Carcinoma, Renal Cell
Conditions
Keywords
Hypoxia inducible factor (HIF), Hypoxia inducible factor 1B (HIF-1B), Hypoxia inducible factor 2 alpha (HIF-2 alpha), Hypoxia inducible factor 2α (HIF-2α), Renal Cell Carcinoma (RCC), Kidney cancer
Brief summary
This study will compare the efficacy and safety of two doses of belzutifan in participants with advanced renal cell carcinoma (RCC) with clear cell component after prior therapy. The primary hypothesis is that the higher dose of belzutifan is superior to the standard dose in terms of objective response rate (ORR).
Interventions
DRUGBelzutifan
Oral administration
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Has a histologically confirmed diagnosis of locally advanced/metastatic RCC with clear cell component * Has measurable disease per RECIST 1.1 as assessed by BICR * Can submit an archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated * Has experienced disease progression on or after systemic treatment with an anti-programmed cell death 1 (PD-1)/Ligand 1 (L1) therapy for locally advanced or metastatic RCC. The anti-PD-1/L1 therapy may be monotherapy or in combination with other agent(s) such as anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) or vascular endothelial growth factor (VEGF) targeted- tyrosine kinase inhibitor (TKI). The immediately preceding line of treatment has to have been an anti-PD-1/L1 therapy * Has received no more than 3 prior systemic regimens for locally advanced or metastatic RCC * Has received only 1 prior anti-PD-1/L1 therapy for locally advanced or metastatic RCC * Has recovered from all AEs due to previous therapies to ≤Grade 1 or baseline, with the exception of ≤Grade 2 neuropathy or endocrine-related AEs ≤Grade 2 requiring treatment or hormone replacement * Has a Karnofsky performance status (KPS) score of at least 70% assessed within 10 days prior to the first dose of study intervention * A male participant is eligible to participate if he is abstinent from heterosexual intercourse or agrees to use contraception during the intervention period and for at least 7 days after the last dose of study intervention * A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least 1 of the following conditions applies: Not a (woman of childbearing potential) WOCBP or a WOCBP who agrees to follow the contraceptive guidance during the intervention period and for at least 30 days after the last dose of study intervention * A WOCBP must have a negative highly sensitive pregnancy test (urine or serum) within 24 hours before the first dose of study intervention
Exclusion criteria
* Has hypoxia (a pulse oximeter reading \<92% at rest), requires intermittent supplemental oxygen, or requires chronic supplemental oxygen * Has a known additional malignancy that is progressing or has required active treatment within the past 3 years except for basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ \[e.g., breast carcinoma, cervical cancer in situ\] that have undergone potentially curative therapy * Has known central nervous system (CNS) metastases and/or carcinomatous meningitis * Has clinically significant cardiac disease, including unstable angina, acute myocardial infarction ≤6 months from Day 1 of study drug administration or New York Heart Association Class III or IV congestive heart failure * Has moderate to severe hepatic impairment (Child-Pugh B or C) * Has received colony-stimulating factors (eg, granulocyte colony-stimulating factor \[G-CSF\], granulocyte-macrophage colony-stimulating factor \[GM-CSF\], or recombinant erythropoietin \[EPO\]) ≤28 days prior to the first dose of study intervention * Has a known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the study * Is unable to swallow orally administered medication or has a gastrointestinal disorder affecting absorption (eg, gastrectomy, partial bowel obstruction, malabsorption) * Has known hypersensitivity or allergy to the active pharmaceutical ingredient or any component of the study intervention (belzutifan) formulations * Has received prior treatment with belzutifan or another hypoxia-inducible factor (HIF)-2α inhibitor * Has received any type of small molecule kinase inhibitor (including investigational kinase inhibitor) ≤2 weeks before randomization * Has received any type of systemic anticancer antibody (including investigational antibody) ≤4 weeks before randomization * Has received prior radiotherapy ≤2 weeks prior to first dose of study intervention. Participants must have recovered from all radiation-related toxicities and not require corticosteroids * Has had major surgery ≤3 weeks prior to first dose of study intervention * Is currently receiving either strong (phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or moderate (eg, bosentan, efavirenz, modafinil) inducers of cytochrome P450 (CYP)3A4 that cannot be discontinued for the duration of the study * Is currently participating in a study of an investigational agent or is currently using an investigational device * Has an active infection requiring systemic therapy * Has active tuberculosis (TB) * Has a diagnosis of immunodeficiency * Has a known history of human immunodeficiency virus (HIV) infection * Has a known history of hepatitis B (HBV) or known active hepatitis C (HCV) infection * Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not the best interest of the participant to participate, in the opinion of the treating investigator
