A Study of the Anti-PD1 Antibody PDR001, in Combination With Dabrafenib and Trametinib in Advanced Melanoma

Change from baseline in CD8+ cells (as determined by flow cytometry in blood samples) upon treatment with spartalizumab in combination with dabrafenib and trametinib in participants from Part 2

Time frame: Baseline, Cycle 1 Day 15 and Cycle 3 Day 1 (Part 2). Each cycle is 28 days

Population: Participants in Part 2 who received at least one dose of study treatment and with evaluable data at the pre-specified time points

Change from baseline in PD-L1 expression (as determined by immunohistochemistry in tissue samples) upon treatment with spartalizumab in combination with dabrafenib and trametinib in participants from Part 2

Time frame: Baseline, Cycle 1 Day 15 and Cycle 3 Day 1 (Part 2). Each cycle is 28 days

Population: Participants in Part 2 who received at least one dose of study treatment and with evaluable data at the pre-specified time points

Progression-free survival was defined as the time from the date of first dose to the date of the first documented radiological progression per investigator's assessment according to RECIST 1.1 or death due to any cause. The distribution of PFS was estimated using the Kaplan-Meier (KM) method. If a patient had not had an event at the time of data cut-off, progression-free survival was censored at the date of last adequate tumor assessment.

Time frame: Up to disease progression or death due to any cause, whichever occurs first, assessed up to 2.8 years (Part 3)

Population: All participants in Part 3 to whom study treatment was assigned by randomization regardless of whether or not treatment was administered.

DLT was defined as an adverse event or abnormal laboratory value that was unrelated to disease, disease progression, inter-current illness, or concomitant medications and occured within 8 weeks of treatment with spartalizumab in combination with dabrafenib and trametinib. The DLT criteria included Grade 4 hematological adverse events, Grade 4 bilirubin elevation, specific gastrointestinal adverse events, symptomatic serum amylase or lipase elevation, Grade 3 or higher hypertension, Grade 3 or higher cardiac events, Grade 2 or higher pneumonitis, Grade 3 or higher immune-related toxicities, infusion-related reactions, other clinically significant adverse events, and toxicities leading to a dosing delay of over 12 weeks. NCI CTCAE v4.03 was used for grading DLTs

Time frame: Up to 8 weeks (Part 1)

Population: Dose-Determining Set (DDS) including all subjects in Part 1 who received at least one dose of study treatment who either 1) met the minimum exposure criterion and had sufficient safety evaluations, or 2) experienced a DLT during the first 8 weeks (56 days) of spartalizumab in combination with dabrafenib and trametinib dosing.

DCR was defined as the percentage of participants with CR or PR or subjects with stable disease (SD) lasting for a duration of at least 24 weeks as per local review according to RECIST 1.1 criteria. CR: Disappearance of all non-nodal 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: Part 1: Up to 3.3 years. Part 2: Up to 3 years. Part 3: Up to 2.8 year

Population: For Part 1 and 2: all subjects to whom study treatment was assigned and who received at least one dose of any study treatment. For Part 3: all subjects to whom study treatment was assigned by randomization, regardless of whether or not treatment was administered.

DOR was defined as the time from first documented response of CR or PR to date of first documented progression or death, according to RECIST 1.1 criteria. The distribution of DOR was estimated using the KM method. CR: Disappearance of all non-nodal 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 date of first documented progression or death, up to 3.3 years (Part 1), 3 years (Part 2) and 2.8 years (Part 3)

Population: For Part 1 and 2: all subjects to whom study treatment was assigned and who received at least one dose of any study treatment for whom best overall response was CR or PR. For Part 3: all subjects to whom study treatment was assigned by randomization (regardless of whether or not treatment was administered) for whom best overall response was CR or PR.

Number of participants with dose interruptions for spartalizumab, dabrafenib and trametinib

Time frame: From baseline to end of treatment, assessed up to approximately 7 years

Population: All participants who received at least one dose of study treatment

Number of patients with dose reductions for spartalizumab, dabrafenib and trametinib

Time frame: From baseline to end of treatment, assessed up to approximately 7 years

Population: All participants who received at least one dose of study treatment

ORR was defined as the percentage of subjects with confirmed best overall response of complete response (CR) or partial response (PR), as per investigator's assessment by RECIST 1.1. CR: Disappearance of all non-nodal 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: Part 1: Up to 3.3 years. Part 2: Up to 3 years. Part 3: Up to 2.8 years

Population: For Part 1 and 2: all subjects to whom study treatment was assigned and who received at least one dose of any study treatment. For Part 3: all subjects to whom study treatment was assigned by randomization, regardless of whether or not treatment was administered.

Overall survival was defined as the time from date of randomization to date of death due to any cause

Time frame: Up to death due to any cause, assessed up to approximately 7 years

Population: All participants to whom study treatment was assigned by randomization regardless of whether or not treatment was administered.

