treatment-emergent adverse events, defined as adverse events that were either reported for the first time or the worsening of pre-existing events after the first dose of study drug until 30 days after the last dose of study drug, are reported for members of the Safety Population (all randomized participants who received at least one dose of study treatment).

Participants will receive 13.5mg QD Pemigatinib

Cohort A: Participants With FGFR1-3 In-frame Fusions or FGFR2 Intron 17 Rearrangements

Cohort B: Participants With Known/Predicted Activating Point Mutations in FGFGR1-3

Total

Age, Categorical

Sex: Female, Male

Race (NIH/OMB)

No participants were enrolled in Cohort B.

The Sponsor made a decision unrelated to safety to halt study enrollment. Due to early termination of the study with only1 participant, no analysis of efficacy endpoints was done.

Study Director

Due to low participant enrollment (n=1), efficacy analyses were not conducted.

Objective Response Rate (ORR)

Progression-free Survival (PFS)

Duration of Response (DOR)

Disease Control Rate (DCR)

Overall Survival (OS)

Number of Treatment-related Adverse Events

Overall Study

All Drugs and Chemicals

Mitogens

Cohort A (Solid tumor malignancies with FGFR1-3 in frame fusions; any FGFR2 rearrangement; FGFR1/3 rearrangement with known partner\*). Cohort B (Solid tumor malignancies with known or likely activating mutations (excluding kinase domain) in FGFR1-3) Cohort C (Solid tumor malignancies with FGFR1-3 known activating mutations in kinase domain; FGFR1-3 putatively activating mutations; other FGFR1/3 rearrangements\* (not eligible for Cohort A)).

\*Only FGFR fusions or rearrangements with an intact kinase domain are eligible

Pemigatinib administered orally once daily (QD).

Peter Langmuir, MD

The purpose of this study is to evaluate the efficacy and safety of pemigatinib in participants with previously treated locally advanced/metastatic or surgically unresectable solid tumor malignancies harboring activating FGFR mutations or translocations.

This study consists of 3 cohorts that will have study drug administered in parallel, Cohort A, Cohort B, and Cohort C. There is no difference in the treatment regimen between the cohorts.

Efficacy and Safety of Pemigatinib in Previously Treated Locally Advanced/Metastatic or Surgically Unresectable Solid Tumor Malignancies Harboring Activating FGFR Mutations or Translocations (FIGHT-207)

A Phase 2, Open-Label, Single-Arm, Multicenter Study to Evaluate the Efficacy and Safety of Pemigatinib in Participants With Previously Treated Locally Advanced/Metastatic or Surgically Unresectable Solid Tumor Malignancies Harboring Activating FGFR Mutations or Translocations (FIGHT-207)

Per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1): CR: disappearance of all target/non-target lesions; no appearance of new lesions. PR: complete disappearance or a ≥30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum diameters; no new lesions; no progression of non-target lesions. Per Response Assessment in Neuro-Oncology (RANO; for participants with primary brain tumors): CR: disappearance of all enhancing lesions; stable/improved non-enhancing lesions; stable/improved clinically. PR: ≥50% decrease in sum of perpendicular diameters of measurable enhancing lesions; no progression of non-measurable disease; stable/improved non-enhancing lesions; stable/improved clinically. Cohort determination was based on FGFR status from a central genomics laboratory. Response data were from an independent centralized radiological review committee per RECIST v1.1 and RANO, and response was confirmed.

Per RECIST v1.1: CR: disappearance of all target/non-target lesions; no appearance of new lesions. PR: complete disappearance or a ≥30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum diameters; no new lesions; no progression of non-target lesions. Per RANO (for participants with primary brain tumors): CR: disappearance of all enhancing lesions; stable/improved non-enhancing lesions; stable/improved clinically. PR: ≥50% decrease in sum of perpendicular diameters of measurable enhancing lesions; no progression of non-measurable disease; stable/improved non-enhancing lesions; stable/improved clinically. Cohort determination was based on FGFR status from a central genomics laboratory. Response data were from an independent centralized radiological review committee per RECIST v1.1 and RANO, and response was confirmed.

