4720 - Phase 1 study evaluating safety, pharmacokinetics (PK), pharmacodynamics, and preliminary efficacy of ABBV-428, first-in-class mesothelin (MSLN)-CD40 bispecific, in patients (pts) with advanced solid tumors

Background

ABBV-428 is a bispecific antibody designed for MSLN-dependent CD40 activation. Preliminary results of a phase I first-in-human, dose-escalation (DE)/dose-expansion study of ABBV-428 in pts with advanced solid tumors including pts who express MSLN at high levels are reported (NCT02955251).

Methods

Pts received ABBV-428 in a 3 + 3 DE design: 0.01–3.6 mg/kg IV doses every 2 weeks. Response was assessed per RECIST v1.1. Serial PK and biomarker samples were collected. Primary objectives were to evaluate ABBV-428 monotherapy safety, PK, and preliminary efficacy.

Results

As of 28 Feb 2019, 59 pts were enrolled in DE (≤0.4 mg/kg, n = 21; 0.8–2.4 mg/kg, n = 10; 3.6 mg/kg, n = 28). Median prior treatment (Tx): 3 (range 1.0–11.0); median Tx duration: 6.1 weeks (range 0.1–73.1). PK exhibited a dose-proportional increase with half-life value 10–17 hours (0.4–3.6 mg/kg); no accumulation was observed between cycles 1–3. Antidrug antibodies were detected across all dose levels in 64% of pts, with impact on exposure observed at dose levels <0.8 mg/kg. No DLTs occurred. Expansion dose: 3.6 mg/kg; >90% receptor occupancy did not result in serious/high-grade liver function test abnormalities or cytokine release syndrome. Transient B-cell depletion and upregulation of B-cell activation markers was observed in peripheral blood (all dose groups). Overall, 56 (94.9%) pts reported ≥1 Tx-emergent adverse event (TEAE); 36 pts reported grade ≥3 TEAE, 3 possibly related to ABBV-428. TEAEs leading to death (n = 14) were not related to ABBV-428. Of the 50 evaluable pts, none had an objective response (confirmed partial or complete response), 25 (50.0%) had stable disease (SD), and 25 (50.0%) had progressive disease. Tx is ongoing in 3 pts (all SD > 6 months).

Conclusions

Targeting the tumor microenvironment with ABBV-428 was successful in achieving immune agonism without systemic toxicity in MSLN-expressing advanced solid tumors; however, no significant clinical benefit was observed. Potential mechanisms and additional biomarker/translational findings related to these observations will be presented.

Clinical trial identification

NCT02955251.

Editorial acknowledgement

Mary L. Smith, PhD, CMPP, from Aptitude Health, Atlanta, GA, funded by AbbVie.

Legal entity responsible for the study

AbbVie Inc.

Funding

AbbVie Inc.

