Melanoma
Conditions
Keywords
Unresectable, melanoma, metastatic melanoma, advanced melanoma, spartalizumab, PDR001, LAG525, capmatinib, INC280, canakinumab, ACZ885, ribociclib, LEE011, immunotherapy, platform study, LAG-3
Brief summary
The primary purpose of this study is to evaluate the efficacy of novel spartalizumab (PDR001) combinations in previously treated unresectable or metastatic melanoma
Detailed description
This study was a randomized, open-label, two-part, multi-center, open platform phase II study designed to evaluate the efficacy and safety of the anti-PD-1 antibody PDR001 in combination with novel agents for previously treated unresectable or metastatic melanoma. Additionally, a non-randomized single-arm was added based on interim analysis findings to assess the efficacy and safety of PDR001 in combination with LAG525 in subjects with previously treated unresectable or metastatic LAG-3 positive melanoma. The study consisted of two parts: the selection part and the expansion part, which were applicable to both the randomized and non-randomized sections. In the randomized section, participants were randomized to one of four combination arms available for enrollment: * Arm 1: LAG525 600 mg intravenously (i.v.) every 4 weeks (Q4W) and PDR001 400 mg i.v. Q4W. * Arm 2: INC280 400 mg orally (p.o.) twice daily (BID) and PDR001 400 mg i.v. Q4W. * Arm 3: ACZ885 300 mg subcutaneously (s.c.) every 4 weeks (Q4W) and PDR001 400 mg i.v. Q4W. * Arm 4: LEE011 600 mg p.o. once daily (QD) on Days 1-21 of a 28-day cycle and PDR001 400 mg i.v. Q4W. At each interim analysis, the following determinations were made: (1) which arm met the pre-specified efficacy criteria and expanded to the expansion part, (2) which arms continued enrollment in selection part (up to 45 subjects), and (3) which arms were discontinued due to futility, considering efficacy, safety, and biomarker data. The expansion phase included enrollment of subjects only in the combination arms that met the pre-specified criteria in selection part. In the non-randomized section, a single combination arm was opened for enrollment in selection part: • Arm 1A: LAG525 600 mg i.v. Q4W and PDR001 400 mg i.v. Q4W, assessed in a population selected based on the LAG-3 status of their tumor. Arm 1A would be eligible for enrollment in expansion part only if it met the pre-specified criterion for this arm. Participants received the study treatment corresponding to their assigned arm on a 28-day cycle basis until disease progression, as determined by local assessment using RECIST v1.1 criteria, or until certain events occurred, such as unacceptable toxicity, initiation of subsequent anti-cancer therapy, withdrawal of consent, investigator's decision, loss to follow-up, death, or termination of the study by the sponsor. Following discontinuation of the study treatment, all subjects were monitored for safety evaluations for up to 150 days after their last dose of the study treatment.
Interventions
DRUGPDR001
400 mg of PDR001 administered every 4 weeks intravenously
DRUGLAG525
600 mg of LAG525 administered every 4 weeks intravenously
DRUGINC280
400 mg of INC280 administered twice daily orally
DRUGACZ885
200 mg of ACZ885 administered every 4 weeks subcutaneosuly
DRUGLEE011
600 mg of LEE011 orally taken once daily on Days 1-21 of a 28-day cycle
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
After approval of protocol amendment 5 (26Jun2020), a non-randomized single arm was added
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key inclusion criteria for Arm 1, 2, 3, 4: * Histologically confirmed unresectable or metastatic stage IIIB/C/D or IV melanoma using AJCC edition 8. * Previously treated for unresectable or metastatic melanoma: * Subjects with V600BRAF wild-type disease had to have received prior systemic therapy for unresectable or metastatic melanoma with anti-PD-1/PD-L1. Additionally, subjects may have received anti-CTLA-4 as a single agent or in combination with anti-PD-1/PD-L1, irrespective of the sequence. No additional systemic treatment was allowed for advanced or metastatic melanoma. A maximum of two prior lines of systemic therapies for unresectable or metastatic melanoma were allowed. The last dose of prior therapy (anti-PD-1, anti-PD-L1, or anti-CTLA-4) had to have been received more than four weeks before randomization. * Subjects with V600BRAF mutant disease had to have received prior systemic therapy for unresectable or metastatic melanoma with anti-PD-1/PD-L1 and V600BRAF inhibitor. Additionally, subjects may have received anti-CTLA-4 as a single agent or in combination with anti-PD-1/PD-L1, or MEK inhibitor (in combination with V600BRAF inhibitor or as a single agent), irrespective of the sequence. No additional systemic treatment was allowed for advanced or metastatic melanoma. * A maximum of three prior lines of systemic therapies for unresectable or metastatic melanoma were allowed. * The last dose of prior therapy had to have been received more than 4 weeks (for anti-PD-1, anti-PD-L1, or anti-CTLA-4) or more than 2 weeks (for V600BRAF or MEK inhibitor) prior to randomization. * All subjects (with V600BRAF wild-type disease and with V600BRAF mutant disease) had to have documented disease progression as per RECIST v1.1 while on/after the last therapy received prior to study entry and while on/after