1019O - Phase I studies of Sym021, an anti-PD-1 antibody, alone and in combination with Sym022 (anti-LAG-3) or Sym023 (anti-TIM-3)

Background

Although anti-PD-(L)1 Abs are efficacious in the treatment of various cancers, only a minority of patients benefit and many eventually relapse. Therefore, combination strategies are being pursued to further improve outcome. Sym021 is a humanized, effector-function silenced anti-PD-1 IgG1 mAb. Preclinical models demonstrate that Sym021 combined with Abs targeting other checkpoints (e.g., Sym022, anti-LAG-3; Sym023, anti-TIM-3) results in enhanced immunostimulatory and antitumor activity. We present here first-in-human studies of Sym021, Sym022, and Sym023 alone and Sym021 in combination with either Sym022 or Sym023.

Methods

Safety, tolerability, and activity of single agent Sym021, Sym022, or Sym023 and combinations were evaluated at escalating doses up to 10-20 mg/kg on a Q2W schedule in patients (pts) with advanced solid tumors or lymphomas. Samples were collected for assessment of PK profiles, immunogenicity, and pharmacodynamic markers in all pts.

Results

Dose escalation studies of Sym021, 022, and 023 as single agents have been completed. The MTD was not reached for any single agent. The Sym021 dose was fixed at 3 mg/kg based on PK/PD analysis for subsequent dose escalation in combination with Sym022 or Sym023. The MTD was not reached for either combination. Number of pts treated, the most commonly observed Grade 3-4 treatment-related adverse events (TRAEs) as well as objective responses are detailed in the table below. Assessment of PK, immunogenicity, and pharmacodynamic markers is ongoing. Table: 1019O

CR, Complete response; PR, Partial response; *Unconfirmed.

Conclusions

Sym021, Sym022 and Sym023 alone and Sym021 in combination with either Sym022 or Sym023 were well tolerated with AE profiles typical of immune checkpoint inhibitors. Responses were observed with single agent Sym021 and Sym022, and with both combinations. Evaluation of the antitumor activity of Sym021+022 and Sym021+023 doublets in select tumor types post-PD-(L)1 treatment is planned.

Clinical trial identification

NCT03311412; NCT03489369; NCT03489343.

Editorial acknowledgement

Legal entity responsible for the study

Symphogen.

Funding

Symphogen.

