FIRST TrialFirst-line ovarian cancer treatment with Niraparib plus TSR-042

ENGOT-ov44/GINECO/First trial

A RANDOMIZED PHASE 3 COMPARING

PLATINUM AND TSR-042 (PD-L1 INHIBITOR) FOLLOWED BY

NIRAPARIB AND TSR-042 MAINTENANCE THERAPY VERSUS

ADAPTATIVE STANDARD PLATINUM-BASED TREATMENT

IN PATIENTS WITH STAGE III OR IV CANCER OF THE OVARY,

FALLOPIAN TUBE OR PERITONEUM

ENGOT model C (id NOVA & PRIMA)

Sponsor: TESARO 1L OvCaStudy (3000-01-0005)

ENGOT group leader: GINECO

What is TSR-042 ?

1185P - Safety, pharmacodynamic, and pharmacokinetic profile of TSR-042, an anti–PD–1 monoclonal antibody, in patients (pts) with advanced solid tumors

1185P - Safety, pharmacodynamic, and pharmacokinetic profile of TSR-042,

an anti–PD–1 monoclonal antibody, in patients (pts) with advanced solid

tumors

Conclusions

TSR-042 is safe and well tolerated, with a safety profile expected for an agent

targeting the PD-1 pathway, with evidence of linear PK and sustained target

engagement at administration intervals up to 6 weeks. TSR-042 showed

clinical benefit in heavily pretreated pts in the initial phase 1 study

Sachev JC et al, Ann Oncol (2017) 28 (suppl_5)

TSR-042 is an anti-PD-1 immunoglobulin G4 (IgG4) humanized

monoclonal antibody (mAb) generated using SHM-XELTM technology 2

that binds with high affinity to PD-1

PARPi + PD-L1/PD1 developmentin first-line OC

Carboplatin-paclitaxel

+ PARPi

Control arm Add or stratify ?bevacizumab

Biological Stratification factor:

Experimental armmonotherapy

+ PD-L1/PD1i

Experimental armbitherapy + PARPi & PD-L1/PD1i

NoneBRCA/HRD status/wt

SOLO1PAOLA1PRIMA

JAVELIN100IMaGYN050

FIRST Trial: Overview of the Adaptive Design

SOC*

Study Schema

SOC* SOC* + 042

1 2 3

Oral PBO NIR NIR+042

Pt population: • Stage III/IV epithelial non-mucinous OC• Inoperable disease & NACT planned,

macroscopic residual disease following primary debulking surgery

Initial Randomization1:1:2

Main

tenance T

x

SOC: Standard chemotherapy with paclitaxel/carboplatin ±bevacizumab and bevacizumab maintenance per local

Stratification factors• tRCA/HRD status (test to be determined)• Concurent use of bevacizumab• ECOG PS OR REGION?

Niraparib dose: 200 mg once dailyNo PBO for 042screening for first cycle; randomization at 2nd cycle

Primary endpoint: PFS

FIRST Trial: objectives

Primary

To compare the progression-free survival (PFS) of patients with Stage III or IV epithelial non-mucinous ovarian cancer treated with platinum-based therapy and TSR-042 followed nirapariband TSR-042 maintenance therapy or with standard platinum-based therapy

Progression will be defined by RECIST v1.1 as assessed by investigator with sensitivity analysis by a blinded independent central review committee (BIRC).

Key Secondary Overall Survival (OS), Time to Subsequent Second Treatment TSST, PRO’s, safety and tolerability

Secondary ORR, TFST, PFS2, RECIST v. 1.1 or CA-125 PFS

Exploratory To retrospectively evaluate biomarkers related to ovarian cancer, PARP inhibition and PD-1 therapy (e.g. DNA

repair pathways, immune checkpoint pathway, etc.) To assess population pharmacokinetics (PK) and immunogenicity (TSR-042 only) and measure PK parameters

for niraparib and TSR 042

FIRST Trial: Overview of the Adaptive Design

SOC*

Initial Study Schema

Design

1st Event: SOLO1 is positive in gBRCAmut pts (Q1/2 2018)

SOC* SOC* + 042

1 2 3

1 2 3 1

gBRCAmut Non-gBRCAmut(no change)

Study Design Following Change in SOC

Oral Placebo

NIR NIR+042

Main

tenance T

x

Pt population: • Stage III/IV epithelial non-mucinous OC• Inoperable disease & NACT planned,

macroscopic residual disease following primary debulking surgery

Initial Randomization1:1:2

2 3

FIRST Trial: Overview of the Adaptive Design

SOC*

Initial Study Schema

Design

1st Event: SOLO1 is positive in gBRCAmut pts (Q1 2018)

Scenario 2

Pos in HRD+ pts

SOC* SOC* + 042

1 2 3

1 2 3 1

HRD+ HRD-

Scenario 1

Pos in all pts

No change to gBRCAmut pts regardless of

PAOLA1/PRIMA

gBRCAmut Non-gBRCAmut(no change)

Study Design Following Change in SOC

Scenario 3:

Neg in all pts

Oral Placebo

NIR NIR+042

Main

tenance T

x

Pt population: • Stage III/IV epithelial non-mucinous OC• Inoperable disease & NACT planned,

macroscopic residual disease following primary debulking surgery

Initial Randomization1:1:2

2 3

2nd Event: PAOLA1 and/or PRIMA Results (H1 2019)

1 2 3

Non-gBRCAmut Non-gBRCAmut

1 2 3

21 3 21 3

FIRST Trial: Overview of the Adaptive Design

Randomization ratio (Arm 1: Arm 2: Arm 3) Initial: 1:1:2 (to increase patient interest) Final: 1:1 (SOC versus Arm 3)

ITT population (all randomized/treated pts) versus modified ITT population (randomized/treated final control pts)

ITT rationale: gold standard in randomized trials

mITT rationale

– When SOC changes, SOC control arm will be adapted and pts in the obsolete control arm will be notified and discontinued from study treatment to pursue new SOC

It will be required a maximum of 700 patients to detect a difference of median PFS of 6 months with an HR of 0.70 (up to 0.73 according to the scenario), power 90% and global alpha of 0.05

Timelines• ENGOT Group feasibility questionnaires: Nov 2017

• Steering Committee for protocol comments and aproval: Dec 2017

• FPI: June 2018