treatment with anti-PD1/PD-L1. The last progression had to have occurred within 12 weeks prior to randomization in the study. * ECOG performance status 0-2. * At least one measurable lesion per RECIST v1.1. * At least one lesion, suitable for sequential mandatory tumor biopsies (screening and on-treatment) in accordance with the biopsy guidelines specified in the protocol. The same lesion had to be biopsied sequentially. * Screening tumor biopsy had to fulfill the tissue quality criteria outlined in the protocol, as assessed by a local pathologist. Key inclusion criteria for Arm 1A: * Histologically confirmed unresectable or metastatic stage IIIB/C/D or IV melanoma according to AJCC Edition 8. * Previously treated for unresectable or metastatic melanoma: * All subjects had to have received anti-PD-1 checkpoint inhibitor therapy (i.e., pembrolizumab or nivolumab) either as monotherapy or in combination with ipilimumab as the last systemic therapy prior to enrollment and had to have confirmed disease progression as per RECIST v1.1 (confirmed on a subsequent scan, which could be the scan performed during screening) while on or after this therapy prior to enrollment. * Subjects with V600BRAF wild-type disease had to have received no more than 2 prior systemic therapies, including prior anti-PD-1/PD-L1 (as monotherapy or in combination with ipilimumab). * Subjects with V600BRAF mutant disease had to have received no more than 3 prior systemic therapies, including anti-PD-1/PD-L1 (as monotherapy or in combination with ipilimumab) and V600BRAF inhibitor (as monotherapy or in combination with a MEK inhibitor). * The last dose of anti-PD-1-based therapy had to have been received more than four weeks prior to the first dose of study treatment. * The last documented disease progression had to have occurred within 12 weeks prior to the first dose of study treatment. * No additional systemic treatment was allowed for advanced or metastatic melanoma (this included, for example, tumor-infiltrating lymphocyte therapy). * ECOG performance status 0-1. * At least one measurable lesion per RECIST v1.1. * Subjects had to have a baseline tumor sample that was positive for LAG-3 per central assessment. Key
Exclusion criteria
common to all combination arms: * Subjects with uveal or mucosal melanoma. * Presence of clinically active or unstable brain metastasis at the time of screening. * Use of any live vaccines against infectious diseases within 3 months before randomization/enrollment. * Active infection requiring systemic antibiotic therapy at the time of randomization/enrollment. * Subjects with a condition requiring systemic treatment with either corticosteroids (\>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of randomization/enrollment. Inhaled or topical steroids, and adrenal replacement steroid doses \>10 mg daily prednisone equivalent, were permitted in the absence of active autoimmune disease. * Active, known or suspected autoimmune disease or a documented history of autoimmune disease. * Prior allogenic bone marrow or solid organ transplant. * History of known hypersensitivity to any of the investigational drugs used in this study. * Malignant disease, other than that being treated in this study. * Prior systemic therapy for unresectable or metastatic melanoma with any investigational agent or with any other agent except anti-PD-1/PD-L1 and anti-CTLA-4 (and V600BRAF and MEK inhibitors if the subject has V600BRAF mutant disease). Prior neoadjuvant and/or adjuvant therapy for melanoma completed less than 6 months before the start of the study treatment. * Medical history or current diagnosis of myocarditis. * Cardiac Troponin T (or Troponin I) level \> 2 x ULN at screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) | Up to 49 months (randomized section) and 18 months (non-randomized section) | ORR defined as the percentage of patients with a best overall response of either confirmed complete response (CR) or partial response (PR) as per local review by Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) and assessed by computed tomography (CT)/ magnetic resonance imaging (MRI). CR:Disappearance of all non-nodal target and non-target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | From randomization (or start of treatment for non-randomized section) to death due to any cause, assessed up to 49 months (randomized section) and 24 months (non-randomized section) | OS was defined as the time from date of randomization (or date of first dose of study treatment in non-randomized part) to date of death due to any cause. The OS distribution was estimated using the Kaplan-Meier method, and the medians and 95% confidence intervals of the medians were presented. |
| Progression Free Survival (PFS) | From randomization (or start of treatment for non-randomized section) to disease progression or death due to any cause, whichever occurs first, assessed up to 49 months (randomized section) and 18 months (non-randomized section) | PFS was defined as the time between the date of randomization (or date of first dose of study treatment in non-randomized section) to the date of event defined as the first documented disease progression (as per local review by RECIST v1.1 and assessed by CT/MRI) or death due to any cause. If a subject had not had an event before leaving study or initiation of subsequent anticancer therapy, PFS was censored at the date of last adequate tumor assessment. The PFS distribution was estimated using the Kaplan-Meier method, medians and 95% confidence interval of the medians were presented. |
