Locally Advanced Renal Cell Carcinoma, Locally Advanced Urothelial Cancer, Metastatic Clear-Cell Renal Cell Carcinoma, Metastatic Melanoma, Metastatic Non-small Cell Lung Cancer, Metastatic Urothelial Cancer, Unresectable Melanoma
Conditions
Keywords
PD-1inhibitor, non-small cell lung cancer, urothelial cancer, melanoma, renal cell carcinoma
Brief summary
The purpose of this study is to assess the clinical activity and safety of INCMGA00012 in participants with advanced solid tumors where the efficacy of PD-1 inhibitors has previously been established.
Interventions
DRUGRetifanlimab
Retifanlimab administered intravenously at 500 mg every 4 weeks
Sponsors
Incyte Corporation
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Confirmed diagnosis of one of the following: treatment-naïve metastatic non-small cell lung cancer with high PD-L1 expression (tumor proportion score ≥ 50%) and no epidermal growth factor receptor (EGFR), alkaline phosphatase (ALK), or ROS activating genomic tumor aberrations; locally advanced or metastatic urothelial carcinoma in participants who are not eligible for cisplatin therapy and whose tumors express PD-L1 with a combined positive score ≥ 10; unresectable or metastatic melanoma; locally advanced or metastatic renal cell carcinoma with clear cell component (with or without sarcomatoid features) and having received no prior systemic therapy. * Measurable disease per RECIST v1.1. * Eastern Cooperative Oncology Group performance status 0 to 1. * Willingness to avoid pregnancy or fathering children.
Exclusion criteria
* Receipt of anticancer therapy or participation in another interventional clinical study within 21 days before the first administration of study drug. * Prior treatment with PD-1 or PD-L1 directed therapy (other immunotherapies may be acceptable with prior approval from the medical monitor). * Radiotherapy within 14 days of first dose of study treatment with the following caveats: 28 days for pelvic radiotherapy; 6 months for thoracic region radiotherapy that is \> 30 Gy. * Toxicity of prior therapy that has not recovered to ≤ Grade 1 or baseline (with the exception of anemia not requiring transfusion support and any grade of alopecia). Endocrinopathy, if well-managed, is not exclusionary and should be discussed with sponsor medical monitor. * Has not recovered adequately from toxicities and/or complications from surgical intervention before starting study drug. * Laboratory values outside the protocol-defined range at screening. * Known additional malignancy that is progressing or requires active treatment, or history of other malignancy within 3 years of study entry. * Active autoimmune disease requiring systemic immunosuppression in excess of physiologic maintenance doses of corticosteroids (\> 10 mg of prednisone or equivalent). * Evidence of interstitial lung disease or active noninfectious pneumonitis. * Known active central nervous system metastases and/or carcinomatous meningitis. * Known active hepatitis B antigen, hepatitis B virus, or hepatitis C virus infection. * Active infections requiring systemic therapy. * Known to be HIV-positive, unless all of the following criteria are met: CD4+ count ≥ 300/μL, undetectable viral load, receiving antiretroviral therapy. * Known hypersensitivity to another monoclonal antibody that cannot be controlled with standard measures (eg, antihistamines and corticosteroids). * Impaired cardiac function or clinically significant cardiac disease. * Is pregnant or breastfeeding. * Has received a live vaccine within 28 days of the planned start of study drug.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) | up to 25.9 months | ORR was defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR), per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (v1.1), as determined by the investigator, at any post-Baseline visit until new anti-cancer therapy or first Progressive Disease. CR: disappearance of all target and non-target lesions and no appearance of any new lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to \<10 millimeters (mm). PR: complete disappearance or at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum diameters, no new lesions, and no progression of non-target lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease Control Rate (DCR) | up to 25.9 months | DCR was defined as the proportion of participants with an overall response of CR, PR, or stable disease (SD), per RECIST v1.1. CR: disappearance of all target and non-target lesions and no appearance of any new lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to \<10 mm. PR: complete disappearance or at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum diameters, no new lesions, and no progression of non-target lesions. PD: progression of a target or non-target lesion or presence of a new lesion. SD: no change in target lesions to qualify for CR, PR, or PD. |
