Abstract CT301: A phase Ib study to evaluate RO7198457, an individualized Neoantigen Specific immunoTherapy (iNeST), in combination with atezolizumab in patients with locally advanced or metastatic solid tumors

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, a systemically administered RNA-Lipoplex iNeST was designed to stimulate T cell responses against neoantigens. A first-in-human Phase Ib study of RO7198457, in combination with the aPD-L1 antibody atezolizumab is being conducted in patients with locally advanced or metastatic solid tumors. Methods: RO7198457 is manufactured on a per-patient basis and contains up to 20 tumor-specific neoepitopes. Nine doses of RO7198457 were administered i.v. in weekly and bi-weekly intervals during the 12-week induction stage and every 24 weeks during the maintenance stage. Atezolizumab 1200 mg was administered on Day 1 of each 21-day cycle. Results: In total, 132 patients enrolled in cohorts with doses ranging from 15-50 μg RO7198457 in combination with atezolizumab. Most common tumor types were NSCLC, TNBC, melanoma and CRC. The median number of prior therapies was 3 (range 1-11). 39% of patients received prior immunotherapy. Most patients had low levels of PD-L1 expression (93% patients with <5% PD-L1 expression on tumor cells, 79% patients with <5% expression on immune cells). The median number of RO7198457 doses received was 8; 16% 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 ≥ 15% 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. There were no DLTs. Seven patients (5%) discontinued treatment due to AEs related to study drugs. 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 37/49 (77%) patients by ex vivo ELISPOT or MHC multimer analysis. Induction of up to 6% MHC multimer-stained CD8+ T-cells with memory phenotype was observed in peripheral blood. RO7198457-induced T cells against multiple neoantigens that were detected in post-treatment tumor biopsies. Of 108 patients who underwent at least one tumor assessment, 9 responded (ORR 8%, including 1 CR) and 53 had SD (49%). Conclusion: RO7198457 in combination with atezolizumab has a manageable safety profile consistent with the mechanisms of action of the study drugs and induces significant levels of neoantigen-specific immune responses. A randomized Ph2 study of RO7198457 1L melanoma patients in combination with pembrolizumab has been initiated, and two randomized clinical trials are planned for the adjuvant treatment of patients with NSCLC and CRC. Citation Format: Juanita S. Lopez, Ross Camidge, Marco Iafolla, Sylvie Rottey, Martin Schuler, Matthew Hellmann, Ani Balmanoukian, Luc Dirix, Michael Gordon, Ryan Sullivan, Brian S. Henick, Charles Drake, Kit Wong, Patricia LoRusso, Patrick Ott, Lawrence Fong, Aglaia Schiza, Jeffery Yachnin, Christian Ottensmeier, Fadi Braiteh, Johanna Bendell, Rom Leidner, George Fisher, Guy Jerusalem, Laura Molenaar-Kuijsten, Marcus Schmidt, Scott A. Laurie, Raid Aljumaily, Achim Rittmeyer, Eelke Gort, Ignacio Melero, Lars Mueller, Rachel Sabado, Patrick Twomey, Jack Huang, Manesh Yadav, Jingbin Zhang, Felicitas Mueller, Evelyna Derhovanessian, Ugur Sahin, Özlem Türeci, Thomas Powles. A phase Ib study to evaluate RO7198457, an individualized Neoantigen Specific immunoTherapy (iNeST), in combination with atezolizumab 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 CT301.

Advances in the development of personalized neoantigen-based therapeutic cancer vaccines

“…145 ) RO7198457, also known as iNeST (RNA–lipoplex) Up to 20 Not disclosed NA Phase Ib Advanced-stage solid tumours, most commonly NSCLC, TNBC, melanoma and CRC RO7198457 alone or with atezolizumab (anti-PD-L1 antibody) NCT03289962 (ref. 137 ) Randomized phase II ctDNA-positive resected stage III NSCLC RO7198457 plus atezolizumab vs atezolizumab alone, after adjuvant chemoradiotherapy NCT04267237 Randomized phase II Advanced-stage melanoma (treatment-naive) RO7198457 plus pembrolizumab vs pembrolizumab alone NCT03815058 mRNA-4157 (lipid encapsulated RNA) Up to 20 Proprietary algorithm NA Phase I Advanced-stage solid tumours mRNA-4157 alone for patients with resected tumours or with pembrolizumab for those with unresectable tumours NCT03313778 (ref. 138 ) Phase I Resected high-risk melanoma (stage III) mRNA-4157 plus pembrolizumab NCT03897881 Not specified (DNA) Not specified Not disclosed Intramuscular TriGrid Delivery System (TDS-IM) Randomized phase I Stage II or III TNBC Vaccine vs vaccine plus durvalumab (anti-PD-L1 antibody), following SoC therapy NCT03199040 TDS-IM Phase I Resectable PDAC Vaccine alone, following surgery and adjuvant chemotherapy NCT03122106 VB10.NEO (plasmid DNA) Up to 20 NeoSELECT PharmaJet Stratis injection system Phase I/IIa Advanced-stage RCC, HNSCC, melanoma or NSCLC without a complete response to SoC immune-checkpoint inhibitor therapy VB10.NEO plus bempegaldesleukin (pegylated IL-2, a CD122-preferential IL-2 pathway agonist) NCT03548467 (ref.…”

“…In an ongoing multicentre phase I/IIa study (NCT03633110), eight patients with solid tumours with a high risk of recurrence after completion of curative-intent treatment received GEN-009 and tolerated the vaccine well, with only local injection-site discomfort reported 136 . All patients were found to have peripheral CD4 + T cell and CD8 + responses against at least one neoantigen, and 99% of all peptides stimulated T cell responses (74% induced CD8 + T cell responses and 92% induced CD4 + T cell responses) 137 . Of note, T cell responses were often sustained for more than 12 months 136 .…”

“…In a phase Ib study 137 , a personalized RNA–lipoplex neoantigen-based vaccine encoding up to 20 neoantigens (RO7198457) was tested in combination with the anti-PD-L1 antibody atezolizumab in 132 patients with advanced-stage solid tumours (NCT03289962) (Table 2 ). Circulating T cell responses to a median of 2.6 neoantigens were detected ex vivo in 77% of patients.…”

“…Circulating T cell responses to a median of 2.6 neoantigens were detected ex vivo in 77% of patients. Vaccine-specific CD8 + T cells were detected at frequencies >5% in the peripheral blood and had a T EM phenotype with high levels of PD-1 expression 137 . Vaccine-specific TCRs were also detected in post-vaccination but not in pre-vaccination tumour specimens.…”

“…Vaccine-specific TCRs were also detected in post-vaccination but not in pre-vaccination tumour specimens. The antitumour activity of RO7198475 in combination with atezolizumab was modest, with two objective responses in 28 patients (7%) with various advanced-stage solid tumours who were enrolled in the dose-escalation part of the study and objective response rates (ORRs) between 4% and 30% (8% overall) in the expansion cohorts, which comprised patients with triple-negative breast cancer, urothelial carcinoma, RCC, melanoma or NSCLC 137 . The ORRs were not higher than those expected with PD-L1 inhibition alone in these patient groups.…”