| Disease Control Rate (DCR) | Up to 49 months (randomized section) and 18 months (non-randomized section) | DCR was defined as the percentage of participants with best overall response of CR, PR or stable disease (SD) (as per local review by RECIST v1.1 and assessed by CT/MRI). CR:Disappearance of all non-nodal target and non-target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. SD: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease. |
| Percentage of Participants With PDR001 Anti-drug Antibodies (ADA) Positive Result at Baseline | At Baseline | Percentage of participants who had a PDR001 ADA positive result at baseline. |
| Percentage of Participants With LAG525 Anti-drug Antibodies (ADA) Positive Result at Baseline | At Baseline | Percentage of participants who had a LAG525 ADA positive result at baseline. Only applicable for participants enrolled in Arm 1 and Arm 1A. |
| Duration of Response (DOR) | From first documented response to disease progression or death due to any cause, whichever occurs first, assessed up to 49 months (randomized part) and 18 months (non-randomized part) | DOR defined as the time from date of first documented CR or PR to date of first documented disease progression (as per local review by RECIST v1.1 and assessed by CT/MRI) or death due to any cause. Subjects continuing without progression or death due to underlying cancer were censored at the date of their last adequate tumor assessment. CR:Disappearance of all non-nodal target and non-target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. |
| Percentage of Participants Who Were Treatment-induced ADA Positive and Treatment-boosted ADA Positive for PDR001 | Pre-infusion on Day 1 of Cycle 1, 2, 3, 4, 5, 6 and thereafter every 3 cycles until end of treatment (EOT), EOT, and 30 and 150 days post-EOT (assessed up to 49 months randomized section and 24 months non-randomized section). Cycle= 28 days | Percentage of participants who tested positive for treatment-induced ADA for PDR001 (subjects with ADA-negative sample at baseline with at least one post-baseline ADA positive sample) as well as treatment-boosted ADA for PDR001 (subjects with baseline positive ADA titre that was boosted to a 4-fold or higher-level following treatment). |
| Percentage of Participants Who Were Treatment-induced ADA Positive and Treatment-boosted ADA Positive for LAG525 | Pre-infusion on Day 1 of Cycle 1, 2, 3, 4, 5, 6 and thereafter every 3 cycles until end of treatment (EOT) and EOT (assessed up to 49 months in the randomized section and 18 months in the non-randomized section). Cycle= 28 days | Percentage of participants who tested positive for treatment-induced ADA for LAG525 (subjects with ADA-negative sample at baseline with at least one post-baseline ADA positive sample) as well as treatment-boosted ADA for LAG525 (subjects with baseline positive ADA titre that was boosted to a 4-fold or higher-level following treatment). Only applicable for subjects enrolled in Arm 1 and Arm 1A. |
| Percentage of Participants Who Were Treatment-induced ADA Positive and Treatment-boosted ADA Positive for ACZ885 | Pre-infusion on Day 1 of Cycle 1, 2, 3, 4, 5, 6 and thereafter every 3 cycles until end of treatment (EOT) and EOT (assessed up to 40 months). Cycle= 28 days | Percentage of participants who tested positive for treatment-induced ADA for ACZ885 (subjects with ADA-negative sample at baseline with at least one post-baseline ADA positive sample) as well as treatment-boosted ADA for ACZ885 (subjects with baseline positive ADA titre that was boosted to a 4-fold or higher-level following treatment). Only applicable for subjects enrolled in Arm 3. |
| Percentage of Participants With a Favorable Biomarker Profile (pFBP) | Baseline and after 3-4 weeks of treatment | Biomarker parameters included: 1) number of tumor infiltrating T cells (TIL), 2) activation level of TIL, and 3) changes in immune response gene expression signatures. For the number of TILs, an increase in tumoral CD8+ cell numbers compared to baseline was considered favorable. The activation level of TIL was assessed by the percentage of tumoral CD8+ cells expressing GzmB (a marker for cytotoxic activity) or Ki67 (a marker for cell proliferation), where an increase in either GZMB+/CD8+ or KI67+/CD8+ post-baseline was considered favorable. Changes in immune response gene expression signatures were evaluated by the levels in T-cell inflamed signature (TIS), where an increase from baseline was considered favorable. To be categorized as having a pFBP, a subject must meet the favorable criteria for at least two of the three biomarker parameters. The percentage of participants with pFBP was assessed. |
| Percentage of Participants With ACZ885 Anti-drug Antibodies (ADA) Positive Result at Baseline | At Baseline | Percentage of participants who had an ACZ885 ADA positive result at baseline. Only applicable for subjects enrolled in Arm 3. |
Countries
Australia, Canada, France, Germany, Italy, Netherlands, Spain, Switzerland, United Kingdom, United States
Participant flow
Recruitment details
None of the arms were opened in the extension part.