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) | Up to approximately 27 months | ORR was defined as the percentage of participants who had a complete response (CR: Disappearance of all target lesions) or a partial response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1. The percentage of participants who experienced a CR or PR as assessed by blinded independent central review based on RECIST 1.1 was presented. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response (DOR) Per RECIST 1.1 as Assessed by BICR | Up to approximately 27 months | For participants who demonstrated a confirmed complete response (CR: Disappearance of all target lesions) or confirmed partial response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, DOR was defined as the time from first documented evidence of CR or PR until disease progression or death. The DOR as assessed by blinded independent central review was presented. |
| Clinical Benefit Rate (CBR) Per RECIST 1.1 as Assessed by BICR | Up to approximately 27 months | CBR is defined as the percentage of participants who have a complete response (CR: Disappearance of all target lesions) or a partial response (PR: At least a 30% decrease in the sum of diameters of target lesions) or stable disease (SD: Neither sufficient decrease to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.) ≥6 months per RECIST 1.1. The percentage of participants with CBR will be presented. |
| Overall Survival (OS) | Up to approximately 27 months | OS was defined as the time from randomization to death due to any cause. |
| Progression-Free Survival (PFS) According to RECIST 1.1 as Assessed by BICR | Up to approximately 27 months | PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurs first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. PFS as assessed by blinded independent central review was presented. |
| Number of Participants Who Discontinue Study Treatment Due to an AE | Up to approximately 26 months | An AE was defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The number of participants who discontinued study treatment due to an AE was presented. |
| Maximum Plasma Concentration (Cmax) of Belzutifan | Weeks 1 and 3 on Day 1: predose and 1, 2, and 4 hours. Week 5 on Day 1: predose only | Blood samples were obtained at designated time points for the determination of the Cmax of belzutifan. |
| Trough Plasma Concentration (Ctrough) of Belzutifan | Weeks 1 and 3 on Day 1: predose and 1, 2, and 4 hours. Week 5 on Day 1: predose only | Blood samples were obtained at designated time points for the determination of the Ctrough of belzutifan. |
| Number of Participants Who Experience One or More Adverse Events (AEs) | Up to approximately 27 months | An AE was defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The number of participants who experienced one or more AEs was presented. |
Countries
Australia, Belgium, Greece, Ireland, Israel, Netherlands, Russia, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Belzutifan 200 mg Participants received 200 mg of belzutifan by oral administration, QD, until disease progression or discontinuation. | 78 |
| Belzutifan 120 mg Participants received 120 mg of belzutifan by oral administration, QD, until disease progression or discontinuation. | 76 |
| Total | 154 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 27 | 25 |
| Overall Study | Participants Ongoing in Study | 50 | 51 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Belzutifan 200 mg | Total | Belzutifan 120 mg |
|---|---|---|---|
| Age, Continuous | 64.5 Years STANDARD_DEVIATION 9.8 | 63.1 Years STANDARD_DEVIATION 9.9 | 61.6 Years STANDARD_DEVIATION 9.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 7 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 69 Participants | 141 Participants | 72 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants | 6 Participants | 2 Participants |
| International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) Risk Factor Favorable | 13 Participants | 27 Participants | 14 Participants |
| International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) Risk Factor Intermediate or Poor | 65 Participants | 127 Participants | 62 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 5 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 6 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) White | 71 Participants | 140 Participants | 69 Participants |
| Sex: Female, Male Female | 19 Participants | 31 Participants | 12 Participants |
| Sex: Female, Male Male | 59 Participants | 123 Participants | 64 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 28 / 78 | 25 / 76 |
| other Total, other adverse events | 75 / 78 | 74 / 76 |
| serious Total, serious adverse events | 33 / 78 | 33 / 76 |
Outcome results
Primary
Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR)
ORR was defined as the percentage of participants who had a complete response (CR: Disappearance of all target lesions) or a partial response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1. The percentage of participants who experienced a CR or PR as assessed by blinded independent central review based on RECIST 1.1 was presented.
Time frame: Up to approximately 27 months
Population: The analysis population consisted of all randomized participants based on the treatment group to which they were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Belzutifan 200 mg | Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) | 23.1 Percentage of Participants |
| Belzutifan 120 mg | Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) | 23.7 Percentage of Participants |
p-value: 0.531295% CI: [-14, 12.9]Miettinen & Nurminen
Secondary
Clinical Benefit Rate (CBR) Per RECIST 1.1 as Assessed by BICR
CBR is defined as the percentage of participants who have a complete response (CR: Disappearance of all target lesions) or a partial response (PR: At least a 30% decrease in the sum of diameters of target lesions) or stable disease (SD: Neither sufficient decrease to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.) ≥6 months per RECIST 1.1. The percentage of participants with CBR will be presented.
