Abstract CT169: A phase Ia study to evaluate RO7198457, an individualized Neoantigen Specific immunoTherapy (iNeST), in patients with locally advanced or metastatic solid tumors
Authors: Braiteh Fadi , LoRusso Patricia , Balmanoukian Ani , Klempner Sam , Camidge D R. , Hellmann Matthew , Gordon Michael , Bendell Johanna , Mueller Lars , Sabado Rachel , Twomey Patrick , Delamarre Leila , Huang Jack , Yadav Mahesh , Zhang Jingbin , McDonald Patrick , Müller Felicitas , Derhovanessian Evelyna , Türeci Özlem , Sahin Ugur , Siu Lillian 
Published: September 2020

Abstract
Background: Neoantigens arising from somatic mutations are attractive targets for cancer immunotherapy as they may be recognized as foreign by the immune system. RO7198457 is a systemically administered RNA-Lipoplex iNeST designed to stimulate T cell responses against neoantigens. A first-in-human Phase Ia study of RO7198457 was conducted in patients with locally advanced or metastatic solid tumors.
Methods: RO7198457 is manufactured on a per-patient basis and contains up to 20 patient- specific neoantigens. Nine doses of RO7198457 were administered i.v. at weekly and bi-weekly intervals during the 12-week induction stage and every 24 weeks during the maintenance stage.
Results: In total, 29 patients enrolled in cohorts with doses ranging from 25-100 μg. The most common tumor types were HR+/HER2+ breast, prostate, and ovarian cancer. The median number of prior therapies was 5 (range 1-17). 34% of patients received prior immunotherapy. Most patients had low PD-L1 expression (97% patients with &lt;5% PD-L1 expression on tumor cells, 93% patients with &lt;5% expression on immune cells). The median number of RO7198457 doses received was 6; 28% of patients discontinued due to PD prior to completing 6 weeks of therapy. The majority of adverse events (AE) were Grade 1-2. AEs occurring in ≥ 20% of patients included infusion related reaction (IRR)/cytokine release syndrome (CRS), fatigue, nausea, and diarrhea. IRR/CRS were transient and reversible and presented primarily as Grade 1-2 chills and fever. A single DLT of Grade 3 CRS occurred at the 100 μg dose level. No patients discontinued due to AEs. RO1798457 induced pulsatile release of pro-inflammatory cytokines with each dose, consistent with the innate immune agonist activity of the RNA. RO7198457-induced neoantigen specific T cell responses were observed in peripheral blood in 14/16 patients (87%) by ex vivo ELISPOT or MHC multimer analysis. MHC multimer analysis showed the induction of up to 5% neo-epitope specific CD8 T-cells with memory phenotype in the peripheral blood. RO7198457-induced T cells against multiple neoantigens detected in post-treatment tumor biopsies. Of 26 patients who underwent at least one tumor assessment, 1 patient (4%) with gastric cancer had a response (CR ongoing for ≥10 months), and 11 patients (42%) had SD.
Conclusion: RO7198457 can be manufactured for individual patients with clinically relevant turn-around times. RO7198457 has a manageable safety profile consistent with its mechanism of action, and induced strong neoantigen-specific immune responses in patients with low and intermediate mutational load tumors types. A Ph1b study in combination with atezolizumab and a randomized Ph2 study of RO7198457 in 1L melanoma patients with pembrolizumab have been initiated, and two randomized clinical trials are planned in resected lung and CRC.
Citation Format: Fadi Braiteh, Patricia LoRusso, Ani Balmanoukian, Sam Klempner, D R. Camidge, Matthew Hellmann, Michael Gordon, Johanna Bendell, Lars Mueller, Rachel Sabado, Patrick Twomey, Leila Delamarre, Jack Huang, Mahesh Yadav, Jingbin Zhang, Patrick McDonald, Felicitas Müller, Evelyna Derhovanessian, Özlem Türeci, Ugur Sahin, Lillian Siu. A phase Ia study to evaluate RO7198457, an individualized Neoantigen Specific immunoTherapy (iNeST), in patients with locally advanced or metastatic solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT169.