Pre-assignment details
The screening period began once written informed consent was provided and ended after 28 days (or after 35 days for subjects screened for Arm 1A) or when subject was randomized/enrolled, whichever came first. 1 participant randomized to Arm 3 discontinued before study treatment due to an AE.
Participants by arm
| Arm | Count |
|---|---|
| Arm 1: LAG525 + PDR001 (Randomized Section) Participants randomized to receive LAG525 at a dosage of 600 mg administered intravenously every 4 weeks, in combination with PDR001 at a dosage of 400 mg administered intravenously every 4 weeks | 45 |
| Arm 2: INC280+PDR001 (Randomized Section) Participants randomized to receive INC280 orally at a dosage of 400 mg twice daily, in combination with PDR001 at a dosage of 400 mg administered intravenously every 4 weeks | 43 |
| Arm 3: ACZ885 + PDR001 (Randomized Section) Participants randomized to receive ACZ885 at a dosage of 300 mg administered subcutaneously every 4 weeks, in combination with PDR001 at a dosage of 400 mg administered intravenously every 4 weeks | 43 |
| Arm 4: LEE011 + PDR001 (Randomized Section) Participants randomized to receive LEE011 orally at a dosage of 600 mg once daily on Days 1-21 of a 28-day cycle, in combination with PDR001 at a dosage of 400 mg administered intravenously every 4 weeks | 44 |
| Arm 1A: LAG525 + PDR001 (Non-randomized Section) LAG-3 positive participants received LAG525 at a dosage of 600 mg administered intravenously every 4 weeks, in combination with PDR001 at a dosage of 400 mg administered intravenously every 4 weeks | 21 |
| Total | 196 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 3 | 3 | 5 | 11 | 1 |
| Overall Study | Death | 2 | 2 | 3 | 0 | 1 |
| Overall Study | Physician Decision | 6 | 7 | 6 | 3 | 2 |
| Overall Study | Progressive disease | 33 | 28 | 26 | 30 | 16 |
| Overall Study | Subject Decision | 1 | 3 | 3 | 0 | 1 |
Baseline characteristics
| Characteristic | Arm 1: LAG525 + PDR001 (Randomized Section) | Arm 2: INC280+PDR001 (Randomized Section) | Arm 3: ACZ885 + PDR001 (Randomized Section) | Arm 4: LEE011 + PDR001 (Randomized Section) | Arm 1A: LAG525 + PDR001 (Non-randomized Section) | Total |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 16 Participants | 14 Participants | 15 Participants | 16 Participants | 13 Participants | 74 Participants |
| Age, Categorical Between 18 and 65 years | 29 Participants | 29 Participants | 28 Participants | 28 Participants | 8 Participants | 122 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 4 Participants | 2 Participants | 0 Participants | 7 Participants |
| Race (NIH/OMB) White | 45 Participants | 42 Participants | 38 Participants | 42 Participants | 20 Participants | 187 Participants |
| Sex: Female, Male Female | 17 Participants | 21 Participants | 15 Participants | 14 Participants | 9 Participants | 76 Participants |
| Sex: Female, Male Male | 28 Participants | 22 Participants | 28 Participants | 30 Participants | 12 Participants | 120 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 | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk | EG014 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 5 / 45 | 14 / 45 | 18 / 26 | 3 / 43 | 11 / 43 | 19 / 29 | 3 / 42 | 15 / 42 | 15 / 24 | 3 / 44 | 11 / 44 | 19 / 30 | 1 / 21 | 4 / 21 | 7 / 14 |
| other Total, other adverse events | 40 / 45 | 5 / 45 | 0 / 0 | 42 / 43 | 6 / 43 | 0 / 0 | 32 / 42 | 5 / 42 | 0 / 0 | 44 / 44 | 9 / 44 | 0 / 0 | 18 / 21 | 2 / 21 | 0 / 0 |
| serious Total, serious adverse events | 21 / 45 | 5 / 45 | 0 / 0 | 21 / 43 | 0 / 43 | 0 / 0 | 12 / 42 | 4 / 42 | 0 / 0 | 22 / 44 | 8 / 44 | 0 / 0 | 7 / 21 | 2 / 21 | 0 / 0 |
Outcome results
Primary
Overall Response Rate (ORR)
ORR defined as the percentage of patients with a best overall response of either confirmed complete response (CR) or partial response (PR) as per local review by Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) and assessed by computed tomography (CT)/ magnetic resonance imaging (MRI). CR:Disappearance of all non-nodal target and non-target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
Time frame: Up to 49 months (randomized section) and 18 months (non-randomized section)
Population: Randomized section: All participants to whom study treatment was assigned by randomization.~Non-randomized section: All participants who received at least one dose of study treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1: LAG525 + PDR001 (Randomized Section) | Overall Response Rate (ORR) | 8.9 Percentage of participants |
| Arm 2: INC280+PDR001 (Randomized Section) | Overall Response Rate (ORR) | 4.7 Percentage of participants |
| Arm 3: ACZ885 + PDR001 (Randomized Section) | Overall Response Rate (ORR) | 4.7 Percentage of participants |
| Arm 4: LEE011 + PDR001 (Randomized Section) | Overall Response Rate (ORR) | 6.8 Percentage of participants |
| Arm 1A: LAG525 + PDR001 (Non-randomized Section) | Overall Response Rate (ORR) | 14.3 Percentage of participants |
Secondary
Disease Control Rate (DCR)
DCR was defined as the percentage of participants with best overall response of CR, PR or stable disease (SD) (as per local review by RECIST v1.1 and assessed by CT/MRI). CR:Disappearance of all non-nodal target and non-target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. SD: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease.
