Safety and Efficacy of SGN-LIV1A Plus Pembrolizumab for Patients With Locally-Advanced or Metastatic Triple-Negative Breast Cancer

An AE was any untoward medical occurrence in a study participant administered a medicinal product and which did not necessarily have a causal relationship with the study treatment. AEs severities were graded using the NCI CTCAE v4.03; where Grade 1= mild AE, Grade 2= moderate AE, Grade 3= severe AE, and Grade 4= life-threatening consequences; urgent intervention indicated, Grade 5= indicated death related to AE.

Time frame: From start of study treatment up to 30 days for AEs (maximum exposure to any study treatment = 27 months; follow-up: AEs = maximum up to 28 months)

Population: Safety analysis set included all participants who received any amount of SGN-LIV1A or pembrolizumab. As pre-specified in the SAP, data was summarized by dose levels. Since Arm A and Arm B share the same dose levels (2.0 mg/kg and 2.5 mg/kg), these dose levels were combined across both arms.

DLT : hematologic and/or non-hematologic AE specified in protocol that is considered related to SGN-LIV or the combination and cannot be attributed to pembrolizumab alone including: any clinically significant, non-hematologic AE\>= Grade 3 according to NCI CTCAE v4.03, Grade 3 febrile neutropenia, Grade 4 thrombocytopenia or Grade 3 thrombocytopenia associated with clinically significant bleeding that required medical intervention, Grade 4 anemia unrelated to underlying disease, discontinuation during Cycle 1 due to treatment-related toxicity/ inability to receive all 3 doses of SGN-LIV (Days 1, 8, and 15) as participant not met dosing criteria (Part C only)prolonged delay (\>2 weeks) in initiating Cycle 2 due to treatment-related toxicity and Grade 5 event (death).

Time frame: Cycle 1 (up to 21 days)

Population: DLT-evaluable (DE) analysis included all treated participants in Part A who either (1) experienced a DLT or (2) received at least 75% of intended SGN-LIV1A and pembrolizumab doses and were followed for the full DLT evaluation period. This outcome measure was planned to be analyzed only in Part A and Part C arms.

In this outcome measure, number of participants with maximum post-baseline laboratory toxicity grade in any hematology parameter are reported. As per NCI-CTCAE v4.03: Grade 1= mild, Grade 2= moderate, Grade 3= severe, and Grade 4= life-threatening consequences; urgent intervention indicated; Grade 0 = within normal limits. Baseline was defined as most recent non-missing lab result before first dose. Hematology parameters evaluated: hemoglobin, leukocytes, lymphocytes, neutrophils and platelets.

Time frame: Post-baseline up to 30 days after last dose (maximum exposure to any study intervention was 27 months; follow-up = maximum up to 28 months)

Population: Safety analysis set included all participants who received any amount of SGN-LIV1A or pembrolizumab. As pre-specified in the SAP, data was summarized by dose levels. Since Arm A and Arm B share the same dose levels (2.0 mg/kg and 2.5 mg/kg), these dose levels were combined across both arms.

In this outcome measure, number of participants with maximum post-baseline laboratory toxicity grade in any serum chemistry parameters are reported. As per NCI-CTCAE v4.03: Grade 1= mild, Grade 2= moderate, Grade 3= severe, and Grade 4= life-threatening consequences; urgent intervention indicated; Grade 0 = within normal limits. Baseline was defined as most recent non-missing lab result before first dose. Serum chemistry parameters evaluated: alanine aminotransferase, albumin, alkaline phosphatase, amylase, aspartate aminotransferase, bilirubin, calcium corrected for albumin, calcium- ionized, creatinine, gamma glutamyl transferase, glucose, lipase, phosphate, potassium, sodium and urate. In this outcome measure, only those grades as rows are reported which had at least one participant for at least 1 reporting group.

Time frame: Post-baseline up to 30 days after last dose (maximum exposure to any study intervention was 27 months; follow-up = maximum up to 28 months)

Population: Safety analysis set included all participants who received any amount of SGN-LIV1A or pembrolizumab. As pre-specified in the SAP, data was summarized by dose levels. Since Arm A and Arm B share the same dose levels (2.0 mg/kg and 2.5 mg/kg), these dose levels were combined across both arms.

An adverse event (AE) was any untoward medical occurrence in a study participant administered a medicinal product and which did not necessarily have a causal relationship with the study treatment. SAEs was defined as any untoward medical occurrence that, at any dose, meets one or more of the criteria: death, life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, congenital anomaly or birth defect and other medically significant events. TEAEs were defined as newly occurring (not present at baseline) or worsened after first dose of investigational product within 30 days after last dose date or within 90 days for SAE. AEs included SAEs and all non-SAEs.

Time frame: From start of study treatment up to 30 days and up to 90 days post last dose for AEs and SAEs respectively (maximum exposure to any study treatment = 27 months; follow-up: AEs = maximum up to 28 months; SAEs = maximum up to 30 months)

Population: Safety analysis set included all participants who received any amount of SGN-LIV1A or pembrolizumab. As pre-specified in the SAP, data was summarized by dose levels. Since Arm A and Arm B share the same dose levels (2.0 mg/kg and 2.5 mg/kg), these dose levels were combined across both arms.