PFS was defined as the time from the first dose until progressive disease (according to RECIST v1.1 or RANO for participants with primary brain tumors and assessed by an independent centralized radiological review committee) or death (whichever occurred first).

Assessment was by an independent centralized radiological review committee; response was confirmed. Per RECIST v1.1: CR: disappearance of all target (TLs)/non-target lesions (NTLs); no appearance of new lesions. PR: complete disappearance or a ≥30% decrease in the sum of the diameters of TLs, taking as a reference the baseline sum diameters; no new lesions; no progression of NTLs. PD: progression of a TL/NTL or presence of new lesion. Per RANO (participants with primary brain tumors): CR: disappearance of all enhancing lesions (ELs); stable/improved non-enhancing lesions (NELs); stable/improved clinically. PR: ≥50% decrease in sum of perpendicular diameters of measurable ELs; no progression of non-measurable disease; stable/improved NELs; stable/improved clinically. PD: \>25% increase in sum of perpendicular diameters of all measurable ELs; significant increase of NELs; new lesions; clear clinical deterioration; failure to return for evaluation due to death/deteriorating condition.

Overall survival was defined as the time from the first dose of study drug to death of any cause.

An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug-related. An AE could be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study treatment. TEAEs were defined as AEs reported for the first time or the worsening of pre-existing events after the first dose of study treatment. Treatment-related AEs were defined as TEAEs judged as related by the investigator or with a missing causality.

Treatment-emergent adverse events (TEAEs), defined as adverse events reported for the first time or the worsening of pre-existing events after the first dose of study treatment, are reported.

Participants with fibroblast growth factor receptor (FGFR) 1-3 in-frame fusions or fibroblast growth factor receptor 2 (FGFR2) rearrangements self-administered oral pemigatinib at a starting dose of 13.5 milligrams (mg) once daily (QD) continuously in 21-day cycles. Pemigatinib was administered until documented disease progression or unacceptable toxicity.

Cohort A: FGFR1-3 In-frame Fusions or FGFR2 Arrangements

Participants with known or likely activating mutations in FGFR1-3 self-administered oral pemigatinib at a starting dose of 13.5 mg QD continuously in 21-day cycles. Pemigatinib was administered until documented disease progression or unacceptable toxicity.

Cohort B: Known or Likely Activating FGFR1-3 Mutations

Participants with other FGFR mutations or arrangements self-administered oral pemigatinib at a starting dose of 13.5 mg QD continuously in 21-day cycles. Pemigatinib was administered until documented disease progression or unacceptable toxicity.

Cohort C: Other FGFR Mutations or Arrangements

Participants with an FGF/FGFR status for whom the local laboratory FGF/FGFR results could not be confirmed centrally self-administered oral pemigatinib at a starting dose of 13.5 mg QD continuously in 21-day cycles. Pemigatinib was administered until documented disease progression or unacceptable toxicity.

Other

Age, Continuous

White

Black or African American

Asian

Participant Declined to Provide

Not Available

Not Required in Country of Origin

Missing

Race/Ethnicity, Customized

Hispanic or Latino

Not Hispanic or Latino

Not Reported

Unknown

Captured as "Other"

Efficacy Evaluable Population: all enrolled participants in Cohorts A, B, and C who received at least 1 dose of pemigatinib. Confidence interval was calculated based on the exact method for binomial distribution.

Objective Response Rate (ORR), Defined as the Percentage of Participants With a Best Overall Response of Complete Response (CR) or Partial Response (PR) Based on RECIST v1.1 or RANO, in Participants With FGFR1-3 In-frame Fusions or FGFR2 Arrangements

Efficacy Evaluable Population. Confidence interval was calculated based on the exact method for binomial distribution.

ORR, Defined as the Percentage of Participants With a Best Overall Response of CR or PR Based on RECIST v1.1 or RANO, in Participants With Known or Likely Activating FGFR1-3 Mutations

Efficacy Evaluable Population. The 95% confidence interval is calculated using the Brookmeyer and Crowley's method.