Time frame: Up to 49 months (randomized section) and 18 months (non-randomized section)
Population: Randomized section: All participants to whom study treatment was assigned by randomization.~Non-randomized section: All participants who received at least one dose of study treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1: LAG525 + PDR001 (Randomized Section) | Disease Control Rate (DCR) | 15.6 Percentage of participants |
| Arm 2: INC280+PDR001 (Randomized Section) | Disease Control Rate (DCR) | 16.3 Percentage of participants |
| Arm 3: ACZ885 + PDR001 (Randomized Section) | Disease Control Rate (DCR) | 18.6 Percentage of participants |
| Arm 4: LEE011 + PDR001 (Randomized Section) | Disease Control Rate (DCR) | 31.8 Percentage of participants |
| Arm 1A: LAG525 + PDR001 (Non-randomized Section) | Disease Control Rate (DCR) | 33.3 Percentage of participants |
Secondary
Duration of Response (DOR)
DOR defined as the time from date of first documented CR or PR to date of first documented disease progression (as per local review by RECIST v1.1 and assessed by CT/MRI) or death due to any cause. Subjects continuing without progression or death due to underlying cancer were censored at the date of their last adequate tumor assessment. CR:Disappearance of all non-nodal target and non-target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
Time frame: From first documented response to disease progression or death due to any cause, whichever occurs first, assessed up to 49 months (randomized part) and 18 months (non-randomized part)
Population: Randomized section: All participants to whom study treatment was assigned by randomization for whom best overall response was complete response or partial response.~Non-randomized section: All participants who received at least one dose of study treatment for whom best overall response was complete response or partial response
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1: LAG525 + PDR001 (Randomized Section) | Duration of Response (DOR) | 476 Days |
| Arm 2: INC280+PDR001 (Randomized Section) | Duration of Response (DOR) | 941.5 Days |
| Arm 3: ACZ885 + PDR001 (Randomized Section) | Duration of Response (DOR) | 617.5 Days |
| Arm 4: LEE011 + PDR001 (Randomized Section) | Duration of Response (DOR) | 217 Days |
| Arm 1A: LAG525 + PDR001 (Non-randomized Section) | Duration of Response (DOR) | 281 Days |
Secondary
Overall Survival (OS)
OS was defined as the time from date of randomization (or date of first dose of study treatment in non-randomized part) to date of death due to any cause. The OS distribution was estimated using the Kaplan-Meier method, and the medians and 95% confidence intervals of the medians were presented.
Time frame: From randomization (or start of treatment for non-randomized section) to death due to any cause, assessed up to 49 months (randomized section) and 24 months (non-randomized section)
Population: Randomized section: All participants to whom study treatment was assigned by randomization.~Non-randomized section: All participants who received at least one dose of study treatment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1: LAG525 + PDR001 (Randomized Section) | Overall Survival (OS) | 8.8 Months |
| Arm 2: INC280+PDR001 (Randomized Section) | Overall Survival (OS) | 12.1 Months |
| Arm 3: ACZ885 + PDR001 (Randomized Section) | Overall Survival (OS) | 8.7 Months |
| Arm 4: LEE011 + PDR001 (Randomized Section) | Overall Survival (OS) | 10.1 Months |
| Arm 1A: LAG525 + PDR001 (Non-randomized Section) | Overall Survival (OS) | 14.0 Months |
Secondary
Percentage of Participants Who Were Treatment-induced ADA Positive and Treatment-boosted ADA Positive for ACZ885
Percentage of participants who tested positive for treatment-induced ADA for ACZ885 (subjects with ADA-negative sample at baseline with at least one post-baseline ADA positive sample) as well as treatment-boosted ADA for ACZ885 (subjects with baseline positive ADA titre that was boosted to a 4-fold or higher-level following treatment). Only applicable for subjects enrolled in Arm 3.
