Locally Advanced Unresectable or Metastatic Melanoma
Conditions
Keywords
Karyopharm, Locally advanced unresectable or metastatic melanoma, KPT-330, Recurrent advanced melanoma, Selinexor, Pembrolizumab
Brief summary
Approximately 40 participants with locally advanced or metastatic melanoma will be enrolled in 20 sites in the United States into 1 of the following 2 arms: Primary resistance to initial checkpoint inhibitor (CPI) therapy in Arm A and Acquired resistance to initial CPI therapy in Arm B. Participants who have disease progression (PD) after discontinuation of CPIs, especially in neoadjuvant or adjuvant therapy, will be considered to have acquired resistance in this study. Participants will receive study treatment (Selinexor and Pembrolizumab) until PD, intolerable toxicity or withdrawal from the study, whichever occurs first.
Interventions
DRUGSelinexor
Dose and formulation: 80 mg (4 tablets of 20 mg)
DRUGPembrolizumab
Dose and formulation: 400 mg (25 milligrams per milliliter \[mg/mL\]) Solution
Sponsors
Karyopharm Therapeutics Inc
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
* Age greater than or equal to (≥) 18 years at the time of informed consent. * Participant must have a histologically confirmed diagnosis of locally advanced unresectable stage III or metastatic stage IV melanoma not amenable to local therapy. 1. Participants must have confirmed PD per Response Evaluation Criteria in Solid Tumors (RECIST) on or within 12 weeks of the last dose of anti-PD-1/L1 monotherapy or combination therapy (including relatlimab or other anti-LAG-3 mAb) per Society for Immunotherapy in Cancer Guidelines (Kluger,2020). 2. Arm A (primary resistance): participant has disease progression after receiving at least 6 weeks of prior anti-PD-1/L1 mAb with the best response as PD, or stable disease (SD) less than (\<) 6 month (participants with a partial response \[PR\] or complete response \[CR\] who have disease progression within 6 months will be considered to have primary resistance in this study). 3. Arm B (secondary/acquired resistance): participant has disease progression after receiving at least 6 months of prior anti-PD-1/L1 mAb with the best response as CR, PR, or SD greater than (\>) 6 months (participants who have disease progression after neoadjuvant or adjuvant therapy, will be considered to have secondary resistance in this study). 4. Participants who progress on or within 12 weeks after elective discontinuation of anti-PD-1/L1 mono or combination treatment in the absence of PD or treatment limiting toxicity must have confirmed PD per RECIST. * Participants should have at least 1 prior line of CPI therapy but no more than 2. * Measurable disease according to RECIST v1.1. * Participants with stable previously treated brain metastases are permitted in this study. * Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to (≤) 1. * Adequate bone marrow function at screening, defined as: 1. Absolute neutrophil count (ANC) ≥1.5 \* 10\^9 per liter (L). 2. Hemoglobin ≥10 gram per deciliter (gm/dL) (≥6.2 millimoles per liter \[mmol/L\]). 3. Platelet count ≥100 \* 10\^9/L. * Serum direct bilirubin ≤1.5 \* upper limit of normal (ULN); aspartate transaminase (AST) and alanine transaminase (ALT) ≤2.5 \* ULN (with confirmed liver metastases: AST and ALT ≤5 \* ULN). * Calculated creatinine clearance (CrCl) ≥15 milliliters per minute (mL/min) based on the Cockcroft and Gault formula. * Female participants of childbearing potential must have a negative serum pregnancy test at screening and agree to use highly effective methods of contraception throughout the study and for at least four months following the last dose of study treatment. Childbearing potential excludes: Age \>50 years and naturally amenorrhoeic for \>1 year, or previous bilateral salpingo-oophorectomy, or hysterectomy. * Male participants who are sexually active must use highly effective methods of contraception throughout the study and for at least four months following the last dose of study treatment. Male participants must agree not to donate sperm during the study treatment period. * Written informed consent signed in accordance with federal, local, and institutional guidelines.
