Solid Tumor Malignancy
Conditions
Keywords
Fibroblast growth factor receptor (FGFR) inhibitor, FGFR mutations, FGFR translocations, solid tumor malignancy
Brief summary
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.
Interventions
DRUGPemigatinib
Pemigatinib administered orally once daily (QD).
Sponsors
Incyte Corporation
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically or cytologically confirmed solid tumor malignancy that is advanced or metastatic or is surgically unresectable. * Radiographically measurable disease (per RECIST v1.1 or RANO for primary brain tumors). Tumor lesions located in a previously irradiated area or in an area subjected to other loco-regional therapy are considered measureable if progression has been clearly demonstrated in the lesion. * Documentation of an FGFR1-3 gene mutation or translocation. * Objective progression after at least 1 prior therapy and no therapy available that is likely to provide clinical benefit. Participants who are intolerant to or decline the approved therapy are eligible only if they have no therapy available that is likely to provide clinical benefit. * Eastern Cooperative Oncology Group performance status 0 to 2. * Baseline archival tumor specimen (if less than 24 months from date of screening) or willingness to undergo a pretreatment tumor biopsy to obtain the specimen. Must be a tumor block or approximately 15 unstained slides from biopsy or resection of primary tumor or metastasis. * Willingness to avoid pregnancy or fathering children.
Exclusion criteria
* Prior receipt of a selective FGFR inhibitor in the past 6 months. * Receipt of anticancer medications or investigational drugs for any indication or reason within 28 days before first dose of pemigatinib. * Cannot be a candidate for potentially curative surgery. * Current evidence of clinically significant corneal or retinal disorder as confirmed by ophthalmologic examination. * Radiation therapy administered within 2 weeks of enrollment/first dose of study treatment. * Untreated brain or central nervous system (CNS) metastases or brain or CNS metastases that have progressed (eg, evidence of new or enlarging brain metastasis or new neurological symptoms attributable to brain or CNS metastases). * Known additional malignancy that is progressing or requires active treatment. * History of calcium and phosphate hemostasis disorder or systemic mineral imbalance with ectopic calcification of soft tissues. * Clinically significant or uncontrolled cardiac disease. * Active chronic or current infectious disease requiring systemic antibiotic, antifungal, or antiviral treatment within 2 weeks before enrollment (participants with asymptomatic chronic infections on prophylactic treatment are allowed). * Evidence of active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (defined as elevated transaminases or cirrhosis; chronic HBV/HCV infection with no cirrhosis and no elevated transaminases is allowed). * Known HIV infection. * Use of any potent CYP3A4 inhibitors or inducers or moderate CYP3A4 inducers within 14 days or five half-lives (whichever is longer) before the first dose of study drug/treatment. * Women who are pregnant or breastfeeding.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | up to 483 days | 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. |
| 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 | up to 449 days | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | up to 532 days | 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). |
| 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 | up to 24.90 months | 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 in Participants With FGFR1-3 In-frame Fusions or FGFR2 Arrangements and in Participants With Known or Likely Activating FGFR1-3 Mutations | up to 532 days | Overall survival was defined as the time from the first dose of study drug to death of any cause. |
| Number of Participants With Any Treatment-emergent Adverse Event (TEAE) and Any Treatment-related Adverse Event (AE) | up to 651 days | 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. |
Countries
Denmark, France, Germany, Israel, Italy, Japan, South Korea, Spain, Switzerland, United Kingdom, United States
Participant flow
Pre-assignment details
This study enrolled participants at 49 study sites in the United States, South Korea, United Kingdom, France, Italy, Israel, Germany, Spain, Denmark, and Japan.
Participants by arm
| Arm | Count |
|---|---|
| Cohort A: FGFR1-3 In-frame Fusions or FGFR2 Arrangements 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. | 49 |
| Cohort B: Known or Likely Activating FGFR1-3 Mutations 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. | 32 |
| Cohort C: Other FGFR Mutations or Arrangements 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. | 26 |
| Other 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. | 4 |
| Total | 111 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Death | 18 | 17 | 12 | 4 |
| Overall Study | Disease Progression | 1 | 2 | 1 | 0 |
| Overall Study | Lost to Follow-up | 1 | 2 | 3 | 0 |
| Overall Study | Never Returned to Hospital | 0 | 0 | 1 | 0 |
| Overall Study | Study Terminated by Sponsor | 25 | 11 | 6 | 0 |
| Overall Study | Withdrawal by Subject | 4 | 0 | 3 | 0 |
Baseline characteristics
| Characteristic | Cohort A: FGFR1-3 In-frame Fusions or FGFR2 Arrangements | Cohort C: Other FGFR Mutations or Arrangements | Other | Total | Cohort B: Known or Likely Activating FGFR1-3 Mutations |
|---|---|---|---|---|---|
| Age, Continuous | 59.4 years STANDARD_DEVIATION 11.51 | 61.5 years STANDARD_DEVIATION 13.32 | 48.0 years STANDARD_DEVIATION 14.45 | 61.4 years STANDARD_DEVIATION 12.11 | 66.0 years STANDARD_DEVIATION 10.04 |
| Race/Ethnicity, Customized Asian | 9 Participants | 7 Participants | 4 Participants | 29 Participants | 9 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Captured as Other | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants | 3 Participants | 1 Participants |
| Race/Ethnicity, Customized Missing | 1 Participants | 2 Participants | 0 Participants | 4 Participants | 1 Participants |
| Race/Ethnicity, Customized Not Available | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 44 Participants | 20 Participants | 3 Participants | 92 Participants | 25 Participants |
| Race/Ethnicity, Customized Not Reported | 2 Participants | 3 Participants | 1 Participants | 8 Participants | 2 Participants |
| Race/Ethnicity, Customized Not Required in Country of Origin | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Participant Declined to Provide | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Unknown | 1 Participants | 0 Participants | 0 Participants | 3 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 38 Participants | 16 Participants | 0 Participants | 74 Participants | 20 Participants |
| Sex: Female, Male Female | 28 Participants | 14 Participants | 1 Participants | 62 Participants | 19 Participants |
| Sex: Female, Male Male | 21 Participants | 12 Participants | 3 Participants | 49 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 18 / 49 | 17 / 32 | 13 / 26 | 4 / 4 | 52 / 111 |
| other Total, other adverse events | 49 / 49 | 32 / 32 | 26 / 26 | 4 / 4 | 111 / 111 |
| serious Total, serious adverse events | 21 / 49 | 7 / 32 | 10 / 26 | 2 / 4 | 40 / 111 |
Outcome results
Primary
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
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.