Time frame: Pre-infusion on Day 1 of Cycle 1, 2, 3, 4, 5, 6 and thereafter every 3 cycles until end of treatment (EOT) and EOT (assessed up to 40 months). Cycle= 28 days
Population: Participants randomized to Arm 3 with a determinant baseline immunogenicity sample and at least one determinant post-baseline immunogenicity sample.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1: LAG525 + PDR001 (Randomized Section) | Percentage of Participants Who Were Treatment-induced ADA Positive and Treatment-boosted ADA Positive for ACZ885 | 1 Participants |
Secondary
Percentage of Participants Who Were Treatment-induced ADA Positive and Treatment-boosted ADA Positive for LAG525
Percentage of participants who tested positive for treatment-induced ADA for LAG525 (subjects with ADA-negative sample at baseline with at least one post-baseline ADA positive sample) as well as treatment-boosted ADA for LAG525 (subjects with baseline positive ADA titre that was boosted to a 4-fold or higher-level following treatment). Only applicable for subjects enrolled in Arm 1 and Arm 1A.
Time frame: Pre-infusion on Day 1 of Cycle 1, 2, 3, 4, 5, 6 and thereafter every 3 cycles until end of treatment (EOT) and EOT (assessed up to 49 months in the randomized section and 18 months in the non-randomized section). Cycle= 28 days
Population: Randomized section: Participants randomized to Arm 1 with a determinant baseline immunogenicity sample and at least one determinant post-baseline immunogenicity sample.~Non-randomized section: Participants who received at least one dose of study treatment with a determinant baseline immunogenicity sample and at least one determinant post-baseline immunogenicity sample.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1: LAG525 + PDR001 (Randomized Section) | Percentage of Participants Who Were Treatment-induced ADA Positive and Treatment-boosted ADA Positive for LAG525 | 7 Participants |
| Arm 2: INC280+PDR001 (Randomized Section) | Percentage of Participants Who Were Treatment-induced ADA Positive and Treatment-boosted ADA Positive for LAG525 | 2 Participants |
Secondary
Percentage of Participants Who Were Treatment-induced ADA Positive and Treatment-boosted ADA Positive for PDR001
Percentage of participants who tested positive for treatment-induced ADA for PDR001 (subjects with ADA-negative sample at baseline with at least one post-baseline ADA positive sample) as well as treatment-boosted ADA for PDR001 (subjects with baseline positive ADA titre that was boosted to a 4-fold or higher-level following treatment).
Time frame: Pre-infusion on Day 1 of Cycle 1, 2, 3, 4, 5, 6 and thereafter every 3 cycles until end of treatment (EOT), EOT, and 30 and 150 days post-EOT (assessed up to 49 months randomized section and 24 months non-randomized section). Cycle= 28 days
Population: Randomized section: Participants to whom study treatment was assigned by randomization with a determinant baseline immunogenicity sample and at least one determinant post-baseline immunogenicity sample.~Non-randomized section: Participants who received at least one dose of study treatment with a determinant baseline immunogenicity sample and at least one determinant post-baseline immunogenicity sample.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1: LAG525 + PDR001 (Randomized Section) | Percentage of Participants Who Were Treatment-induced ADA Positive and Treatment-boosted ADA Positive for PDR001 | 3 Participants |
| Arm 2: INC280+PDR001 (Randomized Section) | Percentage of Participants Who Were Treatment-induced ADA Positive and Treatment-boosted ADA Positive for PDR001 | 5 Participants |
| Arm 3: ACZ885 + PDR001 (Randomized Section) | Percentage of Participants Who Were Treatment-induced ADA Positive and Treatment-boosted ADA Positive for PDR001 | 3 Participants |
| Arm 4: LEE011 + PDR001 (Randomized Section) | Percentage of Participants Who Were Treatment-induced ADA Positive and Treatment-boosted ADA Positive for PDR001 | 0 Participants |
| Arm 1A: LAG525 + PDR001 (Non-randomized Section) | Percentage of Participants Who Were Treatment-induced ADA Positive and Treatment-boosted ADA Positive for PDR001 | 0 Participants |
Secondary
Percentage of Participants With ACZ885 Anti-drug Antibodies (ADA) Positive Result at Baseline
Percentage of participants who had an ACZ885 ADA positive result at baseline. Only applicable for subjects enrolled in Arm 3.
