Role of Dual HER-2 targeting in high grade serous endometrial cancer

Carboplatin+Paclitaxel and Trastuzumab+Pertuzumab

Prof Clare Scott and ANZGOGDr Mahesh Iddawela

Genomics and Endometrial cancer

High-grade serous adenocarcinoma of the endometrium (HGSEC)

is a rare gynaecological cancer 40-50% of uterine cancer deaths.

Genomic analysis:

1. EGF type-2 receptor (HER-2) amplification

2. PIK3CA/AKT/mTOR pathway abnormalities

3. cyclin E abnormalities [1].

[1] TCGA, Nature 2013, 497(7447):67-73

Study Total Endometrioid SerousHER-2 - HER-2 + HER-2 - HER-2 +

Halle et al 2018 790 561(88%) 80(12%) 37 (51%) 35 (49%)

Buza et al. 2013 108 70 (65%) 38 (35%)

Szumczyk et al. 2015 400 253(63%) 147(37%)

Konecny et al. 2009 279 140 (99%) 2(1%) 87( 83%) 18 (17%)

Grushko et al. 2008 234 130 (66%) 104 (44%)

Slomovotz et al. 2004 68 56 (82%) 12 (18%)

Grordon et al. 2006 86 30 (72%) 12 (28%)

Satin et al. 2002 10 2(20%) 8 (80%)

Rolitsky et al. 1999 72 57 (79%) 15 (21%)

Total 2047 1141 (70%) 348 (30%) 282 (70%) 123 (30%)

Analysis of all published HER-2 expression data in Endometrial cancer

Fader et alJCOApril 2018

Proposal – GCIG and ANZGOG – one of two “similar studies”: ROW and NRG

An International Randomized Phase III Trial of first-line Carboplatin-Paclitaxel Versus Carboplatin-Paclitaxel-Trastuzumab Versus Carboplatin-Paclitaxel-Trastuzumab-Pertuzumab in Uterine Serous Carcinomas That Overexpress Human Epidermal Growth Factor Receptor 2/neu (HER2).• Study Design:Phase 3 Randomised First-line Multi-Centre-International Study, FIGO grade III or IV disease

• Pathologic Considerations:HER2 to be defined based on Fader et al as:• HER2 3+ by IHC, • or 2+ by IHC confirmed with ISH,

HER2 scoring will be performed according to guidelines set forth by the 2007 ASCO/College of American Pathologists (ASCO-CAP) for breast cancer

First-lineEndometrialSerous/CSC HER2 3+2+/ISH+

Arm ACarboplatin AUC 5 q21Paclitaxel 175 mg/kg q21

CarboplatinPaclitaxel

Arm BCarboplatin AUC 5 q21Paclitaxel 175 mg/kg q21Trastuzumab 8mgkg then 6 mg/kg

Trastuzumab

Arm CCarboplatin AUC 5 q21Paclitaxel 175 mg/kg q21Trastuzumab 8mgkg then 6 mg/kgPertuzumab 840 mg then 420 mg

Pertuzumab

Trastuzumab maintenance till PD or toxicity

Trastuzumab maintenance till PD or toxicity+Pertuzumab

Randomisation

Synopsis

“not ethical in the US”“not possible to exclude

this arm in Europe!”

Proposal – GCIG and ANZGOG – one of two similar studies: ROW and NRG

End Points: Phase IIPrimary end point:• Progression free survival (PFS) - The time from randomization until objective radiological progression

(modified RECIST version 1.1 criteria) or death from any causeSecondary end points:

• Response rate (RR-RECIST)

• Clinical Benefit Rate (CR, PR, SD) ? Prolonged SD• Progression free survival 2 (PFS2) The time from randomization to the earliest progression event

subsequent to the progression event used for the primary PFS analysis or deathPhase II Objective

To determine based on progression free survival whether two of the three treatment arms, of first-line Carboplatin-Paclitaxel Versus Carboplatin-Paclitaxel-Trastuzumab Versus Carboplatin-Paclitaxel-Trastuzumab-Pertuzumab in Uterine Serous Carcinomas That Overexpress Human Epidermal Growth Factor Receptor 2/neu (HER2) are superior in a phase II international multi-centre trial and suitable to take forward into a Phase III international multicentre trial.

Proposal – GCIG and ANZGOG – one of two similar studies: ROW and NRG

End points: Phase IIIPrimary end point:• Progression free survival (PFS)

Secondary end point:• PFS BICR (? BICR blinded independent central review possible)

• Response rate (RR-RECIST)

• Overall Survival (OS)• Clinical Benefit Rate (CR, PR, SD)

• Progression free survival 2 (PFS2)Phase III Objective

To determine based on progression free survival which of the two winning treatment arms, of first-line Carboplatin-Paclitaxel Versus Carboplatin-Paclitaxel-Trastuzumab Versus Carboplatin-Paclitaxel-Trastuzumab-Pertuzumab in Uterine Serous Carcinomas That Overexpress Human Epidermal Growth Factor Receptor 2/neu (HER2) is superior in a phase III international multicenter trial.