| Progression-free Survival (PFS) | up to 25.9 months | According to RECIST 1.1, PFS was defined as the length of time from the initial infusion of study drug until the earliest date of disease progression, determined by investigator assessment, or death due to any cause, if occurring sooner than progression. |
| Overall Survival | up to 28.2 months | Overall survival was defined as the time in months between the first dose date (Day 1) and the date of death due to any cause. |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | up to approximately 2.3 years | An adverse event (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 therefore have been any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study drug. A TEAE was defined as any AE either reported for the first time or the worsening of a pre-existing event after the first dose of retifanlimab and until the earlier of 90 days of the last administration of retifanlimab and new anti-cancer therapy start if any, are reported. |
| First-dose Cmax of Retifanlimab | preinfusion and 10 minutes postinfusion (± 10 minutes) on Day 1 of Cycle 1 | Cmax was defined as the maximum observed plasma or serum concentration of retifanlimab. |
| Cmax of Retifanlimab at Steady-state | preinfusion and 10 minutes postinfusion (± 10 minutes) on Day 1 of Cycles 1, 2, 4, and 6 (up to approximately 168 days; each cycle was 28 days) | Cmax was defined as the maximum observed plasma or serum concentration of retifanlimab. |
| Duration of Response (DOR) | up to 24.0 months | DOR was defined as the time from initial objective response (CR or PR) per RECIST v1.1 until the first observation of documented disease progression (PD), as determined by the investigator, or death due to any cause. CR: disappearance of all target and non-target lesions and no appearance of any new lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to \<10 mm. PR: complete disappearance or at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum diameters, no new lesions, and no progression of non-target lesions. PD: progression of a target or non-target lesion or presence of a new lesion. |
| Tmax of Retifanlimab at Steady-state | preinfusion and 10 minutes postinfusion (± 10 minutes) on Day 1 of Cycles 1, 2, 4, and 6 (up to approximately 168 days; each cycle was 28 days) | tmax was defined as the time to the maximum concentration of retifanlimab. |
| First-dose Cmin of Retifanlimab | preinfusion and 10 minutes postinfusion (± 10 minutes) on Day 1 of Cycle 1 | Cmin was defined as the minimum observed plasma or serum concentration over the dose interval of retifanlimab. |
| Cmin of Retifanlimabv at Steady-state | preinfusion and 10 minutes postinfusion (± 10 minutes) on Day 1 of Cycles 1, 2, 4, and 6 (up to approximately 168 days; each cycle was 28 days) | Cmin was defined as the minimum observed plasma or serum concentration over the dose interval of retifanlimab. |
| First-dose AUC0-t of Retifanlimab | preinfusion and 10 minutes postinfusion (± 10 minutes) on Day 1 of Cycle 1 | AUC0-t was defined as the area under the plasma or serum concentration-time curve from time = 0 to the last measurable concentration at time = t of retifanlimab. |
| AUC0-t of Retifanlimab at Steady-state | preinfusion and 10 minutes postinfusion (± 10 minutes) on Day 1 of Cycles 1, 2, 4, and 6 (up to approximately 168 days; each cycle was 28 days) | AUC0-t was defined as the area under the plasma or serum concentration-time curve from time = 0 to the last measurable concentration at time = t of retifanlimab. |
| First-dose Tmax of Retifanlimab | preinfusion and 10 minutes postinfusion (± 10 minutes) on Day 1 of Cycle 1 | tmax was defined as the time to the maximum concentration of retifanlimab. |
Countries
Austria, France, Hungary, Italy, Poland, Romania, Spain, United States
Participant flow
Recruitment details
This study was conducted at 34 study centers in Austria, Spain, France, Hungary, Italy, Poland, Romania, and the United States.
