Phase III randomized trial of atezolizumab in combination with - PowerPoint PPT Presentation

Phase III randomized trial of atezolizumab in combination with paclitaxel and carboplatin in women with advanced/recurrent endometrial cancer Principal Investigator: Nicoletta Colombo, Istituto Europeo di Oncologia – Milano Sponsor: Istituto di Ricerche Farmacologiche Mario Negri, Milano

Rational for Trial Design • Advanced and/or recurrent endometrial cancer has a poor prognosis with limited therapeutic options available – Combination paclitaxel and carboplatin is the standard of care with median PFS of 8-12 months. • Rational for immunotherapy – Endometrial cancers have high mutational load – POLE -mutated and MSI tumors exhibited significantly elevated TILs, higher expression of PD-1 and PD-L1; greater peritumoral T-lymphocytes compared to MSS tumors. – Mismatch-repair deficiency has increased number of mutation- associated neoantigens – Mismatch-repair deficiency is present in 20-30% endometrial cancers – Pole mutations occur in approximately 6% of endometrial cancers Howitt et al. at 2015 ASCO Annual Meeting J Clin Oncol 33, 2015 (suppl; abstr 5511) Billingsley et al. Cancer 2015

Pembrolizumab – Phase Ib trial KEYNOTE-028 evaluating RR in patients with refractory PD-L1+ solid tumors • Cohort endometrial cancer patients (N=24) • PR+SD=26% – Phase Ib trials KEYNOTE-028/016/158 evaluating RR in patients with MSI or MMR deficient solid tumors • Cohort endometrial cancer patients (N=14) • Objective response rate 46.% • Duration of response 1.9 to 22.1 months FDA 2017; Ott PA et al. JCO 2017

Study design PD Paclitaxel 175mg/m 2 carboplatin AUC 5 or 6 Maintenance placebo 1:1 placebo Stage III/IV or recurrent R endometrial cancer Paclitaxel 175mg/m 2 Maintenance atezo carboplatin AUC 5 or 6 Stratified by 1200mg atezolizumab 1200mg  Prior RT  Recurrent disease Primary Endpoints: OS, PFS and PFS in MSI  MSI Secondary Endpoints: PFS2, RR, QoL, safety Translational Endpoints: PD1, PDL1, TILs, blood based biomarkers Statistical analysis: Powered for PFS and OS in ITT population and PFS in MSI subgroup Study Duration : accrual 2 years; Follow-up : 3 years 5

Statistical Design-1 • The primary endpoints will be: • OS in ITT • PFS in the ITT population • PFS in MSI • Secondary endpoints: ORR, PFS2, safety, QoL (EORTC-QLQ-C30 and EORTC-QLQ-EN-34) • Translational endpoints: PD1, PDL1, TILs, blood based biomarkers

Statistical Design-2 – Median OS control group: 30 months – HR for OS: 0.70 – type 1 error: 1.7% - two tails (corrected for 3 tests) – Power: 80% – Accrual length: 24 months – Further follow-up: 36 months 550 patients needed to be enrolled

Statistical Design-3 • PFS hypotheses (n=550) – Median PFS control group: 8 months – HR for PFS: 0.70 – type 1 error: 1.7%, two tails (corrected for 3 tests) – Power: 80% – Accrual length: 24 months – Further follow-up: 4 months

Statistical Design-4 • PFS in MSI (n=550) – Prevalence of MSI ≈ 30% – Median PFS control group: 8 months – type 1 error: 1.7%, two tails (corrected for 3 tests) – Power: 80% – HR for PFS: < 0.60 – Accrual length: 24 months – Further follow-up: 36 months

Main Inclusion Criteria • Advanced stage III or IV, or recurrent histologically confirmed endometrial cancer, including endometrioid, serous, clear cell carcinoma. • ECOG/GOG PS < 2 • Age > 18 years • One prior line of chemotherapy with carboplatin is permitted if PFI > 6 months • Measurable and evaluable disease • Adequate bone marrow, renal, and hepatic function • Prior radiation allowed if target lesion(s) is outside of irradiated filed.