Plasma concentration of dabrafenib immediately prior to the administration of a dose of dabrafenib.

Time frame: Pre-infusion on Day 1 of every cycle from Cycle 2 to 12, and then every 6 cycles from Cycle 18 to 36, up to 3.3 years (Part 1), 3 years (Part 2) and 2.8 years (Part 3). Cycle=28 days

Population: All subjects who provided at least one evaluable dabrafenib PK concentration at the specified time points.

Plasma concentration of trametinib immediately prior to the administration of a dose of trametinib.

Time frame: Pre-infusion on Day 1 of every cycle from Cycle 2 to 12, and then every 6 cycles from Cycle 18 to 36, up to 3.3 years (Part 1), 3 years (Part 2) and 2.8 years (Part 3). Cycle=28 days

Population: All subjects who provided at least one evaluable trametinib PK concentration at the specified time points.

The EORTC QLQ-C30 was a 30-item questionnaire that patients complete, consisting of both multi-item scales and single-item measures. It included five functional scales, three symptom scales, six single items, and a Global Health Status/Quality of Life (GHS/QoL) scale. The GHS/QoL scale had seven possible response scores ranging from 1 (very poor) to 7 (excellent), which were averaged and transformed to a 0-100 scale. A higher score on this scale indicated a better quality of life. The change from baseline in GHS/QoL scores was calculated. A positive change from baseline indicated improvement in the patient's quality of life.

Time frame: From baseline to 60 days post progression, assessed up to 2.8 years (Part 3)

Population: All participants in Part 3 to whom study treatment was assigned by randomization (regardless of whether or not treatment was administered) and with available data at the pre-specified time points

The EORTC QLQ-C30 was a patient completed 30 item questionnaire that was composed of both multi-item scales and single-item measures. These included five functional scales, three symptom scales, six single items and a global health status/QoL scale. The EORTC QLQ-C30 pain symptom scale was one of the symptom scales in the questionnaire, which measured the severity of pain experienced by the patient. The pain symptom scale consisted of two items, one measuring the severity of pain and the other measuring the use of painkillers. The items were rated on a 4-point scale ranging from 1=not at all to 4=very much. The scores for each item were summed and transformed to a 0 to 100 scale, with higher scores indicating more severe pain. The change from baseline in pain symptom scale scores was calculated. A negative change from baseline indicated improvement.

Time frame: From baseline to 60 days post progression, assessed up to 2.8 years (Part 3)

Population: All participants in Part 3 to whom study treatment was assigned by randomization (regardless of whether or not treatment was administered) and with available data at the pre-specified time points

The EORTC QLQ-C30 was a patient completed 30 item questionnaire that was composed of both multi-item scales and single-item measures. These included five functional scales, three symptom scales, six single items and a global health status/QoL scale. The EORTC QLQ-C30 physical functioning scale measured a patient's ability to carry out daily activities and tasks requiring physical exertion. It consisted of five questions asking patients to rate their level of physical functioning, with response options ranging from 1=not at all to 4=very much. The scores for each item were summed and transformed to a 0 to 100 scale, with higher scores indicating better physical functioning. The change from baseline in physical functioning scale scores was calculated. A positive change from baseline indicated improvement in physical functioning.

Time frame: From baseline to 60 days post progression, assessed up to 2.8 years (Part 3)

Population: All participants in Part 3 to whom study treatment was assigned by randomization (regardless of whether or not treatment was administered) and with available data at the pre-specified time points

The EQ-5D-5L is a standardized questionnaire used to assess health-related quality of life, and it includes a Visual Analog Scale (VAS). The VAS score is obtained by asking the individual to rate their current health status on a scale from 0 to 100, where 0 represents the worst possible health state and 100 represents the best possible health state. The change from baseline in EQ-5D-5L VAS score was calculated. A positive change from baseline indicates improvement in the health status.

Time frame: From baseline to 60 days post progression, assessed up to 2.8 years (Part 3)

Population: All participants in Part 3 to whom study treatment was assigned by randomization (regardless of whether or not treatment was administered) and with available data at the pre-specified time points

The Functional Assessment of Cancer Therapy-Melanoma (FACT-M) quality of life questionnaire was composed of the FACT-General (FACT-G) plus the Melanoma Subscale and the Melanoma Surgery Subscale, which complemented the general scale with items specific to quality of life (QoL) in melanoma. The Melanoma Subscale of FACT-M included 16 questions, with response options of 0= Not at all, 1= a little bit, 2= somewhat, 3= quite a bit and 4= very much. The FACT-M melanoma subscale score ranged from 0 to 64, with higher scores indicating a higher quality of life in relation to melanoma. The change from baseline in melanoma subscale scores was calculated. A positive change from baseline indicated improvement.