Pre-assignment details
A total of 121 participants with advanced solid tumors (melanoma, non-small cell lung cancer, urethelial carcinoma, and renal cell carcinoma) were enrolled in the study and treated with retifanlimab.
Participants by arm
| Arm | Count |
|---|---|
| Melanoma Participants with melanoma received retifanlimab 500 milligrams (mg), administered by intravenous (IV) infusion over 30 minutes on Day 1 of each 28-day cycle (Q4W). | 35 |
| Non-small Cell Lung Cancer Participants with non-small cell lung cancer received retifanlimab 500 mg, administered by IV infusion over 30 minutes on Day 1 Q4W. | 23 |
| Urethelial Carcinoma Participants with urethelial carcinoma received retifanlimab 500 mg, administered by IV infusion over 30 minutes on Day 1 Q4W. | 29 |
| Renal Cell Carcinoma Participants with renal cell carcinoma received retifanlimab 500 mg, administered by IV infusion over 30 minutes on Day 1 Q4W. | 34 |
| Total | 121 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Death | 16 | 11 | 17 | 10 |
| Overall Study | Entered Hospice Care | 0 | 0 | 0 | 1 |
| Overall Study | Follow-up Completed | 18 | 11 | 11 | 20 |
| Overall Study | Lost to Follow-up | 1 | 1 | 1 | 1 |
| Overall Study | Progressive Disease | 0 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Melanoma | Non-small Cell Lung Cancer | Urethelial Carcinoma | Renal Cell Carcinoma | Total |
|---|---|---|---|---|---|
| Age, Continuous | 67.2 Years STANDARD_DEVIATION 15.24 | 67.8 Years STANDARD_DEVIATION 8.68 | 72.0 Years STANDARD_DEVIATION 8.23 | 66.6 Years STANDARD_DEVIATION 10.28 | 68.3 Years STANDARD_DEVIATION 11.36 |
| Race/Ethnicity, Customized Asian | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 4 Participants | 0 Participants | 1 Participants | 0 Participants | 5 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 30 Participants | 22 Participants | 12 Participants | 29 Participants | 93 Participants |
| Race/Ethnicity, Customized Not Reported | 1 Participants | 1 Participants | 16 Participants | 5 Participants | 23 Participants |
| Race/Ethnicity, Customized White/Caucasian | 35 Participants | 22 Participants | 20 Participants | 33 Participants | 110 Participants |
| Sex: Female, Male Female | 20 Participants | 7 Participants | 4 Participants | 10 Participants | 41 Participants |
| Sex: Female, Male Male | 15 Participants | 16 Participants | 25 Participants | 24 Participants | 80 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 | 16 / 35 | 11 / 23 | 17 / 29 | 10 / 34 | 54 / 121 |
| other Total, other adverse events | 30 / 35 | 19 / 23 | 25 / 29 | 30 / 34 | 104 / 121 |
| serious Total, serious adverse events | 8 / 35 | 9 / 23 | 12 / 29 | 11 / 34 | 40 / 121 |
Outcome results
Primary
Overall Response Rate (ORR)
ORR was defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR), per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (v1.1), as determined by the investigator, at any post-Baseline visit until new anti-cancer therapy or first Progressive Disease. CR: disappearance of all target and non-target lesions and no appearance of any new lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to \<10 millimeters (mm). PR: complete disappearance or at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum diameters, no new lesions, and no progression of non-target lesions.
Time frame: up to 25.9 months
Population: Full Analysis Set (FAS) Population: all study participants who had received at least 1 dose of study drug. Participants were to be analyzed based on disease-specific diagnosis. Confidence intervals were calculated based on the exact method for binomial distributions.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Melanoma | Overall Response Rate (ORR) | 40.0 percentage of participants |
| Non-small Cell Lung Cancer | Overall Response Rate (ORR) | 34.8 percentage of participants |
| Urethelial Carcinoma | Overall Response Rate (ORR) | 37.9 percentage of participants |
| Renal Cell Carcinoma | Overall Response Rate (ORR) | 23.5 percentage of participants |
Secondary
AUC0-t of Retifanlimab at Steady-state
AUC0-t was defined as the area under the plasma or serum concentration-time curve from time = 0 to the last measurable concentration at time = t of retifanlimab.