Proposal – GCIG and ANZGOG – one of two similar studies: ROW and NRG

Statistics and Power calculations:1) Phase II part:The patients will be stratified for those with no residual disease (post-surgery, stage III and

no residual disease) vs. residual disease (Stage IV and incompletely debulked)Arm 1 - 27 patients, Arm 2 - 27 patients, Arm 3 - 27 patients

Total - 81

2) Phase III part: Best two arms from Phase II

Assuming 36 months recruitment and 24 months follow- up20 to 35 months improvement in PFS with the triplet

80% power and 95% confidence.

Arm 1 - 75Arm 2 - 150

Arm 3 - 150Total - 375

Proposal – GCIG and ANZGOG – one of two similar studies: ROW and NRG

Translational projectsCollection of tumour blocks/sections for translational researchHER-2/ERBB2 cellular localization

NGS for evaluating signal transduction pathways (mTOR, AKT, MAPK, PIK3CA etc)Blood collection prior to initiating treatment and at the time of progression from all patients

for ctDNA (including HER2 amplification)

Patient-derived xenografts using fresh biopsies (when available)

Quality of Life measurementThe patients will have QOL questioners prior to treatment and after 2 and 6 months after

starting treatment (FACT-G_Endometrial cancer).

Proposal – GCIG and ANZGOG – one of two similar studies: ROW and NRG

Radiotherapy considerations:First option for consideration:• Patients not having radiotherapy will be randomized to the study treatment.• Those patients requiring radiotherapy will receive chemoradiotherapy (with

cisplatin) and then commence study treatment 4-6 weeks after completion of chemoradiotherapy.

Second option for consideration:• Those patients requiring radiotherapy will receive study treatment followed

by XRT with cisplatin, with cessation of pertuzumab during cycles 2-3.

Proposal – GCIG and ANZGOG – one of two similar studies: ROW and NRG

Pathology considerations:• Testing for HER2 status would be performed on all newly diagnosed

endometrial carcinomas as soon as p53 status is clarified: • p53 strongly positive (3+) or p53 negative.

• Carcinomas testing 3+ positive for HER2 will be eligible for screening.• Carcinomas with areas testing 2+ positive, should be screened by HER2 ISH (SISH or FISH

in the 2+ area: IHC is very useful prior to ISH to guide the ISH as uterine HER2 carcinoma can be very heterogeneous).• Breast cancer guidelines have been used for uterine serous cancer in the US for the past

~10 months successfully, so with hindsight are of practical use.• Different requirements will need to be implemented in each region for first-line HER2

testing for the purposes of this trial (Roche / ANZGOG to consider outside US).• Scott Lab / WEHI Stafford Fox Rare Cancer Progam in conjunction with ANZGOG and

Gayanie Ratnayake have been collecting a training set of images (with consent)

Proposal – GCIG and ANZGOG – one of two similar studies: ROW and NRGInclusion Criteria1. Provision of informed consent prior to any study specific procedures

2. Patients must be ≥ 18 years of age

3. Female patients with histologically diagnosed endometrial serous carcinoma with HER2/neu over-expression 3+ or 2+ with gene amplification by in situ hybridization (7 gene copies or more).

4. Endometrial carcinosarcoma with over-expression of HER2 (~15% of CS)

5. FIGO grade III or IV disease

6. No prior lines of systemic chemotherapy for this cancer

7. Patients must have normal organ and bone marrow function measured within 28 days of randomisation, as defined:

8. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (see Appendix X

9. Patients must have a life expectancy ≥ 16 weeks

10. Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations

11. Formalin fixed, paraffin embedded (FFPE) tumour sample from the cancer must be made available for central testing.

12. Adequate cardiac function with cardiac ejection fraction greater than 45%

Proposal – GCIG and ANZGOG – one of two similar studies: ROW and NRG

Exclusion CriteriaPatients must not enter the study if any of the following exclusion criteria are fulfilled1. Any previous treatment with a HER2 targeted agent, including trastuzumab or pertuzumab

2. Patients with a known hypersensitivity to carboplatin, paclitaxel, trastuzumab or Pertuzumab or any of the excipients of these products

3. Other malignancy within the last 5 years except: adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS), or other solid tumours including lymphomas (without bone marrow involvement) curatively treated with no evidence of disease for ≥5 years or breast cancer curatively treated for ≥ 3 years4. Patients who have a significant history of cardiac disease, i.e., uncontrolled hypertension, unstable angina, uncontrolled congestive heart failure, or uncontrolled arrhythmias within 6 months of registration (NYHA classification III-IV).5. Patients receiving any systemic chemotherapy or radiotherapy (except for palliative reasons) within 3 weeks prior to study treatment (or a longer period depending on the defined characteristics of the agents used) (not required if no relapsed patients)