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

Howitt et al. at 2015 ASCO Annual Meeting J Clin Oncol 33, 2015 (suppl; abstr 5511) Billingsley et al. Cancer 2015

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

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

5

Stratified by

• Prior RT
• Recurrent disease
• MSI

Primary Endpoints: OS, PFS and PFS in MSI Secondary Endpoints: PFS2, RR, QoL, safety Translational Endpoints: PD1, PDL1, TILs, blood based biomarkers

Paclitaxel 175mg/m2 carboplatin AUC 5 or 6 placebo Maintenance placebo Paclitaxel 175mg/m2 carboplatin AUC 5 or 6 atezolizumab 1200mg Maintenance atezo 1200mg

Stage III/IV or recurrent endometrial cancer

PD R 1:1

Statistical analysis: Powered for PFS and OS in ITT population and PFS in MSI subgroup Study Duration: accrual 2 years; Follow-up: 3 years

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

SURGERY IN ADVANCED DISEASE

Endometrial Cancer – Surgical Issues

LYMPHADENECTOMY SURGICAL APPROACH CONSERVATIVE SURGERY OVARIAN PRESERVATION

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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%

Barlin , 2010

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

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

Landrum, 2009

• 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

Eto, 2013 21m

Stage IVB EC – Retrospective Study (Japan)

12m 1m

Primary Surgery % Primary Chemotherapy % Palliative 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 Hypertension 19 28 45 0.04 Extra-abd. mets 38 82 86 <0.001 >2 regions 9 43 54

Eto, 2013

Stage IVB EC – Retrospective Study (Japan) Patient/disease Characteristics

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

• utcome after complete resection.
• Impact of adjuvant chemo/radiation therapy.
• The rate of upfront complete cytoreduction is

surgeon dependent.

Advanced EC Cytoreductive Surgery

Survival Benefit

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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

Each participating center will be provided with a study database Advanced EC – Study on Cytoreductive Surgery

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