Study of Efficacy and Safety of NIS793 in Combination With Standard of Care (SOC) Chemotherapy in First-line Metastatic Pancreatic Ductal Adenocarcinoma (mPDAC) - daNIS-2

A dose-limiting toxicity (DLT) was defined as an adverse event or abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurred within the first cycle (i.e., 28 days or 4 weeks) of the treatment with NIS793 in combination with gemcitabine/nab-paclitaxel. The National Cancer Institute Common Terminology Criteria for Adverse events (NCI CTCAE) version 5 was used for all grading.

Overall Survival (OS) was defined as the time from date of randomization/start of treatment to date of death due to any cause. If a patient was not known to have died, survival was censored at the date of last known date patient alive.

An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a clinical investigation participant after providing written informed consent for participation in the study. Therefore, an AE may or may not be temporally or causally associated with the use of a medicinal (investigational) product.

Treatment emergent Adverse Event (TEAEs) in this study are events that started after the first dose of study treatment and until 30 days after last dose of SOC chemotherapies and up to 90 days after NIS793, whichever is later.

No dose reductions were allowed for NIS793 in the Randomized part and beyond the first 28 days period of the Safety Run-in part. Increasing the dosing interval from every 2 weeks (Q2W) to every 2 weeks (Q4W) was allowed.

Dose interruption for NIS793 was permitted if adverse drug reaction was suspected to be related to NIS793. If NIS793 was interrupted or delayed for > 8 weeks due to toxicity that was suspected to be related to treatment, study treatment was permanently discontinued.

Dose intensity was computed as the ratio of actual cumulative dose received and actual duration of exposure.

Progression-Free Survival (PFS) was defined as the time from the enrollment (run-in part) or randomization (randomized part) to the date of the first documented disease progression based on local investigator assessment as per RECIST 1.1 or date of death due to any cause, whichever occurs first. PFS was censored if no PFS event was observed before the analysis cut-off date. The censoring date was the date of the last adequate tumor assessment prior to the analysis cut-off.

Overall Response Rate (ORR) was defined as the proportion of participants with a Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) as per local review. ORR was evaluated according to RECIST 1.1. The BOR was determined from response assessments undertaken while on treatment.

Disease Control Rate (DCR) was defined as the proportion of participants with Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR), or Stable Disease (SD) or Non-CR/Non-progressive disease as per local review. DCR was evaluated according to RECIST 1.1.

Duration of Response (DOR) was defined as the duration of time between the date of first documented response (CR or PR) and the date of first documented progression or death due to any cause.

Time to Response (TTR) was defined as the duration of time between the date of enrollment (run-in part) or randomization (randomized part) and the date of first documented response of either CR or PR as per local review, which was subsequently confirmed. TTR was evaluated according to RECIST 1.1. Participants without a confirmed CR or PR were censored at the time of PFS event (i.e., disease progression or death due to any cause) for participants with a PFS event (i.e., disease progression or death due to any cause), or at the date of the last adequate tumor assessment for participants without a PFS event.

Venous whole blood samples were collected for activity-based pharmacokinetics characterization. Ctrough was listed and summarized using descriptive statistics.

Venous whole blood samples were collected for activity-based pharmacokinetics characterization. Cmax was listed and summarized using descriptive statistics.

Venous whole blood samples were collected for activity-based pharmacokinetics characterization. Tmax was listed and summarized using descriptive statistics.

In the randomized part, participants enrolled for treatment in China were assigned to more intensive PK sampling (taken into account the ability of clinical sites to comply with the instructions in the laboratory manual concerning the preparation of serum samples) to assess PK of NIS793 in Chinese participants. Venous whole blood samples were collected for activity-based pharmacokinetics characterization and Ctrough was summarized using descriptive statistics.

In the randomized part, participants enrolled for treatment in China were assigned to more intensive PK sampling (taken into account the ability of clinical sites to comply with the instructions in the laboratory manual concerning the preparation of serum samples) to assess PK of NIS793 in Chinese participants. Venous whole blood samples were collected for activity-based pharmacokinetics characterization and Cmax was summarized using descriptive statistics.

In the randomized part, participants enrolled for treatment in China were assigned to more intensive PK sampling (taken into account the ability of clinical sites to comply with the instructions in the laboratory manual concerning the preparation of serum samples) to assess PK of NIS793 in Chinese participants. Venous whole blood samples were collected for activity-based pharmacokinetics characterization and Tmax was summarized using descriptive statistics.

In the randomized part, participants enrolled for treatment in China were assigned to more intensive PK sampling (taken into account the ability of clinical sites to comply with the instructions in the laboratory manual concerning the preparation of serum samples) to assess PK of NIS793 in Chinese participants. Venous whole blood samples were collected for activity-based pharmacokinetics characterization and AUClast was summarized using descriptive statistics.

In the randomized part, participants enrolled for treatment in China were assigned to more intensive PK sampling (taken into account the ability of clinical sites to comply with the instructions in the laboratory manual concerning the preparation of serum samples) to assess PK of NIS793 in Chinese participants. Venous whole blood samples were collected and AUCtau was summarized using descriptive statistics.

For participants without intensive PK sampling, venous whole blood samples were collected for activity-based pharmacokinetics characterization. Ctrough was listed and summarized using descriptive statistics.

For Chinese participants without intensive PK sampling schedule and global participants in the randomized part, for which only sparse PK samples were collected for activity-based pharmacokinetics characterization, Cmax was listed and summarized using descriptive statistics.

For Chinese participants without intensive PK sampling schedule and global participants in the randomized part, for which only sparse PK samples were collected for activity-based pharmacokinetics characterization, Tmax was listed and summarized using descriptive statistics.

Anti-drug antibodies (ADA) against NIS793 prevalence at baseline refers to the proportion of subjects who have developed antibodies against the drug NIS793 before starting treatment. This is calculated by dividing the number of subjects with ADA-positive samples at baseline by the total number of subjects whose baseline samples were tested for ADA.

Anti-drug antibodies (ADA) against NIS793 incidence on treatment refers to the proportion of participants who developed antibodies against the drug NIS793 during the treatment period. This can be categorized into two types:

• Treatment-induced ADA positive: Participants who were ADA-negative at baseline but became ADA-positive after starting the treatment.
• Treatment-boosted ADA positive: Participants who were ADA-positive at baseline and showed a significant increase in ADA titer during the treatment.