Disclosure

N. Lakhani: Honoraria (self): Innovent Biologics; Research grant/Funding (institution): ALX Therapeutics, Ascentage, Livzon, Asana Biosciences, Beigene, Innovent Biologics, Constellation Pharma, Alexion, Ikena, Cerulean, Odonate, Forty Seven, Loxo, Macrogenics, Merck, Pfizer, Regeneron, TaiRx, Apexian, Formation Biologics, Symphogen, CytomX. A. Spreafico: Research grant/Funding (institution): Novartis, Bristol-Myers Squibb, Symphogen, AstraZeneca/MedImmune, Merck, Bayer, Surface Oncology, Northern Biologics, Janssen Oncology/Johnson & Johnson, Roche, Regeneron, Alkermes, Array Biopharma; Advisory/Consultancy: Merck, Bristol-Myers Squibb, Novartis, Oncorus, Janssen. A.W. Tolcher: Advisory/Consultancy: Nanobiotix, Pierre Fabre, Ascentage Pharma, AbbVie, EMD Serono, BioInvent, Adagene, ADC Therapeutics, Agenus, Aximmune, Bayer, Boston Biomedical, Forbius (formerly Formation Biologics), HBM Partners, Mekanistic, NBE Therapeutics, Nuvalent, Pelican, Pfizer; Research grant/Funding (institution): AbbVie, Pfizer, Syndax, Asana Biosciences, ADC Therapeutics, Adagene, Aminex, Ascentage Pharma, Arrys, CStone Pharmaceuticals, Deciphera, GlaxoSmithKline, Inhibrx, Innate Pharma, Kiromic, Mersana, Naturewise, NextCure, Nitto BioPharma, Pieris Pharmaceutic. J. Rodon: Travel/Accommodation/Expenses: European Journal of Cancer, Vall d'Hebron Institut of Oncology, Chinese University of Hong Kong, SOLTI, Elsevier, GlaxoSmithKline; Advisory/Consultancy: Novartis, Eli Lilly, Orion Pharmaceuticals, Servier Pharmaceuticals, Peptomyc, Merck Sharp & Dohme, Kelun Pharmaceutical/Klus Pharma, Spectrum Pharmaceuticals Inc, Pfizer, Roche Pharmaceuticals, Ellipses Pharma, NovellusDx, Ionctura and Molecular Partners; Research grant/Funding (self): Blueprint Pharmaceuticals, Bayer and Novartis; Honoraria (institution): Spectrum Pharmaceuticals, Tocagen, Symphogen, BioAtla, Pfizer, GenMab, CytomX, Kelun-Biotech, Takeda-Millenium, GlaxoSmithKline, Ipsen; Travel/Accommodation/Expenses: from ESMO, US Department of Defense, Louissiana State University, Hunstman Cancer Institute, Cancer Core Europe, Karolinska Cancer Institute and King Abdullah International Medical Research Center (KAIMRC), Molecular Partners. F. Janku: Research grant/Funding (self): Novartis, Genentech, BioMed Valley Discoveries, Astellas, Agios, Plexxikon, Deciphera, Piqur, Symphogen, Bristol-Myers Squibb, Asana, Upsher-Smith Laboratories; Advisory/Consultancy: Guardant Health, IFM Therapeutics, Synlogic, and Deciphera; is a paid consultant for Trovagene, Immunomet, Symphogen; Shareholder/Stockholder/Stock options: Trovagene. S.R. Chandana: Honoraria (institution): Alexo, Amgen, Apexian, Asana, Ascentage, Astellas, AstraZeneca, Beigene, Bolt Biotherapeutics, Bristol-Myers Squibb, Compugen, Coordination, Constellation, CytomX, Effector Therapeutics, Exelixis, Formation Biologics, Forty Seven, Ikena, Innovent Biologi; Advisory/Consultancy: Ipsen, JNJ, Amgen, BMS, Astellas, Dicephera, Array Biopharma. M. Oliva: Advisory/Consultancy: BMS; Advisory/Consultancy, Research grant/Funding (self): Mirati Therapeutics; Research grant/Funding (self): Nubyota; Research grant/Funding (institution): Symphogen; Travel/Accommodation/Expenses: MSD Oncology; Travel/Accommodation/Expenses: Merck. M. Sharma: Honoraria (institution): Alexo, Amgen, Apexian, Asana, Ascentage, Astellas, AstraZeneca, Beigene, Bolt Biotherapeutics, Bristol-Myers Squibb, Compugen, Coordination, Constellation, CytomX, Effector Therapeutics, Exelixis, Formation Biologics, Forty Seven, Ikena, Innovent Biologi. R.M. Abdul-Karim: Research grant/Funding (institution): Oric Pharmaceuticals, Synthorx Inc., Adagene, Gilead Sciences, Boston Biomedical, Amphivena Therapeutics Inc., Inhibrx Inc., Pfizer, BJ Bioscience Inc., Spring Bank Pharmaceuticals Inc., Petra Pharma, eFEFECTOR Therapeutics Inc., Takeda, Basilea Pharmaceutica. U.H. Hansen, L. Hansen, N.J.Ø. Skartved, T.T. Poulsen: Full/Part-time employment: Symphogen R.P. Nadal: Advisory/Consultancy, Full/Part-time employment: Symphogen. J. Lantto: Full/Part-time employment: Symphogen A/S. D.L. Wood: Advisory/Consultancy: Symphogen; Advisory/Consultancy: Forbius; Advisory/Consultancy: Tessa Therapeutics; Spouse/Financial dependant: Karyopharm. P.I. Nadler: Advisory/Consultancy, Leadership role: Forbius; Advisory/Consultancy: Symphogen; Advisory/Consultancy: Karyopharm; Advisory/Consultancy: Tessa Therapeutics. L.L. Siu: Research grant/Funding (institution): Novartis, Bristol-Myers Squibb, Pfizer, Boerhinger-Ingelheim, GlaxoSmithKline, Roche/Genentech, Karyopharm, AstraZeneca/MedImmune, Merck, Celgene, Astellas, Bayer, AbbVie, Amgen, Symphogen, Intensity Therapeutics, Mirati, Shattucks, Avid; Advisory/Consultancy: Merck, Pfizer, Celgene, AstraZeneca/MedImmune, Morphosys, Roche, Loxo, Oncorus, Symphogen, Seattle Genetics, GSK, Voronoi, Treadwell Therapeutics, Tessa, Navire, Relay Therapeutics, Rubius Therapeutics; Honoraria (institution): Arvinas; Leadership role: Treadwell therapeutics; Officer/Board of Directors: AACR.