Progression-free Survival (PFS) in Participants With FGFR1-3 In-frame Fusions or FGFR2 Arrangements and in Participants With Known or Likely Activating FGFR1-3 Mutations

Efficacy Evaluable Population. The 95% confidence interval is calculated using the Brookmeyer and Crowley's method. Only participants with a CR or PR were analyzed.

Duration of Response (DOR), Defined as the First CR or PR Assessment Until Progressive Disease (PD) or Death, in Participants With FGFR1-3 In-frame Fusions or FGFR2 Arrangements and in Participants With Known or Likely Activating FGFR1-3 Mutations

Efficacy Evaluable Population. The 95% confidence interval was calculated using the Brookmeyer and Crowley's method.

Overall Survival in Participants With FGFR1-3 In-frame Fusions or FGFR2 Arrangements and in Participants With Known or Likely Activating FGFR1-3 Mutations

TEAEs

Treatment-related AEs

Safety Population: all enrolled participants who received at least 1 dose of pemigatinib

Number of Participants With Any Treatment-emergent Adverse Event (TEAE) and Any Treatment-related Adverse Event (AE)

Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Carcinoma, Non-Small-Cell Lung

Carcinoma

Lung Neoplasms

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Cohort 1: Activating (high confidence) FGFR translocations (max. 15 patients) under daily Erdaifitinib treatment

Cohort 2: Activating (high confidence) hotspot FGFR mutations (max. 15 patients) under daily Erdafitinib treatment

Cohort 3: Activating (low confidence) FGFR alteration (max. 20 patients)

ERDAFITINIB

Lucia Nogova, MD

In the FIND trial, Non Small Cell Lung Carcinoma (NSCLC) patients with Fibroblast Growth Factor Receptor (FGFR) genetic alteration will be treated with the selective FGFR1-4 inhibitor erdafitinib. Archival samples, fresh frozen tumor samples and blood for circulating tumor DNA (ctDNA) will be collected before treatment. Patients will be treated until disease progression or unacceptable toxicity. In case of progression, fresh frozen tumor biopsies and ctDNA analyses will be performed to assess resistance mechanisms. The primary objective of the trial is to analyze the efficacy of erdafitinib in NSCLC patients with FGFR genetic alterations. NSCLC patient number will be based on a statistical hypothesis aiming at increasing the response rate comparing to chemotherapy/immunotherapy after standard treatment.

Downstream signaling of fibroblast growth factor receptors 1-4 (FGFR 1-4) regulates cell proliferation, migration, differentiation and survival in healthy cells. Genetic alterations (amplifications, point-mutations and translocations) in FGFR1-4 genes cause altered signaling and oncogenic transformation. FGFR-alterations with sensitivity to kinase inhibition have been identified in a variety of tumors such as breast-, bladder- and endometrial-cancer, squamous cell lung and head and neck cancer, cholangiocarcinoma and glioblastoma.

First-in-man/phase-I clinical trials with erdafitinib and BGJ398 - both selective FGFR inhibitors - enrolled patients with any genetic alterations in FGFR. The trials showed clinical responses with differences according to the type of FGFR alterations and histological subtypes. In the BGJ398 trial, the partial response rate was 11% (4/36) in patients with FGFR1 amplified squamous NSCLC (sqNSCLC) and 38% (3/8) in patients with FGFR3-mutant bladder cancer. No PR was observed in patients with FGFR1/2 amplified (n=25) and FGFR3 mutant (n=1) breast cancer. All patients with FGFR2-translocated (n=2) and FGFR2-mutated cholangiocarcinoma (n=1) showed reduced tumor burden of 20% and 10%, respectively. In the erdafitinib trial, 5 partial responses were seen in FGFR translocated tumors: 3/8 (37.5%) patients with urothelial carcinoma, 1/3 (33%) patients with glioblastoma and 1 patient with endometrial cancer reached PR. Summing up the results of the phase-I trials, the inhibition of FGFR downstream pathways in FGFR translocated and mutated solid tumors exerted clinical activity. Thus, focusing treatment with FGFR inhibitors on FGFR mutated and translocated solid tumors may increase response rates, progression free and overall survival in these tumors with otherwise adverse prognosis.