Exclusion criteria
* Metastatic uveal or ocular melanoma. * Active central nervous system (CNS) metastases or other CNS (e.g., meningeal) involvement. * Participants must have resolution or improvement of immune-mediated treatment related adverse reactions related to prior treatment(s) to Grade ≤1 without steroid maintenance therapy or his or her previous baseline prior to the corresponding CPI therapy a. History of immune-mediated treatment related adverse reactions leading to discontinuation of prior anti-programmed death protein 1 (PD-1), anti-programmed death protein ligand 1 (PD-L1), or anti programmed death protein ligand 2 (PD-L2) monoclonal antibodies (mAbs) or severe hypersensitivity reaction to any mAb or any excipients which in the opinion of the Investigator precludes future use of anti-PD-1/PDL1 therapy. * Concurrent systemic steroid therapy higher than physiologic dose (\>10 milligrams per day \[mg/day\] of prednisone or equivalent). * Previous treatment with selinexor or other exportin 1 (XPO1) inhibitors. * Insufficient time since or not recovered from procedures or anti-cancer therapy, defined as: 1. Not recovered from major surgery ≤28 days prior to Day 1 dosing. Minor procedures, such as biopsies, dental work, or placement of a port or intravenous (IV) line for infusion are permitted. 2. Have ongoing clinically significant anti-cancer therapy-related toxicities Common Terminology Criteria for Adverse Events (CTCAE) Grade \>1. In specific cases, participants whose toxicity has stabilized or with Grade 2 non-hematologic toxicities can be allowed following documented approval by the Sponsor's Medical Monitor 3. Had last dose of previous anti-cancer therapy ≤14 days prior to Day 1 dosing 4. Palliative radiotherapy \>14 days prior to the study is allowed 5. Received investigational drugs in other clinical trials within 28 days, or 5 half-lives of the investigational drug (whichever is shorter), prior to Cycle 1 Day 1 (C1D1). * Live-attenuated vaccine (e.g., nasal spray influenza vaccine) ≤14 days prior to the intended C1D1. * Impairment of gastrointestinal (GI) function or GI disease that could significantly alter the absorption of selinexor (e.g., vomiting, or diarrhea that is CTCAE version 5.0 grade \>1). * Life expectancy less than (\<) 4 months based on the opinion of the Investigator * Active pneumonitis requiring steroid therapy. * Uncontrolled (i.e., clinically unstable) infection requiring parenteral antibiotics, antivirals, or antifungals within 7 days prior to first dose of study treatment; however, prophylactic use of these agents is acceptable (including parenteral). * Any life-threatening illness, medical condition, or organ system dysfunction which, in the Investigator's opinion, could compromise the participant's safety, prevent the participant from giving informed consent, or being compliant with the study procedures. * Female participants who are pregnant or lactating. * Active hepatitis B virus treated with antiviral therapy for hepatitis B within 8 weeks with a viral load \>100 international units per milliliter (IU/mL). * Untreated hepatitis C virus positive without documentation of negative viral load per institutional standard. * Human immunodeficiency virus positive with CD4+T-cells ≤350 cells per microliter, positive viral load per institutional standard, and a history of acquired immunodeficiency syndrome defining opportunist infections in the last year.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) Assessed as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | From the date of randomization until the documentation of CR or PR, whichever occurs first (up to 24 months) | ORR was defined as the percentage of participants who achieved complete response (CR) or partial response (PR). ORR was assessed by RECIST 1.1 as defined by the Investigator based on radiologic criteria. Per RECIST 1.1 criteria, CR was defined as disappearance of all target lesions, any pathological lymph nodes (whether target or non-target) with reduction in short axis to less than (\<)10 millimeter (mm). PR was defined as at least a 30 percentage (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | From the date of first study treatment up to death (up to 24 months) | OS was defined as the time from date of first study treatment until death due to any cause. If death event did not occur during the follow-up period, the participant was censored at the date of discontinuation from the study (i.e. withdrawal of consent), or date of last participating visit (e.g., a telephone contact with participant status being alive) on or before database cutoff date, whichever occurs first. |
| Complete Response Rate (CRR) | Up to 101 weeks | Complete response rate was defined as percentage of participants who had achieved a complete response (CR) per RECIST 1.1. As per RECIST version 1.1, CR was defined as disappearance of all target lesions, any pathological lymph nodes (whether target or non-target) with reduced in the short axis to \<10 mm. |