New study proposal Stefano Greggi (MITO) Sven Mahner (AGO) Advanced EC – Study on Cytoreductive Surgery • Retrospective (2005-2015) • Multicenter, oncol. ref. centres (ORC) • Mito & AGO

Endometrial Cancer – Surgical Issues SURGICAL APPROACH OVARIAN PRESERVATION LYMPHADENECTOMY ? SURGERY IN ADVANCED DISEASE CONSERVATIVE SURGERY

Pts wi with extraut. raut. disease se sprea ead: d: >50% of all deaths hs 5y OS: S: 10-20% 0% Stage ge IV ip ip 5y OS: S: <40%

Advanced + Rec. EC - Role of Cytoreductive Surgery Metanalysis 1997-09, 14 studies (N=672) Advanced N=515 Recurrent N=157 R0: each 10% increase improving OS by 9.3m P=0.04 Barlin , 2010

Cytoreductive surgery for advanced or recurrent endometrial cancer: A meta-analysis • 14 retrospective cohorts, 672 patients • Huge Heterogeneity – definition of “optimal”: < 2 cm (3 studies) vs< 1 cm (7 studies) vs no-gross residual (4 studies) – R=0 achieved in the range of 18-75% of cases – primary surgery (10 studies, 515 pts) vs for recurrent disease (4 studies; 157 pts) – Histology in primary surgery : 5 studies only UPSC and 5 studies included all histologies – Only data of adjuvant therapy in 12 studies • OS associated with complete surgical cytoreduction (each 10% increase improving survival by 9.3 months, p=0.04) Joyce N. Barlin,IshaPuri , Robert E. Bristow. Gynecol Oncol 2010

Surg. Stage IVB EC (excl. liver/extra-abd. mets) vs OC (by age/RD) ( 1:2) Case Control Study OS: Optimally debulked EC vs OC Landrum, 2009

Stage IVB EC – Retrospective Study (Japan) 21m 12m 1m Eto, 2013

Stage IVB EC – Retrospective Study (Japan) Patient/disease Characteristics Primary Primary Palliative Surgery % Chemotherapy % Care % P Median Age 59 (30-89) 58 (30-83) 73 (53-84) ECOG PS: 0-1 91 77 32 0.002 Diabetes 8 18 18 0.003 19 Hypertension 28 45 0.04 Extra-abd. mets 38 82 86 <0.001 >2 regions 9 43 54 Eto, 2013

Consensus Conference on Endometrial Cancer, 2015 Recommendation 6.4 Complete macroscopic cytoreduction and comprehensive staging is recommended in advanced endometrial cancer Level of evidence: IV Strength of recommendation: A

The management of patients with EC is probably the least uniform when compared to that for patients with other gynecological malignancies

Questionnaire to Italian NHS 283 Institutions with >20 surgical op. for gynecol. cancer/y 92% believe appropriate a surgical cytoreductive intent in advanced disease

Age 77 Diabetes Hypertension BMI: 42 Questionnaire to Italian NHS 283 Institutions with >20 surgical op. for gynecol. cancer/y Declared proportion of pts undergoing surgery with cytored. intent: 5-50%

Limitation of current evidence for upfront surgery • Bias related to the retrospective nature of the data. • Lack of good evidence regarding the impact of histological subtype and endometrioid molecular subtypes in the potential resectability and the outcome after complete resection. • Impact of adjuvant chemo/radiation therapy. • The rate of upfront complete cytoreduction is surgeon dependent.

Advanced EC Cytoreductive Surgery Survival Benefit Feasibility ? Pt Selection NACT

Advanced EC – Study on Cytoreductive Surgery • Retrospective (2005-2015) • Multicenter, oncol. ref. centres (ORC) • Eligible: Clin./intraop. FIGO Stage IIIA-B, IIIC bulky, IV i.p. • Objectives: i) to assess the therapeutic strategy adopted in ORC ii) to evaluate feasibility & compl. of cytoreductive surgery (CRS) iii) to evaluate survival predicting factors iv) to identify predictors of complete surgical cytoreduction (*) v) to evaluate the role of NACT (*) Planned analysis of TGCA subgroups

Advanced EC – Study on Cytoreductive Surgery Each participating center will be provided with a study database Centralised analysis c/o NCI - Naples Data Center

Advanced EC – Study on Cytoreductive Surgery • Ist. Naz. Tumori di Napoli • H San Raffaele, Milano • Centro Rif. Oncologico, Aviano • University, Bologna • University, Bari • University, Varese • H Civili, Bergamo • H Reggio Emilia

Advanced EC – Study on Cytoreductive Surgery • Expanding the study to other Groups • Evaluation of the “geographic” pattern of the decision - making process • If successful CRS is confirmed as the most potent prognosticator after appropriate analysis: - Definition of a score predicting R0-1 (including biomolecular grouping) • Potential subsequent prospective phase to validate

UOC Ginecologia Oncologica Segreteria ginecologia@istitutotumori.na.it 081-5903851-417 Direttore s.greggi@istitutotumori.na.it