Disclosure

J.J. Luke: Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Array BioPharma; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck; Advisory / Consultancy, Travel / Accommodation / Expenses: EMD Serono; Advisory / Consultancy, Travel / Accommodation / Expenses: BeneVir; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Checkmate Pharmaceuticals; Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca/MedImmune; Advisory / Consultancy: 7 Hills Pharma; Advisory / Consultancy, Travel / Accommodation / Expenses: Castle Biosciences; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Actym Therapeutics; Advisory / Consultancy, Travel / Accommodation / Expenses: Gilead Sciences; Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen; Advisory / Consultancy: NewLink Genetics; Advisory / Consultancy, Travel / Accommodation / Expenses: RefleXion Medical; Advisory / Consultancy: Syndax; Advisory / Consultancy: Tempest Therapeutics; Advisory / Consultancy: TTC Oncology; Advisory / Consultancy: Alphamab; Advisory / Consultancy: Mavupharma; Advisory / Consultancy: Aduro Biotech; Advisory / Consultancy, Research grant / Funding (institution): Compugen; Advisory / Consultancy, Travel / Accommodation / Expenses: IDEAYA Biosciences; Advisory / Consultancy: Spring Bank; Advisory / Consultancy: WntRx Pharmaceuticals; Advisory / Consultancy: Jounce Therapeutics; Advisory / Consultancy: Vividion Therapeutics; Licensing / Royalties, Cancer Immunotherapy: Serial #15/612,657 ; Licensing / Royalties, Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Serial #PCT/US18/36052 ; Research grant / Funding (institution): Boston Biomedical; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Celldex; Research grant / Funding (institution): Incyte; Research grant / Funding (self): Genentech/Roche; Research grant / Funding (institution): Pharmacyclics; Research grant / Funding (institution): Five Prime Therapeutics; Research grant / Funding (institution): Corvus Pharmaceuticals; Research grant / Funding (institution): Delcath Systems; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Immunocore; Research grant / Funding (institution): MacroGenics; Research grant / Funding (institution): Tesaro; Research grant / Funding (institution): Xencor; Research grant / Funding (institution): Evelo Therapeutics; Research grant / Funding (institution): Palleon Pharmaceuticals; Research grant / Funding (institution): FLX Bio. L. Fong: Advisory / Consultancy: Atreca; Advisory / Consultancy: BioAtla; Advisory / Consultancy: Bolt; Advisory / Consultancy: IDEAYA; Advisory / Consultancy: Nutcracker; Advisory / Consultancy: Senti; Advisory / Consultancy: TeneoBio; Research grant / Funding (institution): AbbVie ; Research grant / Funding (institution): Bavarian Nordic ; Research grant / Funding (institution): Bristol-Myers Squibb ; Research grant / Funding (institution): Dendreon ; Research grant / Funding (institution): Janssen Oncology ; Research grant / Funding (institution): Merck ; Research grant / Funding (institution): OncoSec ; Research grant / Funding (institution): Roche/Genentech . K. Chung: Speaker Bureau / Expert testimony: Genentech. A.W. Tolcher: Shareholder / Stockholder / Stock options, Ownership: NEXT Oncology; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Payments for Advisory/Consultancy/Research funding are paid to NEXT Oncology: AbbVie; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Payments for Advisory/Consultancy/Research funding are paid to NEXT Oncology: ADC Therapeutics; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Payments for Advisory/Consultancy/Research funding are paid to NEXT Oncology: Adagene; Advisory / Consultancy, Travel / Accommodation / Expenses, Payments for Advisory/Consultancy/Research funding are paid to NEXT Oncology: Agenus; Advisory / Consultancy, Travel / Accommodation / Expenses, Payments for Advisory/Consultancy/Research funding are paid to NEXT Oncology: Aro Biotherapeutics; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Payments for Advisory/Consultancy/Research funding are paid to NEXT Oncology: Ascentage; 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Advisory / Consultancy, Travel / Accommodation / Expenses, Payments for Advisory/Consultancy/Research funding are paid to NEXT Oncology: Scitemex; Advisory / Consultancy, Travel / Accommodation / Expenses, Payments for Advisory/Consultancy/Research funding are paid to NEXT Oncology: Sesen; Advisory / Consultancy, Travel / Accommodation / Expenses, Payments for Advisory/Consultancy/Research funding are paid to NEXT Oncology: Seattle Genetics; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Payments for Advisory/Consultancy/Research funding are paid to NEXT Oncology: Symphogen; Advisory / Consultancy, Travel / Accommodation / Expenses, Payments for Advisory/Consultancy/Research funding are paid to NEXT Oncology: Syneos; Research grant / Funding (institution), Payments for Advisory/Consultancy/Research funding are paid to NEXT Oncology: Aminex; Research grant / Funding (institution), Payments for Advisory/Consultancy/Research funding are paid to NEXT Oncology: Asana; Research grant / Funding (institution), Payments for Advisory/Consultancy/Research funding are paid to NEXT Oncology: Arrys; Research grant / Funding (institution), Payments for Advisory/Consultancy/Research funding are paid to NEXT Oncology: CStone; Research grant / Funding (institution), Payments for Advisory/Consultancy/Research funding are paid to NEXT Oncology: GlaxoSmithKline; Research grant / Funding (institution), Payments for Advisory/Consultancy/Research funding are paid to NEXT Oncology: InhibRx; Research grant / Funding (institution), Payments for Advisory/Consultancy/Research funding