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ENGOT-EN6/NSGO/TSR-042 A Phase 3, Randomized, Open-Label Study of - - PowerPoint PPT Presentation
ENGOT-EN6/NSGO/TSR-042 A Phase 3, Randomized, Open-Label Study of - - PowerPoint PPT Presentation
ENGOT-EN6/NSGO/TSR-042 A Phase 3, Randomized, Open-Label Study of TSR-042, an Anti-PD-1 Monoclonal Antibody, versus Investigators Choice Chemotherapy in Patients with Advanced/Recurrent Endometrial Cancer Prevalence of somatic mutations
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EORTC Annual meeting 2016 H Laken et al ➢TSR -042 demonstrated anti-tumor activity in a xenograft model in humanized mice.
➢ TSR-042 is an immunoglobulin G4 (IgG4) humanized monoclonal antibody (mAb) that binds with high affinity to PD-1, resulting in inhibition of binding to PD-L1 and PD-L2.
➢ Ongoing clinical trial of TSR-042 has been expanded to enroll patients with metastatic microsatellite instability high (MSI-H) endometrial cancer who have progressed following one or two prior chemotherapy treatments
TSR-042 (Anti-PD-1 antibody)
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Fader et al, SGO 2016 #5581: Ott et al, Pembrolizumab in Advanced Endometrial Cancer: Results from the Phase 1b KEYNOTE-028 Study *MSI status of responders are not reported but 1 patient with confirmed MSI high had PD as best response.
– Previously treated endometrial cancer patients were dosed with pembrolizumab at 10 mg/kg Q2W – Nine patients with MSI high recurrent uterine cancer enrolled with 100% having endometrioid histology – Objective RR at 20 weeks was 66.7% (2 CR, 4 PR, 1 SD and 2 patients progressed) and Immune- related PFS at 20 weeks was 77.9% – 6/9 patients remain on study drug beyond 50 weeks
Data from pembrolizumab study in 2L MSI-H endometrial cancer – Previously treated endometrial cancer patients whose tumor had PD-L1 expression were dose with pembrolizumab at 10 mg/kg Q2W – ORR = 13% (3/23), Median PFS: 1.8 months – Median OS: not reached *Data from pembrolizumab study in 2L MSS patients
Clinical Activity of Anti-PD-1 antibody In Endometrial Cancer
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TSR-042 in Endometrial Cancer
Primary objectives:
- To evaluate progression-free survival (PFS) in patients with advanced/recurrent
endometrial cancer with microsatellite instability high (MSI-H) tumors treated with TSR-042 compared with Investigator’s choice single-agent chemotherapy based on Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) confirmed by independent central review (IRC)
- To evaluate overall survival (OS) in patients with advanced/recurrent
endometrial cancer with microsatellite stable (MSS) tumors treated with TSR- 042 compared with Investigator’s choice single-agent chemotherapy
- To evaluate the safety and tolerability of TSR-042 in the MSI-H and MSS cohorts
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TSR-042 in Endometrial Cancer
Secondary objectives:
- Objective response rate (ORR) as assessed by RECIST v1.1 based on the
Investigator’s assessment in the MSI-H and MSS cohorts
- Duration of response (DOR) in the MSI-H and MSS cohorts
- OS in the MSI-H cohort
- PFS based on the Investigator’s assessment in the MSS cohort
- Change from baseline in patient-reported outcomes (PROs)
EORTC QLQ-C30, EORTC QLQ-EN24, EQ-5D-5L
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MSI-H Microsatellite instibility high n = 130 TSR-042 q 3 wkly Physician’s choice chemotherapy
1:1 Randomization
Recurrent Endometrial Cancer MSI test
N = 580
Primary End-Point: PFS
Crossover to TSR-042 Randomization 1:1
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MSI-H Microsatellite instibility high n = 130 TSR-042 q 3 wkly Physician’s choice chemotherapy MSS Microsatellite stable n = 450 TSR-042 q 3 wkly Physician’s choice chemotherapy
1:1 Randomization 1:1 Randomization
Recurrent Endometrial Cancer MSI test
N = 580
Primary End-Point: PFS
Crossover to TSR-042
Primary End-Point: OS
Randomization 1:1 Randomization 1:1
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TSR-042 in Endometrial Cancer
MSI testing: Local MSI testing results performed in certified labs can be used for enrollment. When local MSI tests are not available, central MSI testing must be completed prior to randomization. The MSI test results used for cohort assignment will be used for efficacy analysis. Tumor samples will be collected from all patients for retrospective central MSI testing by next-generation sequencing.
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TSR-042 in Endometrial Cancer
Experimental Regimen (IMP): TSR-042 500 mg IV Q3W for the first 12 weeks followed by 1000 mg TSR-042 IV Q6W for the remainder of the study. Physician’s Choice Single Agent Options: Paclitaxel 175 mg/m2 IV Q3W Pegylated Liposomal doxorubicin 40 mg/m2 IV Q4W Bevacizumab 15 mg/kg Q3W
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TSR-042 in Endometrial Cancer
Duration of treatment: Subjects receiving TSR-042 may continue for up to 2 years or until disease progression, unacceptable toxicity, patient withdrawal, Investigator’s decision, or
- death. Continued treatment with TSR-042 beyond 2 years may be considered
following discussion between the Sponsor and Investigator. Subjects receiving Investigator’s choice single-agent chemotherapy may continue until disease progression, unacceptable toxicity, patient withdrawal, Investigator’s decision, or death.
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TSR-042 in Endometrial Cancer
Main Inclusion criteria:
- Histologically or cytologically confirmed advanced and/or metastatic EC. All
endometrial cancer histologies are allowed except endometrial sarcoma
- Up to 2 lines of previous systemic therapy. Prior hormonal treatment is not
considered a line of treatment in any setting
- Documented radiological evidence of PD per RECIST v1.1, (For MSI-H patients, the
presence of measurable lesion(s) must be confirmed by central radiology review prior to randomization.
- A formalin fixed, paraffin-embedded (FFPE) tumor tissue block or unstained slides
(archival or freshly obtained) must be available for determination of MSI status.
- ECOG performance status of 0 or 1
- Patient has adequate organ function
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