1020O - A phase I, first-in-human, open-label, dose escalation study of MGD019, an investigational bispecific PD-1 x CTLA-4 DART® molecule in patients with advanced solid tumours

Background

MGD019 is a bispecific, Fc-bearing (IgG4) DART molecule that blocks PD-1 and CTLA-4, with increased activity on dual PD-1/CTLA-4-expressing cells. MGD019 enhances in vitro T-cell responses to levels achieved by a combination of nivolumab and ipilimumab replicas. MGD019 was well tolerated in cynomolgus monkeys, with biological evidence of CTLA-4 antagonism but a safety profile similar to PD-1 blockade alone. MGD019 may offer risk/benefit improvements vs PD-1 plus CTLA-4 combinations.

Methods

This study characterizes safety, tolerability, dose-limiting toxicities, maximum tolerated dose (MTD), PK/PD, and preliminary antitumor activity of MGD019 in patients (pts) with advanced solid tumors. Dose Escalation enrolled pts in a 3+3+3 design up to 10 mg/kg. Cohort Expansion will further characterize safety and antitumor activity per RECIST v1.1 in pts treated at the MTD/MAD.

Results

At data-cutoff, 33 pts (39% checkpoint-experienced, 3 median prior lines of therapy) were treated in Dose Escalation from 0.03 to 10 mg/kg. No MTD was defined. Treatment-related adverse events (TRAEs) occurred in 26/33 (78.8%) pts, most commonly fatigue (24%), nausea, arthralgia, pruritus, and rash (18% each). The rate of Grade ≥ 3 TRAEs was 24.2%. Immune-related SAEs included enteritis, enterocolitis, pneumonitis, and myocarditis (n=1 each). Half-life was 12 days; full on-target binding to circulating T cells sustained through trough was observed at doses ≥ 3.0 mg every 3 weeks. Among 25 response-evaluable pts, 4 objective responses were observed (microsatellite stable colorectal cancer, metastatic thymoma [both confirmed PRs], anti-PD-L1-refractory serous fallopian tube carcinoma [unconfirmed PR with >50% reduction of CA-125], and prostatic adenocarcinoma [confirmed CR with resolution of PSA]); 9 pts had stable disease. Dose-dependent ICOS upregulation on circulating CD4+ T cells was evident, consistent with CTLA-4 engagement. Potential correlative biomarkers are being investigated.

Conclusions

MGD019 has demonstrated an acceptable safety profile and encouraging early evidence of anti-tumor activity.

Clinical trial identification

NCT03761017.

Editorial acknowledgement

Legal entity responsible for the study

MacroGenics, Inc.

Funding

MacroGenics, Inc.