| Duration of Response (DOR) as Per RECIST v 1.1 | From first occurrence of CR or PR until disease progression or death, whichever occurs first (up to 24 months) | DOR was defined as the time from first occurrence of CR or PR until the first date of PD per RECIST version 1.1 or death. Per RECIST 1.1 criteria, CR was defined as disappearance of all target lesions, any pathological lymph nodes (whether target or non-target) with reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. PD was defined as at least a 20% increase in the sum of the longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. |
| Percentage of Participants With Disease Control Rate (DCR) as Per RECIST v 1.1 | Up to 24 months | Disease control rate was defined as percentage of participants who have a response of CR, PR, or at least 12 continuous weeks of stable disease (SD) as per RECIST v 1.1. As per RECIST v 1.1 before PD or initiating a new antineoplastic therapy, CR was defined as disappearance of all target lesions; any pathological lymph nodes (whether target or non-target) with reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (at least a 20% increase in the sum of diameters of target lesions) taking as reference the smallest sum diameters while on study. Percentage values were rounded off. |
| Progression-free Survival (PFS) as Per RECIST v 1.1 | From the date of randomization until disease progression or death, due to any cause (up to 24 months) | PFS was defined as time from date of first treatment to the date of first confirmed progressive disease (PD), assessed by RECIST 1.1 is objectively documented or death due to any cause. As per RECIST 1.1 criteria, PD was defined as at least a 20% increase in the sum of the longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. |
| Number of Participants With Clinically Significant Abnormalities in Clinical Laboratory Parameters | From start of the study treatment up to 24 months | Clinical laboratory parameters included clinical chemistry, hematology and urinalysis. Number of participants with clinically significant laboratory abnormalities which were deemed clinically significant by the investigator were reported. |
| Number of Participants With Clinically Significant Changes in Vital Signs | From start of the study treatment up to 24 months | Vital signs included body temperature, blood pressure (systolic blood pressure and diastolic blood pressure). Measurements were made after the participant had been resting supine for a minimum of 5 minutes. The clinically significant change assessment was based on investigator's judgment. Number of participants with clinically significant change from baseline in vital signs values were reported. |
| Number of Participants With Clinically Significant Changes in Physical Examination | From start of the study treatment up to 24 months | Number of participants with clinically significant physical examination abnormalities including general appearance, dermatological, head, eyes, ears, nose, throat, respiratory, cardiovascular, abdominal, lymph nodes, musculoskeletal, and neurological examinations. Number of participants with clinically significant physical examination abnormalities which were deemed clinically significant by the investigator were reported. |
| Number of Participants With Severity of Adverse Events Assessed Using the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 | From start of the study treatment up to 24 months | AEs are graded using the following criteria using Common Terminology Criteria for Adverse events v5.0: Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated; Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL; Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL; Grade 4: Life-threatening consequences; urgent intervention indicated; Grade 5: Death related to AE. |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | From start of the study treatment up to 24 months | An adverse event was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of study treatment, whether or not considered related to the study treatment. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. A TEAE was defined as those AEs that develop or worsen after the first dose of study drug. TEAEs included both serious and non-serious TEAEs. |
Countries
United States
Participant flow
Recruitment details
This study was conducted at 13 sites in United States of America from 12 May 2021 to 22 September 2023.
Pre-assignment details
A total of 15 participants were enrolled and received the study treatment. The study was stopped prematurely due to a lack of sufficient anti-tumor signal for the selinexor/pembrolizumab combination treatment in participants with advanced or metastatic melanoma.