An AE was any untoward medical occurrence in a study participant administered a medicinal product and which did not necessarily have a causal relationship with the study treatment. SAEs was defined as any untoward medical occurrence that, at any dose, meets one or more of the criteria: death, life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, congenital anomaly or birth defect and other medically significant events. AEs included SAEs and all non-SAEs. A treatment-related AE was any untoward medical occurrence attributed to the study drug in a participant who received study drug. AEs were defined as treatment emergent if they were newly occurring or worsened following study treatment. Relatedness to study drug was assessed by the investigator.

Time frame: From start of study treatment up to 30 days and up to 90 days post last dose for AEs and SAEs respectively (maximum exposure to any study treatment = 27 months; follow-up: AEs = maximum up to 28 months; SAEs = maximum up to 30 months)

Population: Safety analysis set included all participants who received any amount of SGN-LIV1A or pembrolizumab. As pre-specified in the SAP, data was summarized by dose levels. Since Arm A and Arm B share the same dose levels (2.0 mg/kg and 2.5 mg/kg), these dose levels were combined across both arms.

ORR was defined as the percentage of participants with confirmed complete response (CR) or partial response (PR) according to RECIST v1.1. CR: disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to \<10 mm. PR: \>=30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Kaplan Meier method was used for analysis.

Time frame: From start of study treatment up to date of confirmed CR or PR (maximum up to 30 months)

Population: All treated analysis set included all participants who received any amount of SGN-LIV1A or pembrolizumab. As pre-specified in the SAP, data was summarized by dose levels. Since Arm A and Arm B share the same dose levels (2.0 mg/kg and 2.5 mg/kg), these dose levels were combined across both arms.

DCR was defined as percentage of participants with CR, PR, or stable disease (SD) per RECIST v1.1. CR: disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to \<10 mm. PR: \>=30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progression, taking as reference the smallest sum diameters while on study. Progression: at least a 20% increase in the sum of diameters of target lesions, taking as reference smallest sum on study (this includes baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 0.5 cm. Appearance of one or more new lesions. Clopper-Pearson method was used for 95% confidence interval.

Time frame: From start of study treatment up to date of CR or PR or SD (maximum up to 30 months)

Population: All treated analysis set included all participants who received any amount of SGN-LIV1A or pembrolizumab. As pre-specified in the SAP, data was summarized by dose levels. Since Arm A and Arm B share the same dose levels (2.0 mg/kg and 2.5 mg/kg), these dose levels were combined across both arms.

DOR = time from first documentation of objective response (subsequently confirmed) per investigator to first documentation of disease progression, or death due to any cause, whichever came first. CR: disappearance of all target lesions. Any pathological lymph nodes (reduction in short axis to \<10 mm). PR: \>=30% decrease in sum of diameters of target lesions, taking reference baseline sum diameters. Progression: at least a 20% increase in sum of diameters of target lesions, reference smallest sum on study (includes baseline sum if that is smallest on study). In addition to relative increase of 20%, sum must also demonstrate an absolute increase of at least 0.5 cm. Appearance of one or more new lesions. Kaplan-Meier method used for DOR evaluation. DOR was only calculated for subgroup of participants who achieved a confirmed CR or PR.

Time frame: From the date of first CR or PR until the date of the first documentation of progression or death, or censoring date, whichever came first (maximum up to 30 months)

Population: All treated analysis set: all participants who received any amount of SGN-LIV1A or pembrolizumab. As pre-specified in the SAP, data was summarized by dose levels. Since Arm A and Arm B share the same dose levels (2.0 mg/kg and 2.5 mg/kg), these dose levels were combined across both arms.

OS was defined as the time from start of study treatment to date of death due to any cause. In the absence of confirmation of death, OS was censored at the last date the participant was known to be alive. Kaplan-Meier method was used for OS evaluation.

Time frame: From start of study treatment until the date of death, or censoring date, whichever came first (maximum up to 30 months)

Population: All treated analysis set included all participants who received any amount of SGN-LIV1A or pembrolizumab. As pre-specified in the SAP, data was summarized by dose levels. Since Arm A and Arm B share the same dose levels (2.0 mg/kg and 2.5 mg/kg), these dose levels were combined across both arms.

PFS was defined as the time from start of study treatment to first documentation of disease progression based upon the disease assessment per RECISTv1.1 or clinical progression, or to death due to any cause, whichever came first. Progression: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 0.5 cm. The appearance of one or more new lesions. Kaplan-Meier method was used for PFS evaluation.

Time frame: From start of study treatment until the date of the first documentation of progression or death, or censoring date, whichever came first (maximum up to 30 months)

Population: All treated analysis set included all participants who received any amount of SGN-LIV1A or pembrolizumab. As pre-specified in the SAP, data was summarized by dose levels. Since Arm A and Arm B share the same dose levels (2.0 mg/kg and 2.5 mg/kg), these dose levels were combined across both arms.