Time frame: At Baseline
Population: Participants randomized to Arm 3 with a determinant baseline immunogenicity sample for ACZ885.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1: LAG525 + PDR001 (Randomized Section) | Percentage of Participants With ACZ885 Anti-drug Antibodies (ADA) Positive Result at Baseline | 0 Participants |
Secondary
Percentage of Participants With a Favorable Biomarker Profile (pFBP)
Biomarker parameters included: 1) number of tumor infiltrating T cells (TIL), 2) activation level of TIL, and 3) changes in immune response gene expression signatures. For the number of TILs, an increase in tumoral CD8+ cell numbers compared to baseline was considered favorable. The activation level of TIL was assessed by the percentage of tumoral CD8+ cells expressing GzmB (a marker for cytotoxic activity) or Ki67 (a marker for cell proliferation), where an increase in either GZMB+/CD8+ or KI67+/CD8+ post-baseline was considered favorable. Changes in immune response gene expression signatures were evaluated by the levels in T-cell inflamed signature (TIS), where an increase from baseline was considered favorable. To be categorized as having a pFBP, a subject must meet the favorable criteria for at least two of the three biomarker parameters. The percentage of participants with pFBP was assessed.
Time frame: Baseline and after 3-4 weeks of treatment
Population: Participants who received at least one dose of treatment with an evaluable baseline tumor biopsy sample and at least one evaluable post-baseline tumor biopsy sample with evaluable results for the three biomarker parameters.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1: LAG525 + PDR001 (Randomized Section) | Percentage of Participants With a Favorable Biomarker Profile (pFBP) | 13.6 Percentage of participants |
| Arm 2: INC280+PDR001 (Randomized Section) | Percentage of Participants With a Favorable Biomarker Profile (pFBP) | 4.8 Percentage of participants |
| Arm 3: ACZ885 + PDR001 (Randomized Section) | Percentage of Participants With a Favorable Biomarker Profile (pFBP) | 6.5 Percentage of participants |
| Arm 4: LEE011 + PDR001 (Randomized Section) | Percentage of Participants With a Favorable Biomarker Profile (pFBP) | 16.7 Percentage of participants |
Secondary
Percentage of Participants With LAG525 Anti-drug Antibodies (ADA) Positive Result at Baseline
Percentage of participants who had a LAG525 ADA positive result at baseline. Only applicable for participants enrolled in Arm 1 and Arm 1A.
Time frame: At Baseline
Population: Randomized section: Participants randomized to Arm 1 with a determinant baseline immunogenicity sample for LAG525.~Non-randomized section: Participants who received at least one dose of treatment with a determinant baseline immunogenicity sample for LAG525.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1: LAG525 + PDR001 (Randomized Section) | Percentage of Participants With LAG525 Anti-drug Antibodies (ADA) Positive Result at Baseline | 3 Participants |
| Arm 2: INC280+PDR001 (Randomized Section) | Percentage of Participants With LAG525 Anti-drug Antibodies (ADA) Positive Result at Baseline | 0 Participants |
Secondary
Percentage of Participants With PDR001 Anti-drug Antibodies (ADA) Positive Result at Baseline
Percentage of participants who had a PDR001 ADA positive result at baseline.
Time frame: At Baseline
Population: Randomized section: Participants to whom study treatment was assigned by randomization with a determinant baseline immunogenicity sample for PDR001.~Non-randomized section: Participants who received at least one dose of treatment with a determinant baseline immunogenicity sample for PDR001.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1: LAG525 + PDR001 (Randomized Section) | Percentage of Participants With PDR001 Anti-drug Antibodies (ADA) Positive Result at Baseline | 1 Participants |
| Arm 2: INC280+PDR001 (Randomized Section) | Percentage of Participants With PDR001 Anti-drug Antibodies (ADA) Positive Result at Baseline | 0 Participants |
| Arm 3: ACZ885 + PDR001 (Randomized Section) | Percentage of Participants With PDR001 Anti-drug Antibodies (ADA) Positive Result at Baseline | 1 Participants |
| Arm 4: LEE011 + PDR001 (Randomized Section) | Percentage of Participants With PDR001 Anti-drug Antibodies (ADA) Positive Result at Baseline | 0 Participants |
| Arm 1A: LAG525 + PDR001 (Non-randomized Section) | Percentage of Participants With PDR001 Anti-drug Antibodies (ADA) Positive Result at Baseline | 0 Participants |
Secondary
Progression Free Survival (PFS)
PFS was defined as the time between the date of randomization (or date of first dose of study treatment in non-randomized section) to the date of event defined as the first documented disease progression (as per local review by RECIST v1.1 and assessed by CT/MRI) or death due to any cause. If a subject had not had an event before leaving study or initiation of subsequent anticancer therapy, PFS was censored at the date of last adequate tumor assessment. The PFS distribution was estimated using the Kaplan-Meier method, medians and 95% confidence interval of the medians were presented.