Time frame: up to 483 days
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A: FGFR1-3 In-frame Fusions or FGFR2 Arrangements | 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 | 26.5 percentage of participants |
Primary
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
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.
Time frame: up to 449 days
Population: Efficacy Evaluable Population. Confidence interval was calculated based on the exact method for binomial distribution.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort B: Known or Likely Activating FGFR1-3 Mutations | 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 | 9.4 percentage of participants |
Secondary
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
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.
Time frame: up to 24.90 months
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A: FGFR1-3 In-frame Fusions or FGFR2 Arrangements | 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 | 7.79 months |
| Cohort B: Known or Likely Activating FGFR1-3 Mutations | 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 | 6.93 months |
Secondary
Number of Participants With Any Treatment-emergent Adverse Event (TEAE) and Any Treatment-related Adverse Event (AE)
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.
Time frame: up to 651 days
Population: Safety Population: all enrolled participants who received at least 1 dose of pemigatinib
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort A: FGFR1-3 In-frame Fusions or FGFR2 Arrangements | Number of Participants With Any Treatment-emergent Adverse Event (TEAE) and Any Treatment-related Adverse Event (AE) | TEAEs | 49 Participants |
| Cohort A: FGFR1-3 In-frame Fusions or FGFR2 Arrangements | Number of Participants With Any Treatment-emergent Adverse Event (TEAE) and Any Treatment-related Adverse Event (AE) | Treatment-related AEs | 46 Participants |
| Cohort B: Known or Likely Activating FGFR1-3 Mutations | Number of Participants With Any Treatment-emergent Adverse Event (TEAE) and Any Treatment-related Adverse Event (AE) | Treatment-related AEs | 32 Participants |
| Cohort B: Known or Likely Activating FGFR1-3 Mutations | Number of Participants With Any Treatment-emergent Adverse Event (TEAE) and Any Treatment-related Adverse Event (AE) | TEAEs | 32 Participants |
| Cohort C: Other FGFR Mutations or Arrangements | Number of Participants With Any Treatment-emergent Adverse Event (TEAE) and Any Treatment-related Adverse Event (AE) | TEAEs | 26 Participants |
| Cohort C: Other FGFR Mutations or Arrangements | Number of Participants With Any Treatment-emergent Adverse Event (TEAE) and Any Treatment-related Adverse Event (AE) | Treatment-related AEs | 26 Participants |
| Other | Number of Participants With Any Treatment-emergent Adverse Event (TEAE) and Any Treatment-related Adverse Event (AE) | TEAEs | 4 Participants |
| Other | Number of Participants With Any Treatment-emergent Adverse Event (TEAE) and Any Treatment-related Adverse Event (AE) | Treatment-related AEs | 4 Participants |
Secondary
Overall Survival in Participants With FGFR1-3 In-frame Fusions or FGFR2 Arrangements and in Participants With Known or Likely Activating FGFR1-3 Mutations
Overall survival was defined as the time from the first dose of study drug to death of any cause.
Time frame: up to 532 days
Population: Efficacy Evaluable Population. The 95% confidence interval was calculated using the Brookmeyer and Crowley's method.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A: FGFR1-3 In-frame Fusions or FGFR2 Arrangements | Overall Survival in Participants With FGFR1-3 In-frame Fusions or FGFR2 Arrangements and in Participants With Known or Likely Activating FGFR1-3 Mutations | 17.48 months |
| Cohort B: Known or Likely Activating FGFR1-3 Mutations | Overall Survival in Participants With FGFR1-3 In-frame Fusions or FGFR2 Arrangements and in Participants With Known or Likely Activating FGFR1-3 Mutations | 11.37 months |
Secondary
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
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).
Time frame: up to 532 days
Population: Efficacy Evaluable Population. The 95% confidence interval is calculated using the Brookmeyer and Crowley's method.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A: FGFR1-3 In-frame Fusions or FGFR2 Arrangements | 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 | 4.53 months |
| Cohort B: Known or Likely Activating FGFR1-3 Mutations | 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 | 3.68 months |