Time frame: preinfusion and 10 minutes postinfusion (± 10 minutes) on Day 1 of Cycles 1, 2, 4, and 6 (up to approximately 168 days; each cycle was 28 days)
Population: PK Evaluable Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Melanoma | AUC0-t of Retifanlimab at Steady-state | 2030 day*mg/L | Standard Deviation 566 |
Secondary
Cmax of Retifanlimab at Steady-state
Cmax was defined as the maximum observed plasma or serum concentration of retifanlimab.
Time frame: preinfusion and 10 minutes postinfusion (± 10 minutes) on Day 1 of Cycles 1, 2, 4, and 6 (up to approximately 168 days; each cycle was 28 days)
Population: PK Evaluable Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Melanoma | Cmax of Retifanlimab at Steady-state | 181 mg/L | Standard Deviation 39.4 |
Secondary
Cmin of Retifanlimabv at Steady-state
Cmin was defined as the minimum observed plasma or serum concentration over the dose interval of retifanlimab.
Time frame: preinfusion and 10 minutes postinfusion (± 10 minutes) on Day 1 of Cycles 1, 2, 4, and 6 (up to approximately 168 days; each cycle was 28 days)
Population: PK Evaluable Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Melanoma | Cmin of Retifanlimabv at Steady-state | 38.2 mg/L | Standard Deviation 16.3 |
Secondary
Disease Control Rate (DCR)
DCR was defined as the proportion of participants with an overall response of CR, PR, or stable disease (SD), per RECIST v1.1. CR: disappearance of all target and non-target lesions and no appearance of any new lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to \<10 mm. PR: complete disappearance or at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum diameters, no new lesions, and no progression of non-target lesions. PD: progression of a target or non-target lesion or presence of a new lesion. SD: no change in target lesions to qualify for CR, PR, or PD.
Time frame: up to 25.9 months
Population: FAS Population. Confidence intervals were calculated based on the exact method for binomial distributions.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Melanoma | Disease Control Rate (DCR) | 54.3 percentage of participants |
| Non-small Cell Lung Cancer | Disease Control Rate (DCR) | 65.2 percentage of participants |
| Urethelial Carcinoma | Disease Control Rate (DCR) | 55.2 percentage of participants |
| Renal Cell Carcinoma | Disease Control Rate (DCR) | 64.7 percentage of participants |
Secondary
Duration of Response (DOR)
DOR was defined as the time from initial objective response (CR or PR) per RECIST v1.1 until the first observation of documented disease progression (PD), as determined by the investigator, or death due to any cause. CR: disappearance of all target and non-target lesions and no appearance of any new lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to \<10 mm. PR: complete disappearance or at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum diameters, no new lesions, and no progression of non-target lesions. PD: progression of a target or non-target lesion or presence of a new lesion.
Time frame: up to 24.0 months
Population: FAS Population. Only those participants with a CR or PR were included in the analysis. The 95% confidence interval was calculated using the Brookmeyer and Crowley's method and Klein and Moeschberger's method with log-log transformation.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Melanoma | Duration of Response (DOR) | NA months |
| Non-small Cell Lung Cancer | Duration of Response (DOR) | 18.2 months |
| Urethelial Carcinoma | Duration of Response (DOR) | 11.5 months |
| Renal Cell Carcinoma | Duration of Response (DOR) | NA months |
Secondary
First-dose AUC0-t of Retifanlimab
AUC0-t was defined as the area under the plasma or serum concentration-time curve from time = 0 to the last measurable concentration at time = t of retifanlimab.