Participants by arm
| Arm | Count |
|---|---|
| Arm A: Primary Resistance to Initial CPI Therapy Participants with advanced or metastatic melanoma where primary resistance to initial CPI therapy received a dose of 80 mg (4 tablets of 20 mg) selinexor orally QW and a dose of pembrolizumab 400 mg IV Q6W, both on Day 1 of a 6-week cycle (each cycle = 42 days) until PD, intolerable toxicity or withdrawal from the study, whichever occurred first. | 9 |
| Arm B: Acquired Resistance to Initial CPI Therapy Participants with advanced or metastatic melanoma had acquired resistance to initial CPI therapy received a dose of 80 mg (4 tablets of 20 mg) selinexor orally QW and a dose of pembrolizumab 400 mg IV Q6W, both on Day 1 of a 6-week cycle (each cycle = 42 days) until PD, intolerable toxicity or withdrawal from the study, whichever occurred first. | 6 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Completed Study Follow-up | 0 | 2 |
| Overall Study | Death | 3 | 2 |
| Overall Study | Other | 2 | 0 |
| Overall Study | Study Terminated by Sponsor | 2 | 2 |
| Overall Study | Withdrawal by Subject | 2 | 0 |
Baseline characteristics
| Characteristic | Arm B: Acquired Resistance to Initial CPI Therapy | Total | Arm A: Primary Resistance to Initial CPI Therapy |
|---|---|---|---|
| Age, Continuous | 53.7 Years STANDARD_DEVIATION 12.4 | 58.3 Years STANDARD_DEVIATION 13.48 | 61.4 Years STANDARD_DEVIATION 13.95 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 3 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 11 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 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 | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) White | 5 Participants | 11 Participants | 6 Participants |
| Sex: Female, Male Female | 3 Participants | 6 Participants | 3 Participants |
| Sex: Female, Male Male | 3 Participants | 9 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 9 | 2 / 6 |
| other Total, other adverse events | 9 / 9 | 6 / 6 |
| serious Total, serious adverse events | 3 / 9 | 2 / 6 |
Outcome results
Primary
Overall Response Rate (ORR) Assessed as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
ORR was defined as the percentage of participants who achieved complete response (CR) or partial response (PR). ORR was assessed by RECIST 1.1 as defined by the Investigator based on radiologic criteria. Per RECIST 1.1 criteria, CR was defined as disappearance of all target lesions, any pathological lymph nodes (whether target or non-target) with reduction in short axis to less than (\<)10 millimeter (mm). PR was defined as at least a 30 percentage (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: From the date of randomization until the documentation of CR or PR, whichever occurs first (up to 24 months)
Population: mITT population consisted of all participants who received at least one dose of any study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Primary Resistance to Initial CPI Therapy | Overall Response Rate (ORR) Assessed as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | 33.3 Percentage of participants |
| Arm B: Acquired Resistance to Initial CPI Therapy | Overall Response Rate (ORR) Assessed as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | 16.7 Percentage of participants |
Secondary
Complete Response Rate (CRR)
Complete response rate was defined as percentage of participants who had achieved a complete response (CR) per RECIST 1.1. As per RECIST version 1.1, CR was defined as disappearance of all target lesions, any pathological lymph nodes (whether target or non-target) with reduced in the short axis to \<10 mm.
Time frame: Up to 101 weeks
Population: mITT population consisted of all participants who received at least one dose of any study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Primary Resistance to Initial CPI Therapy | Complete Response Rate (CRR) | 22.2 Percentage of participants |
| Arm B: Acquired Resistance to Initial CPI Therapy | Complete Response Rate (CRR) | 16.7 Percentage of participants |
Secondary
Duration of Response (DOR) as Per RECIST v 1.1
DOR was defined as the time from first occurrence of CR or PR until the first date of PD per RECIST version 1.1 or death. Per RECIST 1.1 criteria, CR was defined as disappearance of all target lesions, any pathological lymph nodes (whether target or non-target) with reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. PD was defined as at least a 20% increase in the sum of the longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.
Time frame: From first occurrence of CR or PR until disease progression or death, whichever occurs first (up to 24 months)
Population: mITT population consisted of all participants who received at least one dose of any study treatment. Only those participants who had confirmed response were included in the analysis. Here, overall number of participants analyzed signifies those who had response to DOR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Primary Resistance to Initial CPI Therapy | Duration of Response (DOR) as Per RECIST v 1.1 | NA Months |
| Arm B: Acquired Resistance to Initial CPI Therapy | Duration of Response (DOR) as Per RECIST v 1.1 | NA Months |
Secondary
Number of Participants With Clinically Significant Abnormalities in Clinical Laboratory Parameters
Clinical laboratory parameters included clinical chemistry, hematology and urinalysis. Number of participants with clinically significant laboratory abnormalities which were deemed clinically significant by the investigator were reported.