Time frame: From randomization (or start of treatment for non-randomized section) to disease progression or death due to any cause, whichever occurs first, assessed up to 49 months (randomized section) and 18 months (non-randomized section)
Population: Randomized section: All participants to whom study treatment was assigned by randomization.~Non-randomized section: All participants who received at least one dose of study treatment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1: LAG525 + PDR001 (Randomized Section) | Progression Free Survival (PFS) | 2.7 Months |
| Arm 2: INC280+PDR001 (Randomized Section) | Progression Free Survival (PFS) | 2.7 Months |
| Arm 3: ACZ885 + PDR001 (Randomized Section) | Progression Free Survival (PFS) | 2.7 Months |
| Arm 4: LEE011 + PDR001 (Randomized Section) | Progression Free Survival (PFS) | 2.8 Months |
| Arm 1A: LAG525 + PDR001 (Non-randomized Section) | Progression Free Survival (PFS) | 2.8 Months |
Post Hoc
All Collected Deaths
Pre-treatment: deaths collected from day of patient's informed consent to the day before the first administration of study treatment. On-treatment: deaths collected from start of treatment to 30 days after last dose of study treatment. Extended safety follow-up: deaths collected from 31 days after last dose of study treatment up to 150 days after last dose of PDR001 (if this timepoint was later than 30 days after last dose of study treatment) Post-treatment survival follow-up: deaths collected from day 151 post-last dose of PDR001 or 31 days after last dose of study treatment (whichever occurred last) up to end of study.
Time frame: Pre-treatment: up to 28/35 days (randomized/non-randomized). On-treatment: up to 49/19 months (randomized/non-randomized). Extended safety FU and Post-treatment survival FU: up to 49/24 months (randomized/non-randomized).
Population: Randomized section: All participants to whom study treatment was assigned by randomization.~Non-randomized section: All participants who received at least one dose of study treatment
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm 1: LAG525 + PDR001 (Randomized Section) | All Collected Deaths | Post-treatment survival follow-up deaths | 18 Participants |
| Arm 1: LAG525 + PDR001 (Randomized Section) | All Collected Deaths | Extended safety follow-up deaths | 14 Participants |
| Arm 1: LAG525 + PDR001 (Randomized Section) | All Collected Deaths | All deaths | 37 Participants |
| Arm 1: LAG525 + PDR001 (Randomized Section) | All Collected Deaths | On-treatment deaths | 5 Participants |
| Arm 1: LAG525 + PDR001 (Randomized Section) | All Collected Deaths | Pre-treatment deaths | 0 Participants |
| Arm 2: INC280+PDR001 (Randomized Section) | All Collected Deaths | Post-treatment survival follow-up deaths | 19 Participants |
| Arm 2: INC280+PDR001 (Randomized Section) | All Collected Deaths | All deaths | 33 Participants |
| Arm 2: INC280+PDR001 (Randomized Section) | All Collected Deaths | On-treatment deaths | 3 Participants |
| Arm 2: INC280+PDR001 (Randomized Section) | All Collected Deaths | Pre-treatment deaths | 0 Participants |
| Arm 2: INC280+PDR001 (Randomized Section) | All Collected Deaths | Extended safety follow-up deaths | 11 Participants |
| Arm 3: ACZ885 + PDR001 (Randomized Section) | All Collected Deaths | Post-treatment survival follow-up deaths | 15 Participants |
| Arm 3: ACZ885 + PDR001 (Randomized Section) | All Collected Deaths | Extended safety follow-up deaths | 15 Participants |
| Arm 3: ACZ885 + PDR001 (Randomized Section) | All Collected Deaths | All deaths | 33 Participants |
| Arm 3: ACZ885 + PDR001 (Randomized Section) | All Collected Deaths | Pre-treatment deaths | 0 Participants |
| Arm 3: ACZ885 + PDR001 (Randomized Section) | All Collected Deaths | On-treatment deaths | 3 Participants |
| Arm 4: LEE011 + PDR001 (Randomized Section) | All Collected Deaths | Extended safety follow-up deaths | 11 Participants |
| Arm 4: LEE011 + PDR001 (Randomized Section) | All Collected Deaths | Pre-treatment deaths | 0 Participants |
| Arm 4: LEE011 + PDR001 (Randomized Section) | All Collected Deaths | On-treatment deaths | 3 Participants |
| Arm 4: LEE011 + PDR001 (Randomized Section) | All Collected Deaths | Post-treatment survival follow-up deaths | 19 Participants |
| Arm 4: LEE011 + PDR001 (Randomized Section) | All Collected Deaths | All deaths | 33 Participants |
| Arm 1A: LAG525 + PDR001 (Non-randomized Section) | All Collected Deaths | Extended safety follow-up deaths | 4 Participants |
| Arm 1A: LAG525 + PDR001 (Non-randomized Section) | All Collected Deaths | On-treatment deaths | 1 Participants |
| Arm 1A: LAG525 + PDR001 (Non-randomized Section) | All Collected Deaths | All deaths | 12 Participants |
| Arm 1A: LAG525 + PDR001 (Non-randomized Section) | All Collected Deaths | Pre-treatment deaths | 0 Participants |
| Arm 1A: LAG525 + PDR001 (Non-randomized Section) | All Collected Deaths | Post-treatment survival follow-up deaths | 7 Participants |