Time frame: Up to approximately 27 months
Population: The analysis population consisted of all randomized participants based on the treatment group to which they were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Belzutifan 200 mg | Clinical Benefit Rate (CBR) Per RECIST 1.1 as Assessed by BICR | 41.0 Percentage of Participants |
| Belzutifan 120 mg | Clinical Benefit Rate (CBR) Per RECIST 1.1 as Assessed by BICR | 47.4 Percentage of Participants |
p-value: 0.783295% CI: [-21.7, 9.4]Miettinen & Nurminen method
Secondary
Duration of Response (DOR) Per RECIST 1.1 as Assessed by BICR
For participants who demonstrated a confirmed complete response (CR: Disappearance of all target lesions) or confirmed partial response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, DOR was defined as the time from first documented evidence of CR or PR until disease progression or death. The DOR as assessed by blinded independent central review was presented.
Time frame: Up to approximately 27 months
Population: The analysis population consisted of all randomized participants based on the treatment group to which they were randomized who experienced a confirmed CR or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Belzutifan 200 mg | Duration of Response (DOR) Per RECIST 1.1 as Assessed by BICR | 16.1 Months |
| Belzutifan 120 mg | Duration of Response (DOR) Per RECIST 1.1 as Assessed by BICR | NA Months |
Secondary
Maximum Plasma Concentration (Cmax) of Belzutifan
Blood samples were obtained at designated time points for the determination of the Cmax of belzutifan.
Time frame: Weeks 1 and 3 on Day 1: predose and 1, 2, and 4 hours. Week 5 on Day 1: predose only
Population: The analysis population consisted of all randomized participants based on the treatment group to which they were randomized who had at least 1 measurable belzutifan concentration observation.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Belzutifan 200 mg | Maximum Plasma Concentration (Cmax) of Belzutifan | 2512 ng/mL | Geometric Coefficient of Variation 86 |
| Belzutifan 120 mg | Maximum Plasma Concentration (Cmax) of Belzutifan | 1518 ng/mL | Geometric Coefficient of Variation 97 |
Secondary
Number of Participants Who Discontinue Study Treatment Due to an AE
An AE was defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The number of participants who discontinued study treatment due to an AE was presented.
Time frame: Up to approximately 26 months
Population: All randomized participants who received at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Belzutifan 200 mg | Number of Participants Who Discontinue Study Treatment Due to an AE | 11 Number of Participants |
| Belzutifan 120 mg | Number of Participants Who Discontinue Study Treatment Due to an AE | 4 Number of Participants |
Secondary
Number of Participants Who Experience One or More Adverse Events (AEs)
An AE was defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The number of participants who experienced one or more AEs was presented.
Time frame: Up to approximately 27 months
Population: All randomized participants who received at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Belzutifan 200 mg | Number of Participants Who Experience One or More Adverse Events (AEs) | 77 Number of Participants |
| Belzutifan 120 mg | Number of Participants Who Experience One or More Adverse Events (AEs) | 75 Number of Participants |
Secondary
Overall Survival (OS)
OS was defined as the time from randomization to death due to any cause.
Time frame: Up to approximately 27 months
Population: The analysis population consisted of all randomized participants based on the treatment group to which they were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Belzutifan 200 mg | Overall Survival (OS) | NA Months |
| Belzutifan 120 mg | Overall Survival (OS) | NA Months |
p-value: 0.644895% CI: [0.65, 1.9]Log Rank
Secondary
Progression-Free Survival (PFS) According to RECIST 1.1 as Assessed by BICR
PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurs first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. PFS as assessed by blinded independent central review was presented.
Time frame: Up to approximately 27 months
Population: The analysis population consisted of all randomized participants based on the treatment group to which they were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Belzutifan 200 mg | Progression-Free Survival (PFS) According to RECIST 1.1 as Assessed by BICR | 9.1 Months |
| Belzutifan 120 mg | Progression-Free Survival (PFS) According to RECIST 1.1 as Assessed by BICR | 7.3 Months |
p-value: 0.386195% CI: [0.63, 1.4]Log Rank
Secondary
Trough Plasma Concentration (Ctrough) of Belzutifan
Blood samples were obtained at designated time points for the determination of the Ctrough of belzutifan.
Time frame: Weeks 1 and 3 on Day 1: predose and 1, 2, and 4 hours. Week 5 on Day 1: predose only
Population: The analysis population consisted of all randomized participants based on the treatment group to which they were randomized who had at least 1 measurable belzutifan concentration observation.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Belzutifan 200 mg | Trough Plasma Concentration (Ctrough) of Belzutifan | 513 ng/mL | Geometric Coefficient of Variation 158 |
| Belzutifan 120 mg | Trough Plasma Concentration (Ctrough) of Belzutifan | 296 ng/mL | Geometric Coefficient of Variation 159 |