Time frame: preinfusion and 10 minutes postinfusion (± 10 minutes) on Day 1 of Cycle 1
Population: PK Evaluable Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Melanoma | First-dose AUC0-t of Retifanlimab | 1620 day*mg/L | Standard Deviation 506 |
Secondary
First-dose Cmax of Retifanlimab
Cmax was defined as the maximum observed plasma or serum concentration of retifanlimab.
Time frame: preinfusion and 10 minutes postinfusion (± 10 minutes) on Day 1 of Cycle 1
Population: Pharmacokinetic (PK) Evaluable Population: all participants who received at least 1 dose of study drug and provided a Baseline and at least 1 postdose PK sample
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Melanoma | First-dose Cmax of Retifanlimab | 143 milligrams per Liter (mg/L) | Standard Deviation 30.9 |
Secondary
First-dose Cmin of Retifanlimab
Cmin was defined as the minimum observed plasma or serum concentration over the dose interval of retifanlimab.
Time frame: preinfusion and 10 minutes postinfusion (± 10 minutes) on Day 1 of Cycle 1
Population: PK Evaluable Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Melanoma | First-dose Cmin of Retifanlimab | 18.0 mg/L | Standard Deviation 7.52 |
Secondary
First-dose Tmax of Retifanlimab
tmax was defined as the time to the maximum concentration of retifanlimab.
Time frame: preinfusion and 10 minutes postinfusion (± 10 minutes) on Day 1 of Cycle 1
Population: PK Evaluable Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Melanoma | First-dose Tmax of Retifanlimab | 0.500 hours |
Secondary
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
An adverse event (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 therefore have been any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study drug. A TEAE was defined as any AE either reported for the first time or the worsening of a pre-existing event after the first dose of retifanlimab and until the earlier of 90 days of the last administration of retifanlimab and new anti-cancer therapy start if any, are reported.
Time frame: up to approximately 2.3 years
Population: Safety Evaluable Population: all participants who received at least 1 dose of study drug
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Melanoma | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 32 Participants |
| Non-small Cell Lung Cancer | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 21 Participants |
| Urethelial Carcinoma | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 28 Participants |
| Renal Cell Carcinoma | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 32 Participants |
Secondary
Overall Survival
Overall survival was defined as the time in months between the first dose date (Day 1) and the date of death due to any cause.
Time frame: up to 28.2 months
Population: FAS Population. Median survival time in months was estimated using the Kaplan-Meier method. The confidence interval for median survival time was calculated using the method of Brookmeyer and Crowley.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Melanoma | Overall Survival | NA months |
| Non-small Cell Lung Cancer | Overall Survival | 21.9 months |
| Urethelial Carcinoma | Overall Survival | 15.2 months |
| Renal Cell Carcinoma | Overall Survival | NA months |
Secondary
Progression-free Survival (PFS)
According to RECIST 1.1, PFS was defined as the length of time from the initial infusion of study drug until the earliest date of disease progression, determined by investigator assessment, or death due to any cause, if occurring sooner than progression.
Time frame: up to 25.9 months
Population: FAS Population. Median PFS was estimated using the Kaplan-Meier method. The confidence interval for median PFS was calculated using the method of Brookmeyer and Crowley.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Melanoma | Progression-free Survival (PFS) | 3.6 months |
| Non-small Cell Lung Cancer | Progression-free Survival (PFS) | 4.4 months |
| Urethelial Carcinoma | Progression-free Survival (PFS) | 5.7 months |
| Renal Cell Carcinoma | Progression-free Survival (PFS) | 5.4 months |
Secondary
Tmax of Retifanlimab at Steady-state
tmax was defined as the time to the maximum concentration of retifanlimab.
Time frame: preinfusion and 10 minutes postinfusion (± 10 minutes) on Day 1 of Cycles 1, 2, 4, and 6 (up to approximately 168 days; each cycle was 28 days)
Population: PK Evaluable Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Melanoma | Tmax of Retifanlimab at Steady-state | 0.500 hours |