Abstract LB004: Nivolumab (NIVO) and ipilimumab (IPI) treatment in prostate cancer with an immunogenic signature: cohort 1 of the NEPTUNES multi-centre, two-stage biomarker-selected Phase II trial
Authors: Linch Mark D. , Wong Yien Ning Sophia , Jones Robert , Sankey Peter , Josephs Debra H. , Crabb Simon J. , Staffurth John , Zarkar Anjali , White Laura , Duggan Marian , Pellizzari Giulia , Wheeler Graham , Beare Sandy , Cartwright Hayley , Linares Josep , Akarca Ayse , Quezada Sergio A. , Ensell Leah , Hartley John , Attard Gerhardt , Burr Joanna , Jayaram Anuradha , Kularatne Bihani , Kayani Mahaz , Chung Moon , Pritchard Colin C. , Freeman Alex , Haider Aiman , Marafioti Teresa 
Published: July 2021

Abstract
Background: Responses to checkpoint inhibitor (CPI) monotherapy in patients with metastatic castration resistant prostate cancer (mCRPC) have been limited. This is likely due to a “cold” tumour immune microenvironment. We hypothesised that patients with mCRPC will be more likely to respond if they have a positive immunogenic signature (ImS+). We report the response/safety for NIVO + IPI in pts with ImS+ mCRPC from cohort 1 of the NEPTUNES study.
Methods: Pts with mCRPC who progressed following ≥1 line of therapy and ImS+ were eligible. ImS+ was defined by ≥1 of the following: 1) mismatch repair deficient (MMRD) by immunohistochemistry (IHC); 2) DNA damage repair deficient (DDRD) excluding MMRD, detected by the UW-OncoPlex targeted exome sequencing assay and; 3) high tumour infiltrating lymphocytes (TILs) on multiplexed immunohistochemistry (CD4, CD8 or FoxP3+ &gt;20% nucleated cells). Treatment was NIVO 1 mg/kg + IPI 3 mg/kg Q3W for 4 doses, then NIVO 480 mg every 4 weeks. Primary endpoint was composite response rate (CRR) defined by ≥1 of the following: 1) radiological response by RECIST 1.1; 2) PSA response ≥50%; 3) conversion of circulating tumour cells (CTC) at week 9. Treatment would be deemed ineffective if the CRR was &lt;20%. Results: 50/211 pts were ImS+, and 35 patients were treated with NIVO/IPI with a median follow up of 7.2 months (range 2.1-20.5). The overall CRR was 9/35 (26%, 95%CI 12-43%). The ImS+ determinants in responding/all treated patients included MMRD (n=4/5), BRCA1/2 (n=3/4), exclusively high TILs (n=2/9) and CDK12 (n=1/7). In responders, median duration of response was 4.9 months (range 1.8-19.7). Grade 3-4 treatment-related adverse events occurred in 17/35 (49%).
Conclusions: NIVO + IPI demonstrated significant activity in biomarker selected, pre-treated pts with mCRPC. The safety profile is consistent with this dosing schedule. Accrual to expansion cohort 2 started in September 2020.
Determinants of immunogenic signature in responding patientsPatientInflammatory Infiltrate (%)MMRD (Y/N)DDRD (Y/N)TMB Mut/MBNEP-03340NN1NEP-03610NY Biallelic BRCA24NEP-0964NY Biallelic BRCA28NEP-1093Y MSH2/MSH6N14NEP-12625Y MSH2/MSH6N21NEP-13110Y PMS2/MLH1N13NEP-15920Y MSH2/MSH6Y BRCA127NEP-16525NY Biallelic CDK125NEP-06930NN1
Citation Format: Mark D. Linch, Yien Ning Sophia Wong, Robert Jones, Peter Sankey, Debra H. Josephs, Simon J. Crabb, John Staffurth, Anjali Zarkar, Laura White, Marian Duggan, Giulia Pellizzari, Graham Wheeler, Sandy Beare, Hayley Cartwright, Josep Linares, Ayse Akarca, Sergio A. Quezada, Leah Ensell, John Hartley, Gerhardt Attard, Joanna Burr, Anuradha Jayaram, Bihani Kularatne, Mahaz Kayani, Moon Chung, Colin C. Pritchard, Alex Freeman, Aiman Haider, Teresa Marafioti. Nivolumab (NIVO) and ipilimumab (IPI) treatment in prostate cancer with an immunogenic signature: cohort 1 of the NEPTUNES multi-centre, two-stage biomarker-selected Phase II trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB004.