Time frame: From baseline to 60 days post progression, assessed up to 2.8 years (Part 3)

Population: All participants in Part 3 to whom study treatment was assigned by randomization (regardless of whether or not treatment was administered) and with available data at the pre-specified time points

Overall survival was defined as the time from date of randomization to date of death due to any cause. OS analysis was performed by PD-L1 subgroup (positive, negative) where a positive status was defined as having ≥ 1% expression and a negative status was defined as having \< 1% expression.

Time frame: Up to death due to any cause, assessed up to approximately 7 years

Population: All participants in Part 3 to whom study treatment was assigned by randomization (regardless of whether or not treatment was administered) with an evaluable PD-L1 assessment.

PFS was defined as the time from the date of first dose to the date of the first documented radiological progression as per investigator's assessment using RECIST 1.1 response criteria or death due to any cause. The distribution of PFS was estimated using the KM method. If a patient had not had an event at the time of data cut-off, progression-free survival was censored at the date of last adequate tumor assessment. PFS analysis was performed by PD-L1 status (positive, negative) where a positive status was defined as having ≥ 1% expression and a negative status was defined as having \< 1% expression.

Time frame: Up to disease progression or death due to any cause, up to 2.8 years (Part 3)

Population: All participants in Part 3 to whom study treatment was assigned by randomization (regardless of whether or not treatment was administered) with an evaluable PD-L1 assessment.

The EORTC QLQ-C30 was a patient completed 30 item questionnaire that was composed of both multi-item scales and single-item measures. These included five functional scales, three symptom scales, six single items and a global health status/QoL scale. The GHS/QoL scale had seven possible response scores ranging from 1 (very poor) to 7 (excellent), which were averaged and transformed to a 0-100 scale. A higher score on this scale indicated a better quality of life. The time to definitive 10 point deterioration is defined as the time from the date of randomization to the date of event, which is defined as at least 10 points relative to baseline worsening of the GHS/QoL score or death due to any cause. If a subject had not had an event, the time to deterioration was censored at the date of the last adequate assessment. The distribution was estimated using KM method.

Time frame: From baseline to date of at least 10 points relative to baseline worsening of the global health status score or death due to any cause, up to 2.8 years (Part 3)

Population: All participants in Part 3 to whom study treatment was assigned by randomization regardless of whether or not treatment was administered.

Relative dose intensity for spartalizumab, dabrafenib and trametinib computed as the ratio (expressed as percentage) of dose intensity and planned dose intensity: * Spartalizumab (PDR001) = \[Dose intensity (mg/4W) / planned dose intensity (mg/4W)\]\*100. * Trametinib and Dabrafenib = \[Dose intensity (mg/day) / planned dose intensity (mg/day)\]\*100.

Time frame: From baseline to end of treatment, assessed up to approximately 7 years

Population: All participants who received at least one dose of study treatment

Spartalizumab ADA incidence was calculated as the percentage of participants who were treatment-induced spartalizumab ADA positive (post-baseline ADA positive with ADA-negative sample at baseline) and treatment-boosted spartalizumab ADA positive (post-baseline ADA positive with titer that is at least the fold titer change greater than the ADA-positive baseline titer)

Time frame: Throughout study until 150 days after the last dose of spartalizumab, up to 3.3 years (Part 1), 3 years (Part 2) and 2.8 years (Part 3).

Population: Part 1 and 2: All subjects to whom study treatment was assigned and who received any study treatment with a determinant baseline immunogenicity sample and at least one determinant post-baseline immunogenicity sample. Part 3: All subjects randomized to spartalizumab with dabrafenib and trametinib with a determinant baseline immunogenicity sample and at least one determinant post-baseline immunogenicity sample. Determinant sample: sample that is neither ADA-inconclusive nor unevaluable

Spartalizumab ADA prevalence at baseline was calculated as the percentage of participants who had an spartalizumab ADA positive result at baseline.

Time frame: Baseline

Population: Part 1 and 2: All subjects to whom study treatment was assigned and who received any study treatment with a determinant baseline immunogenicity sample and at least one determinant post-baseline immunogenicity sample. Part 3: All subjects randomized to spartalizumab with dabrafenib and trametinib with a determinant baseline immunogenicity sample and at least one determinant post-baseline immunogenicity sample. Determinant sample: sample that is neither ADA-inconclusive nor unevaluable

Ctrough for spartalizumab refers to the serum concentration of spartalizumab immediately prior to the administration of a dose of spartalizumab on Day 1 of Cycle 2 and later cycles.

Time frame: Pre-infusion on Day 1 of each Cycle starting from Cycle 2, up to 3.3 years (Part 1), 3 years (Part 2) and 2.8 years (Part 3). Cycle=28 days

Population: All subjects who provided at least one evaluable spartalizumab PK concentration at the specified time points.