Time frame: From start of the study treatment up to 24 months
Population: Safety population consisted of all enrolled participants who had received at least one dose of both study treatments.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A: Primary Resistance to Initial CPI Therapy | Number of Participants With Clinically Significant Abnormalities in Clinical Laboratory Parameters | Clinical Chemistry | 0 Participants |
| Arm A: Primary Resistance to Initial CPI Therapy | Number of Participants With Clinically Significant Abnormalities in Clinical Laboratory Parameters | Hematology | 0 Participants |
| Arm A: Primary Resistance to Initial CPI Therapy | Number of Participants With Clinically Significant Abnormalities in Clinical Laboratory Parameters | Urinalysis | 0 Participants |
| Arm B: Acquired Resistance to Initial CPI Therapy | Number of Participants With Clinically Significant Abnormalities in Clinical Laboratory Parameters | Clinical Chemistry | 0 Participants |
| Arm B: Acquired Resistance to Initial CPI Therapy | Number of Participants With Clinically Significant Abnormalities in Clinical Laboratory Parameters | Hematology | 0 Participants |
| Arm B: Acquired Resistance to Initial CPI Therapy | Number of Participants With Clinically Significant Abnormalities in Clinical Laboratory Parameters | Urinalysis | 0 Participants |
Secondary
Number of Participants With Clinically Significant Changes in Physical Examination
Number of participants with clinically significant physical examination abnormalities including general appearance, dermatological, head, eyes, ears, nose, throat, respiratory, cardiovascular, abdominal, lymph nodes, musculoskeletal, and neurological examinations. Number of participants with clinically significant physical examination abnormalities which were deemed clinically significant by the investigator were reported.
Time frame: From start of the study treatment up to 24 months
Population: Safety population consisted of all enrolled participants who had received at least one dose of both study treatments.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A: Primary Resistance to Initial CPI Therapy | Number of Participants With Clinically Significant Changes in Physical Examination | 0 Participants |
| Arm B: Acquired Resistance to Initial CPI Therapy | Number of Participants With Clinically Significant Changes in Physical Examination | 0 Participants |
Secondary
Number of Participants With Clinically Significant Changes in Vital Signs
Vital signs included body temperature, blood pressure (systolic blood pressure and diastolic blood pressure). Measurements were made after the participant had been resting supine for a minimum of 5 minutes. The clinically significant change assessment was based on investigator's judgment. Number of participants with clinically significant change from baseline in vital signs values were reported.
Time frame: From start of the study treatment up to 24 months
Population: Safety population consisted of all enrolled participants who had received at least one dose of both study treatments.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A: Primary Resistance to Initial CPI Therapy | Number of Participants With Clinically Significant Changes in Vital Signs | Body Temperature | 0 Participants |
| Arm A: Primary Resistance to Initial CPI Therapy | Number of Participants With Clinically Significant Changes in Vital Signs | Systolic Blood Pressure | 0 Participants |
| Arm A: Primary Resistance to Initial CPI Therapy | Number of Participants With Clinically Significant Changes in Vital Signs | Diastolic Blood Pressure | 0 Participants |
| Arm B: Acquired Resistance to Initial CPI Therapy | Number of Participants With Clinically Significant Changes in Vital Signs | Diastolic Blood Pressure | 0 Participants |
| Arm B: Acquired Resistance to Initial CPI Therapy | Number of Participants With Clinically Significant Changes in Vital Signs | Systolic Blood Pressure | 0 Participants |
| Arm B: Acquired Resistance to Initial CPI Therapy | Number of Participants With Clinically Significant Changes in Vital Signs | Body Temperature | 0 Participants |
Secondary
Number of Participants With Severity of Adverse Events Assessed Using the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0
AEs are graded using the following criteria using Common Terminology Criteria for Adverse events v5.0: Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated; Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL; Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL; Grade 4: Life-threatening consequences; urgent intervention indicated; Grade 5: Death related to AE.
