4P - Targeting PI3K/AKT/mTOR pathway in platinum-resistant ovarian high-grade serous carcinoma: Translational analysis from the randomized phase II OCTOPUS Trial.

Background

In arm 1 of the phase II randomised OCTOPUS trial (ISRCTN16426935), no significant differences in Progression-Free Survival (PFS) or Overall Survival were observed with the addition of vistusertib (V), a dual mTORC1/2 inhibitor, to weekly paclitaxel (wP) in platinum-resistant/refractory ovarian high-grade serous carcinoma. However, preliminary immunohistochemistry (IHC) data suggested that PTEN status may be predictive of benefit of addition of V to wP. Aim: We evaluated if PTEN expression (scored using quantitative digital IHC) or specific genomic features might be predictive of V benefit. We also compared genomic profiles in archival and study entry specimens.

Methods

PTEN expression in archival samples (N=68) was scored using QuPath Histo-score (H-score; range 0-300), and compared to pathologist scoring. In archival (N=43) and study entry (N=35) samples, DNA copy number (CN) and CN signature exposure were assessed using shallow whole genome sequencing; target sequencing was performed using a custom panel (Illumina AmpliSeq).

Results

Digital quantification of PTEN status was feasible with a high correlation between QuPath and pathologist scores (r=0.94, p<0.0001 for tumour; r=0.70, p=0.009 for non-tumour). H-score variability was lower in non-tumour than in tumour cells. Patients with low PTEN tumours (defined as tumour

Conclusions

PTEN loss by IHC and high exposure to CN signature 4 both appear to be associated with longer PFS in patients treated with V+wP. Validation in further sample sets will be required.

Clinical trial identification

ISRCTN16426935 (EudraCT 2014-005221-12).

Legal entity responsible for the study

NHS Greater Glasgow and Clyde/University of Glasgow.

Funding

The study has been funded by AstraZeneca, CRUK, the Imperial/China Scholarship Councill, the NIHR Imperial Biomedical Research Centre, Ovarian Cancer Action, Imperial College London.

Disclosure

G. Giannone: Financial Interests, Personal, Other: Mylan; Financial Interests, Personal, Research Grant, ESMO Translational Fellowship: ESMO. A.R. Clamp: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Institutional, Other, research funding: AstraZeneca. R.M. Glasspool: Financial Interests, Personal, Invited Speaker: AstraZeneca, GlaxoSmithKline, Clovis Oncology; Financial Interests, Personal, Advisory Board: AstraZeneca, GlaxoSmithKline, Clovis Oncology; Financial Interests, Institutional, Other, Research funding: Clovis Oncology, Boehringer Ingelheim; Financial Interests, Personal, Other, Funding to attend virtual conferences: GlaxoSmithKline; Financial Interests, Institutional, Other, Drug Donation Scheme: GlaxoSmithKline. S. Banerjee: Financial Interests, Institutional, Other, Educational Grants: AstraZeneca, GlaxoSmithKline; Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Genmabs, Immunogen, MSD, Merck Sereno, Mersana, Oncxerna, Seagen, Shattuck Labs; Financial Interests, Personal, Invited Speaker: Amgen, AstraZeneca, Clovis, Immunogen, MSD, Mersana, Pfizer, Roche. I. McNeish: Financial Interests, Personal, Invited Speaker: AstraZeneca, GlaxoSmithKline/Tesaro, Clovis Oncology, Roche, Epsila, Takeda, Scancell, Theolytics; Financial Interests, Personal, Advisory Board: AstraZeneca, GlaxoSmithKline/Tesaro, Clovis Oncology, Roche, Epsila, Takeda, Scancell, Theolytics; Financial Interests, Institutional, Other, Institutional grant income: AstraZeneca. All other authors have declared no conflicts of interest.