Disclosure

M. Sharma: Advisory/Consultancy: AbbVie; Advisory/Consultancy: Eisai; Advisory/Consultancy, Research grant/Funding (institution): Exelixis; Advisory/Consultancy: Ipsen; Advisory/Consultancy: Bayer; Research grant/Funding (institution): Astellas; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Bolt Biotherapeutics; Research grant/Funding (institution): Compugen; Research grant/Funding (institution): Coordinaton; Research grant/Funding (institution): Effector Therapeutics; Research grant/Funding (institution): Ikena; Research grant/Funding (institution): InhibRx; Research grant/Funding (institution): Klus; Research grant/Funding (institution): MacroGenics; Research grant/Funding (institution): Symphogen; Research grant/Funding (institution): Syros; Research grant/Funding (institution): Tempest Therapeutics; Research grant/Funding (institution): Tesaro; Research grant/Funding (institution): Alpine; Research grant/Funding (institution): Genmab; Research grant/Funding (institution): Celgene; Research grant/Funding (institution): Shattuck; Research grant/Funding (institution): Sapience. R.E. Sanborn: Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: AstraZeneca; Speaker Bureau/Expert testimony: Amgen; Advisory/Consultancy: Seattle Genetics; Advisory/Consultancy: Peregrine Pharmaceuticals; Advisory/Consultancy: ARIAD/Takeda; Advisory/Consultancy: Genentech/Roche; Advisory/Consultancy: Celldex; Advisory/Consultancy: AbbVie; Research grant/Funding (self): Merck; Research grant/Funding (institution): Bristol-Myers Squibb; Research grant/Funding (institution): MedImmune. G.M. Cote: Advisory/Consultancy, Research grant/Funding (institution): Agios; Advisory/Consultancy, Research grant/Funding (institution): PharmaMar; Advisory/Consultancy, Research grant/Funding (institution): Epizyme; Research grant/Funding (institution): Eisai; Research grant/Funding (institution): MacroGenics; Research grant/Funding (institution): Plexxicon; Research grant/Funding (institution): Merck KGaA; Research grant/Funding (institution): CBA; Research grant/Funding (institution): Springworks; Research grant/Funding (institution): Bayer; Research grant/Funding (institution): Boston Biomedical; Research grant/Funding (institution): Bavarian Nordic; Advisory/Consultancy, Medical Advisory Board: Chordoma Foundation; Advisory/Consultancy, Scientific Advisory Committee: Angiosarcoma AwarenessFoundation. J.C. Bendell: Research grant/Funding (institution): AbbVie; Research grant/Funding (institution): Stemcentrx; Research grant/Funding (institution): ADC Therapeutics; Research grant/Funding (institution): Agios; Research grant/Funding (institution): Arcus Biosciences; Research grant/Funding (institution): ARMO Biosciences; Research grant/Funding (institution): Array BioPharma; Research grant/Funding (institution): Arrys Therapeutics; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Bayer; Research grant/Funding (institution): BeiGene; Research grant/Funding (institution): Bellicum Pharmaceuticals; Research grant/Funding (institution): Bicycle Therapeutics; Research grant/Funding (institution): Blueprint Medicine; Research grant/Funding (institution): Boehringer Ingelheim; Research grant/Funding (institution): Boston Biomedical; Research grant/Funding (institution): BMS; Research grant/Funding (institution): CALGB; Research grant/Funding (institution): Calithera Biosciences; Research grant/Funding (institution): Celgene; Research grant/Funding (institution): Cyteir Therapeutics; Research grant/Funding (institution): CytomX; Research grant/Funding (institution): eFFECTOR Therapeutics; Research grant/Funding (institution): Eisai; Research grant/Funding (institution): Lilly; Research grant/Funding (institution): EMD Serono; Research grant/Funding (institution): Evelo Biosciences; Research grant/Funding (institution): Genentech/Roche; Research grant/Funding (institution): Five Prime Therapeutics; Research grant/Funding (institution): Forty Seven. S. Kaul: Shareholder/Stockholder/Stock options: AbbVie; Shareholder/Stockholder/Stock options: Bristol-Myers Squibb; Shareholder/Stockholder/Stock options: Johnson & Johnson; Shareholder/Stockholder/Stock options: Merck; Shareholder/Stockholder/Stock options: CVS; Shareholder/Stockholder/Stock options: Walgreens; Shareholder/Stockholder/Stock options: Abbott; Shareholder/Stockholder/Stock options: Baxter; Shareholder/Stockholder/Stock options: Boston Scientific; Shareholder/Stockholder/Stock options: Medtronics; Shareholder/Stockholder/Stock options: United Healthcare; Advisory/Consultancy: MacroGenics; Advisory/Consultancy, Travel/Accommodation/Expenses: PharmaEssentia; Advisory/Consultancy: Bristol-Myers Squibb. F. Chen: Shareholder/Stockholder/Stock options, Full/Part-time employment: MacroGenics, Inc. A. Berezhnoy: Shareholder/Stockholder/Stock options, Full/Part-time employment: MacroGenics, Inc. P. Moore, E. Bonvini: Leadership role, Shareholder/Stockholder/Stock options, Full/Part-time employment: MacroGenics, Inc. B.J. Sumrow: Shareholder/Stockholder/Stock options, Full/Part-time employment: MacroGenics, Inc. J.J. Luke: Advisory/Consultancy: TTC Oncology; Advisory/Consultancy: 7 Hills; Advisory/Consultancy, Shareholder/Stockholder/Stock options: Alphamab Oncology; Advisory/Consultancy, Shareholder/Stockholder/Stock options: Pyxis; Advisory/Consultancy, Research grant/Funding (institution): Spring bank; Advisory/Consultancy: Tempest; Advisory/Consultancy, Research grant/Funding (institution): AbbVie; Advisory/Consultancy, Travel/Accommodation/Expenses: Akrevia; Advisory/Consultancy, Research grant/Funding (institution): Algios; Advisory/Consultancy, Research grant/Funding (institution): Array; Advisory/Consultancy, Research grant/Funding (institution): Astellas; Advisory/Consultancy, Travel/Accommodation/Expenses: Bayer; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Bristol-Myers Squibb; Advisory/Consultancy: Eisai; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: EMD Serono; Advisory/Consultancy: Ideava; Advisory/Consultancy, Research grant/Funding (institution): Incyte; Advisory/Consultancy, Travel/Accommodation/Expenses: Janssen; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Merck; Advisory/Consultancy, Travel/Accommodation/Expenses: Mersana; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Novartis; Advisory/Consultancy: PTx; Advisory/Consultancy, Travel/Accommodation/Expenses: RefleXion; Advisory/Consultancy: Regeneron; Advisory/Consultancy: Rubius; Advisory/Consultancy: Silicon; Advisory/Consultancy, Research grant/Funding (institution): Tesaro; Advisory/Consultancy: Vividion; Research grant/Funding (institution): MacroGenics; Advisory/Consultancy: Arch Oncology.