PT  - JOURNAL ARTICLE
AU  - Julie Bauman
AU  - Howard Burris
AU  - Jeffrey Clarke
AU  - Manish Patel
AU  - Daniel Cho
AU  - Martin Gutierrez
AU  - Ricklie Julian
AU  - Aaron Scott
AU  - Pamela Cohen
AU  - Joshua Frederick
AU  - Celine Robert-Tissot
AU  - Honghong Zhou
AU  - Kinjal Mody
AU  - Karen Keating
AU  - Robert Meehan
AU  - Justin Gainor
TI  - 798 Safety, tolerability, and immunogenicity of mRNA-4157 in combination with pembrolizumab in subjects with unresectable solid tumors (KEYNOTE-603): an update
AID  - 10.1136/jitc-2020-SITC2020.0798
DP  - 2020 Nov 01
TA  - Journal for ImmunoTherapy of Cancer
PG  - A477--A477
VI  - 8
IP  - Suppl 3
4099  - http://jitc.bmj.com/content/8/Suppl_3/A477.1.short
4100  - http://jitc.bmj.com/content/8/Suppl_3/A477.1.full
SO  - J Immunother Cancer2020 Nov 01; 8
AB  - Background T-cell targeting of mutation-derived epitopes (neoantigens) has shown to drive anti-tumor responses. Immunizing patients against such neoantigens in combination with a checkpoint inhibitor (CPI) may elicit greater anti-tumor responses than CPI alone. Mutations are rarely shared between patients, thus requiring a personalized approach to vaccine design. mRNA-4157 is a lipid encapsulated mRNA based personalized cancer vaccine encoding neoantigens selected using a proprietary algorithm to induce neoantigen specific T cells and associated anti-tumor responses. This report includes updates from the mRNA-4157 Phase1(P1) study. The initial data was presented at ASCO2019.1 Methods This study evaluates the safety and efficacy of mRNA-4157 as monotherapy in patients with resected solid tumors (Part A) and in combination with pembrolizumab in patients with advanced/metastatic solid tumors (Parts B). The selected solid tumors in Part A-B includes melanoma, bladder carcinoma, HPV-negative (HPV-neg) HNSCC, NSCLC, SCLC, MSI-High (MSI-h), or TMB-High cancers. Expansion cohorts includes patients with CPI-naïve MSS-CRC and HPV-neg HNSCC (Part C) and with resected melanoma (Part D). Patients receive up to 9 cycles (Q3W) of mRNA-4157 by intramuscular injection at up to 1 mg alone (Part A) or in combination with pembrolizumab (200 mg IV Q3W, Parts B-D). Pembrolizumab is administered for two cycles before the first dose of mRNA-4157 and may continue after 9 cycles of combination. Endpoints include safety, tolerability, efficacy and biomarker assessments.Results 79 patients received mRNA-4157; 16 as monotherapy and 63 in combination with pembrolizumab. Only low grade and reversible treatment related AEs were reported. 14/16 Part A patients (3 melanoma, 11 NSCLC, 2 MSI-h CRC) remained disease free on study. 28 patients in Parts B (6 bladder, 2 HNSCC, 3 melanoma, 10 NSCLC, 2 SCLC, 4 MSI-h tumor, 1 TMB-h tumor), 27 patients in Part C (10 HNSCC and 17 MSS-CRC), and 8 patients with resected melanoma (Part D) received combination. 3 CR (1 HNSCC, 1 MSI-h CRC and 1 MSI-h prostate), and 8 PR (1 bladder, 4 HNSCC, 2 SCLC and 1 MSI-h endometrial) were observed with combination. Of 10 CPI-naïve HPV-neg HNSCC patients, the response rate was 50% (1CR, 4PR, 4SD) mPFS 9.8months, which compared favorably to published rates of ~14.6% mPFS 2.0months for pembrolizumab monotherapy.2 3 Biomarker assessments including immune gene expression profiling will be presented.Conclusions mRNA-4157 has an acceptable safety profile along with observed clinical responses in combination with pembrolizumab. Preliminary efficacy analysis from CPI-naïve relapsed/refractory HPV-neg HNSCC cohort suggests activity of this combination. Study is ongoing.Trial Registration NCT03313778Ethics Approval The study was approved by each participating sites’ local IRB.ReferencesBurris H, et al. A phase I multicenter study to assess the safety, tolerability, and immunogenicity of mRNA-4157 alone in patients with resected solid tumors and in combination with pembrolizumab in patients with unresectable solid tumors. Journal of Clinical Oncology20 May 2019;37(15):2523-2523.Seiwert T, et al. Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. Lancet Oncol 2016;17:956–65.Cohen E, et al. Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study. Lancet 2019;393:10167:156-16.