In NSCLC patients without druggable alterations in genes as EGFR, ALK or ROS1 and without high PD-L1 (Programmed cell death 1 ligand 1) expression, prognosis remains adverse with a median survival time of about 18 months. Particularly in sqNSCLC, only few driver mutations have been identified yet. Of these, solely mutations of the KRAS gene (although observed at low frequency in sqNSCLC) were explored in large clinical studies targeting KRAS downstream signaling with no survival benefit comparing to chemotherapy. Immunotherapy with PD-1 antibodies such as nivolumab and pembrolizumab showed benefit in patients with high PD-L1 expression mainly.

The frequency of somatic FGFR1-3 mutations in lung cancer is about 4% (Helsten et al., 2016). Translocations occur with a similar frequency of about 4% in lung cancer. Multiple of these FGFR alterations are shown to have oncogenic potential as demonstrated in multiple in vitro, in vivo and first-in-man studies.

Preclinical models in NSCLC cell lines and xenografts showed oncogenic activity of FGFR2/3 mutations with consecutive sensitivity to FGFR inhibitors. Similarly, FGFR3-TACC translocation exerted kinase activation in sqNSCLC cell lines and other tumor types. Furthermore, patient derived FGFR3-fusion lung xenograft model showed responses to FGFR targeted treatment.

In summary, on the basis of genetically and phenotypically validated cell-line panels, in vivo and particularly on the basis of clinical data, there is strong evidence for a clinical benefit from FGFR inhibition for patients with FGFR altered NSCLC.

The primary objective of the trial is to analyze the efficacy of erdafitinib in NSCLC patients with FGFR genetic alterations. NSCLC patient number will be based on a statistical hypothesis aiming at increasing the response rate comparing to chemotherapy/immunotherapy after standard treatment.

Patients with NSCLC and FGFR alteration with high evidence on oncogenic transformation according to FIND molecular board will be included to cohort 1 (FGFR translocated NSCLC patients) and cohort 2 (FGFR mutated NSCLC patients). Patients with NSCLC and FGFR alterations without enough evidence (intermediate / low evidence according to FIND molecular tumor board) for recruitment into cohorts 1 or 2, will be treated in cohort 3. Overall response rate under Erdafitinib treatment will be the primary endpoint.

FGFR Inhibitor in FGFR Dysregulated Cancer

A Phase II Trial to Evaluate Efficacy and Safety of Erdafitinib in Patients With Advanced Non Small Cell Lung Carcinoma (NSCLC) Harboring Fibroblast Growth Factor Receptor (FGFR) Genetic Alterations After Relapse of Standard Therapy.

Overall response rate (ORR) per RECIST 1.1 under erdafitinib treatment in sqNSCLC with genetic alteration in FGFR

assessment of adverse events according to CTC-AE

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Efficacy and Safety of Pemigatinib in Participants With Solid Tumors With FGFR Mutations or Translocations (FIGHT-208)	NCT04003623	Advanced or Met... FGFR Mutations FGFR Translocat...	Pemigatinib	18 Years -	Incyte Corporation
Efficacy and Safety of Pemigatinib in Previously Treated Locally Advanced/Metastatic or Surgically Unresectable Solid Tumor Malignancies Harboring Activating FGFR Mutations or Translocations (FIGHT-207)	NCT03822117	Solid Tumor Mal...	Pemigatinib	18 Years -	Incyte Corporation
FGFR Inhibitor in FGFR Dysregulated Cancer	NCT03827850	Lung Cancer NSCLC Pulmonary Neopl... Squamous Cell L... NSCLC Stage IV	ERDAFITINIB	18 Years -	Lung Cancer Group Cologne
FGFR Inhibitor in FGFR Dysregulated Cancer	NCT03827850	Lung Cancer NSCLC Pulmonary Neopl... Squamous Cell L... NSCLC Stage IV	ERDAFITINIB	18 Years -	Lung Cancer Group Cologne
Efficacy and Safety of Pemigatinib in Previously Treated Locally Advanced/Metastatic or Surgically Unresectable Solid Tumor Malignancies Harboring Activating FGFR Mutations or Translocations (FIGHT-207)	NCT03822117	Solid Tumor Mal...	Pemigatinib	18 Years -	Incyte Corporation

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