Time frame: From start of the study treatment up to 24 months
Population: Safety population consisted of all enrolled participants who had received at least one dose of both study treatments.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A: Primary Resistance to Initial CPI Therapy | Number of Participants With Severity of Adverse Events Assessed Using the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 | Grade 2 | 5 Participants |
| Arm A: Primary Resistance to Initial CPI Therapy | Number of Participants With Severity of Adverse Events Assessed Using the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 | Grade 4 | 0 Participants |
| Arm A: Primary Resistance to Initial CPI Therapy | Number of Participants With Severity of Adverse Events Assessed Using the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 | Grade 1 | 0 Participants |
| Arm A: Primary Resistance to Initial CPI Therapy | Number of Participants With Severity of Adverse Events Assessed Using the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 | Grade 5 | 0 Participants |
| Arm A: Primary Resistance to Initial CPI Therapy | Number of Participants With Severity of Adverse Events Assessed Using the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 | Grade 3 | 4 Participants |
| Arm B: Acquired Resistance to Initial CPI Therapy | Number of Participants With Severity of Adverse Events Assessed Using the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 | Grade 5 | 0 Participants |
| Arm B: Acquired Resistance to Initial CPI Therapy | Number of Participants With Severity of Adverse Events Assessed Using the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 | Grade 1 | 0 Participants |
| Arm B: Acquired Resistance to Initial CPI Therapy | Number of Participants With Severity of Adverse Events Assessed Using the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 | Grade 2 | 2 Participants |
| Arm B: Acquired Resistance to Initial CPI Therapy | Number of Participants With Severity of Adverse Events Assessed Using the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 | Grade 3 | 4 Participants |
| Arm B: Acquired Resistance to Initial CPI Therapy | Number of Participants With Severity of Adverse Events Assessed Using the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 | Grade 4 | 0 Participants |
Secondary
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs
An adverse event was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of study treatment, whether or not considered related to the study treatment. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. A TEAE was defined as those AEs that develop or worsen after the first dose of study drug. TEAEs included both serious and non-serious TEAEs.
Time frame: From start of the study treatment up to 24 months
Population: Safety population consisted of all enrolled participants who had received at least one dose of both study treatments.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A: Primary Resistance to Initial CPI Therapy | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Participants with TEAEs | 9 Participants |
| Arm A: Primary Resistance to Initial CPI Therapy | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Participants with Serious TEAEs | 3 Participants |
| Arm B: Acquired Resistance to Initial CPI Therapy | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Participants with TEAEs | 6 Participants |
| Arm B: Acquired Resistance to Initial CPI Therapy | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Participants with Serious TEAEs | 2 Participants |
Secondary
Overall Survival (OS)
OS was defined as the time from date of first study treatment until death due to any cause. If death event did not occur during the follow-up period, the participant was censored at the date of discontinuation from the study (i.e. withdrawal of consent), or date of last participating visit (e.g., a telephone contact with participant status being alive) on or before database cutoff date, whichever occurs first.
Time frame: From the date of first study treatment up to death (up to 24 months)
Population: mITT population consisted of all participants who received at least one dose of any study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Primary Resistance to Initial CPI Therapy | Overall Survival (OS) | NA Months |
| Arm B: Acquired Resistance to Initial CPI Therapy | Overall Survival (OS) | NA Months |
Secondary
Percentage of Participants With Disease Control Rate (DCR) as Per RECIST v 1.1
Disease control rate was defined as percentage of participants who have a response of CR, PR, or at least 12 continuous weeks of stable disease (SD) as per RECIST v 1.1. As per RECIST v 1.1 before PD or initiating a new antineoplastic therapy, CR was defined as disappearance of all target lesions; any pathological lymph nodes (whether target or non-target) with reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (at least a 20% increase in the sum of diameters of target lesions) taking as reference the smallest sum diameters while on study. Percentage values were rounded off.
Time frame: Up to 24 months
Population: mITT population consisted of all participants who received at least one dose of any study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Primary Resistance to Initial CPI Therapy | Percentage of Participants With Disease Control Rate (DCR) as Per RECIST v 1.1 | 44.4 Percentage of participants |
| Arm B: Acquired Resistance to Initial CPI Therapy | Percentage of Participants With Disease Control Rate (DCR) as Per RECIST v 1.1 | 50.0 Percentage of participants |
Secondary
Progression-free Survival (PFS) as Per RECIST v 1.1
PFS was defined as time from date of first treatment to the date of first confirmed progressive disease (PD), assessed by RECIST 1.1 is objectively documented or death due to any cause. As per RECIST 1.1 criteria, PD was defined as at least a 20% increase in the sum of the longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.
Time frame: From the date of randomization until disease progression or death, due to any cause (up to 24 months)
Population: mITT population consisted of all participants who received at least one dose of any study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Primary Resistance to Initial CPI Therapy | Progression-free Survival (PFS) as Per RECIST v 1.1 | 3.75 Months |
| Arm B: Acquired Resistance to Initial CPI Therapy | Progression-free Survival (PFS) as Per RECIST v 1.1 | 6.24 Months |