KISIMA-01 trial: Safety, tolerability and immunogenicity of ATP128 with or without ezabenlimab (BI 754091) in patients with stage IV colorectal cancer – preliminary results from a phase 1b study

Background Microsatellite stable/mismatch repair proficient (MSS/MMRp) stage IV colorectal cancer (CRC) remains an area of high unmet medical need, with the vast majority not responding to anti-PD1 checkpoint inhibitors (CPI). It is believed that a cancer vaccine approach could turn such “cold” tumors into “hot” tumors. ATP128 is a single chimeric fusion protein composed of three elements essential to generate potent antitumoral cellular immunity: a proprietary cell-penetrating peptide (CPP) for antigen delivery, a proprietary Toll-like receptor (TLR)-peptide agonist with self-adjuvant properties and a modulable multi-antigenic domain (Mad), where the Mad for CRC includes3 antigens: carcinoembryonic antigen (CEA), Survivin, Achaete-scute complex homolog 2 (ASCL2). Methods KISIMA-01 is an open-label, multi-center phase 1b trial to investigate the safety, tolerability and immunogenicity of AT128 alone or in combination with the anti-PD1 ezabenlimab in patients with stage IV CRC. ATP128 is given subcutaneously every second week for the first 3 immunizations (prime) and every 4 weeks for the last 3 immunizations (boost), for a total of 6 administrations. Ezabenlimab is administered every 3 weeks starting with the first ATP128 administration. Blood and tissue samples are collected before, during and after ATP128 treatment to monitor the induction of a tumor-associated antigen-specific immune response and immune-related changes. Immunogenicity was analyzed in the peripheral blood using ELISpot, and in the tumor microenvironment by immunohistochemical assessment of tumor-infiltrating lymphocytes (TILs) into liver metastases before and during vaccination. Results Nine patients with heavily pre-treated refractory stage IV CRC received ATP128 as single agent, with 6 patients receiving at least 3 administrations, and 6 patients with stage IV CRC in maintenance after one line of chemotherapy received ATP128 in combination with ezabenlimab. ATP128 was well-tolerated with or without ezabenlimab, with only 3 CTCAE Grade 1 adverse events (AEs) related to ATP128 alone, and 6 related G1 AEs in combination with ezabenlimab reported: nausea (2), lightheadedness, rash, injection site reaction, headache, arthralgia, flatulence, and constipation. There were no discontinuations due to AEs in either arm. Dose-limiting toxicities or serious adverse events did not occur. In 2 out of 3 evaluable patients treated with ATP128 alone, a cellular immune response against at least one out of three antigens was observed as determined by IFN-γ ELISpot analyses of patient PBMCs after the 3rd vaccination. Analysis of liver metastases by immunohistochemistry indicated that all patients were positive for all 3 antigens in ATP128. Furthermore, a significant increase of CD8 T cells infiltration into the tumor parenchyma was observed after 3 vaccine administration (PreVac: 72.7±40.5 CD8/mm 2 vs PostVac: 187.7±120.8 CD8/mm 2) along with a notably higher proportion of CD45RO expressing cells within the CD4 population as compared to baseline (PreVac: 42.3±25.3% vs PostVac:52.5±14.11%). Conclusions ATP128 was well tolerated alone, as well as in combination with ezabenlimab. Preliminary analyses indicate induction of ATP128-specific immune response observable in the peripheral circulation as well as increased infiltration of TILs into liver metastases. The KISIMA-01 trial is still recruiting. Clinical trial identification NCT04046445. Legal entity responsible for the study AMAL Therapeutics. Funding AMAL Therapeutics. Disclosure S. Kopetz: Advisory / Consultancy: Roche, Redx Pharma, Jacobio, Merck, Navire Pharma, Holy Stone, Biocartis, Natera, Karyopharm Therapeutics, Repare Therapeutics, Genentech, Lilly, AstraZeneca/MedImmune, EMD Serono, Daiichi Sankyo, Amal Therapeutics, Boehringer Ingelheim, Bayer Health, Lutris, Pfizer, Amgen, Pierre Fabre, Symphogen, Novartis, Boston Biomedical, Ipsen, HalioDx. E. Van Cutsem: Advisory / Consultancy: Array, Astellas, Astrazeneca, Bayer, Beigene, Biocartis, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Daiichi, Halozyme, GSK, Incyte, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Novartis, Pierre Fabre, Roche, Servier, Sirtex, Taiho; Research grant / Funding (institution): Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Novartis, Roche, Servier. J. Mayol: Full / Part-time employment: AMAL Therapeutics, AMAL Therapeutics, AMAL Therapeutics. F. Trapani: Full / Part-time employment: Boehringer Ingelheim. T. Bogenrieder: Full / Part-time employment: AMAL Therapeutics. H. Lenz: Honoraria (self): Bayer, Merck KG, Roche; Advisory / Consultancy: Bayer, Merck KG, Roche. All other authors have declared no conflicts of interest.