2523 Background: T-cell targeting of mutation-derived epitopes (neoantigens) has been demonstrated 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. Methods: A phase I dose escalation study of mRNA-4157 as adjuvant monotherapy in patients with resected solid tumors (melanoma, bladder carcinoma, HPV negative HNSCC, NSCLC, SCLC, MSI-High, or TMB High cancers) and in combination with pembrolizumab in patients with advanced or metastatic cancer is being conducted to evaluate safety. mRNA-4157 is a lipid encapsulated personalized vaccine encoding multiple neoantigens selected using a proprietary algorithm designed to induce neoantigen specific T cells and associated anti-tumor responses. Patients may receive up to 9 cycles (Q3W) of mRNA-4157 by intramuscular injection (0.04 – 1 mg). In the combination arm, pembrolizumab (200 mg) is administered for two cycles prior to combination with mRNA-4157; patients may continue pembrolizumab after completion of 9 cycles of combination therapy. Primary end points include safety, tolerability, and recommended phase 2 dose. Results: 33 patients received mRNA-4157; 13 as monotherapy and 20 in combination with pembrolizumab. No DLTs were reported, and treatment related AEs have generally been of low grade and reversible, and no drug related SAEs or AEs ≥ grade 3 have been observed. Of the 13 patients on adjuvant monotherapy (3 melanoma, 8 NSCLC, 2 MSI-High), 12 patients remain disease free on study, median follow-up of 8 months. 20 patients have been treated in combination (1 TMB-high, 4 bladder, 2 HNSCC, 1 melanoma, 7 NSCLC, 2 SCLC, 3 MSI-high), 12 had progressed on prior CPI, 16 have been restaged and there are 1 CR (on pembrolizumab prior to vaccination), 2 PR, 5 SD for at least 5 combination cycles, 5 PD, 2 iuPD, and 1 patient is non-evaluable for response but remains on study. Neoantigen specific T cell responses have been detected by IFN-γ ELISpot from PBMCs. Conclusions: mRNA-4157 is safe and well tolerated at all dose levels tested. Clinical responses have been observed in combination with pembrolizumab and neoantigen-specific T cells have been induced, supporting the advancement of mRNA-4157 to phase 2. Clinical trial information: NCT03313778.

BackgroundT-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 ASCO2019.1MethodsThis 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.Results79 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 RegistrationNCT03313778Ethics ApprovalThe 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.

93 Background: T-cell targeting of mutation-derived epitopes (neoantigens) has been demonstrated 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. Methods: This is an interim report of a phase I dose escalation study of mRNA-4157 given as monotherapy in patients with resected solid tumors and in combination with pembrolizumab in patients with unresectable solid tumors. mRNA-4157 is a lipid encapsulated personalized vaccine encoding multiple neoantigens selected using a proprietary algorithm designed to induce neoantigen specific T cells and associated anti-tumor responses. Patients received up to 9 cycles (Q3W) of mRNA-4157 by IM injection (0.04 – 1 mg). In combination arm, pembrolizumab (200 mg) was administered for two cycles prior to combination with mRNA-4157 for up to 9 cycles and may continue on pembrolizumab monotherapy for up to 2 years. Results: As of 10-May-2019, 33 patients received mRNA-4157 alone or in combination. No DLTs or related SAEs or AEs ≥ grade 3 were reported. Of the 13 patients treated with monotherapy (3 melanoma, 8 NSCLC, 2 MSI-high CRC), 11 patients remain disease free on study, median follow-up of 10 months. Of the 20 patients treated in combination (1 TMB-high metastatic cutaneous squamous cell, 4 bladder, 2 HNSCC, 1 melanoma, 7 NSCLC, 2 SCLC, 3 MSI-high (CRC, prostate, endometrial), 13 had received prior CPI, 5 PRs (2 in patients previously treated with PD-1/L1 inhibitors), 6 SD, and 8 PD were reported. Neoantigen specific CD8+ T-cell responses have been detected. Conclusions: mRNA-4157 is safe and well tolerated at all dose levels tested. Clinical responses have been observed in combination with pembrolizumab and neoantigen-specific T cells have been induced, supporting the advancement of mRNA-4157 to phase 2. Clinical trial information: NCT 03739931.

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