are paid to NEXT Oncology: Innate ; Research grant / Funding (institution), Payments for Advisory/Consultancy/Research funding are paid to NEXT Oncology: Kiromie; Research grant / Funding (institution), Payments for Advisory/Consultancy/Research funding are paid to NEXT Oncology: Mersana; Research grant / Funding (institution), Payments for Advisory/Consultancy/Research funding are paid to NEXT Oncology: NatureWise; Research grant / Funding (institution), Payments for Advisory/Consultancy/Research funding are paid to NEXT Oncology: NextCure; Research grant / Funding (institution), Payments for Advisory/Consultancy/Research funding are paid to NEXT Oncology: Nitto Biopharma; Research grant / Funding (institution), Payments for Advisory/Consultancy/Research funding are paid to NEXT Oncology: Pieris; Research grant / Funding (institution), Payments for Advisory/Consultancy/Research funding are paid to NEXT Oncology: Syndax; Research grant / Funding (institution), Payments for Advisory/Consultancy/Research funding are paid to NEXT Oncology: Tizona; Research grant / Funding (institution), Payments for Advisory/Consultancy/Research funding are paid to NEXT Oncology: Zymeworks. K. Kelly: Honoraria (self), Travel / Accommodation / Expenses: Merck; Advisory / Consultancy, Research grant / Funding (institution): AbbVie; Advisory / Consultancy, Travel / Accommodation / Expenses: ARIAD; Advisory / Consultancy, Travel / Accommodation / Expenses, Licensing / Royalties: AstraZeneca; Advisory / Consultancy, Travel / Accommodation / Expenses: Boehringer Ingelheim; Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy: G1 Therapeutics; Advisory / Consultancy, Travel / Accommodation / Expenses: Genentech/Roche; Advisory / Consultancy: Janssen; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Lilly; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Regeneron; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): EMD Serono; Research grant / Funding (institution): Five Prime Therapeutics; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Lycera; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Transgene; Licensing / Royalties, evidence-based, peer-reviewed information resource: Author Royalties for UpToDate. A. Hollebecque: Advisory / Consultancy, Travel / Accommodation / Expenses, Non-remunerated activity/ies: Amgen; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca/MedImmune; Advisory / Consultancy: Gritstone Oncology; Advisory / Consultancy: Incyte; Advisory / Consultancy, Travel / Accommodation / Expenses, Non-remunerated activity/ies: Lilly; Advisory / Consultancy: Spectrum Pharmaceuticals; Travel / Accommodation / Expenses, Non-remunerated activity/ies: SERVIER; Non-remunerated activity/ies: AbbVie; Non-remunerated activity/ies: Agios; Non-remunerated activity/ies: Argenx; Non-remunerated activity/ies: Arno Therapeutics; Non-remunerated activity/ies: Astex Pharmaceuticals; Non-remunerated activity/ies: AstraZeneca; Non-remunerated activity/ies: AVEO; Non-remunerated activity/ies: Bayer; Non-remunerated activity/ies: Blueprint Medicines; Non-remunerated activity/ies: Boehringer Ingelheim; Non-remunerated activity/ies: Bristol-Myers Squibb; Non-remunerated activity/ies: Celgene; Non-remunerated activity/ies: Chugai Pharma; Non-remunerated activity/ies: Clovis Oncology; Non-remunerated activity/ies: Daiichi Sankyo; Non-remunerated activity/ies: Debiopharm; Non-remunerated activity/ies: Group; Non-remunerated activity/ies: Eisai; Non-remunerated activity/ies: Exelixis; Non-remunerated activity/ies: GamaMabs Pharma; Non-remunerated activity/ies: Forma Therapeutics; Non-remunerated activity/ies: Genentech; Non-remunerated activity/ies: GlaxoSmithKline; Non-remunerated activity/ies: H3 Biomedicine; Non-remunerated activity/ies: Innate Pharma; Non-remunerated activity/ies: Janssen-Cilag; Non-remunerated activity/ies: Kyowa Hakko Kirin; Non-remunerated activity/ies: Loxo; Non-remunerated activity/ies: Lytix Biopharma ; Non-remunerated activity/ies: MedImmune; Non-remunerated activity/ies: Menarini; Non-remunerated activity/ies: Merck Sharp & Dohme, Merrimack; Full / Part-time employment: Merus; Non-remunerated activity/ies: Millennium Pharmaceuticals; Non-remunerated activity/ies: Nanobiotix; Non-remunerated activity/ies: Nektar; Non-remunerated activity/ies: Novartis; Non-remunerated activity/ies: Octimet; Non-remunerated activity/ies: OncoEthix; Non-remunerated activity/ies: Onyx; Non-remunerated activity/ies: Orion Pharma GmbH; Non-remunerated activity/ies: Oryzon Genomics; Non-remunerated activity/ies: Pfizer; Non-remunerated activity/ies: Pierre Fabre; Non-remunerated activity/ies: Roche/Genentech; Non-remunerated activity/ies: Sanofi/Aventis; Non-remunerated activity/ies: Taiho Pharmaceutical; Non-remunerated activity/ies: Tesaro; Non-remunerated activity/ies: Xencor; Non-remunerated activity/ies: Roche. C. Le Tourneau: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (institution): Novartis; Advisory / Consultancy: Amgen; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy: Merck Serono; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD. V. Subbiah: Advisory / Consultancy: MedImmune; Research grant / Funding (institution), Travel / Accommodation / Expenses: PharmaMar; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): NanoCarrier; Research grant / Funding (institution): Northwest Biotherapeutics; Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): Berg; Research grant / Funding (institution), Travel / Accommodation / Expenses: Bayer; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Fujifilm; Research grant / Funding (institution): D3 Oncology Solutions; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): MultiVir; Research grant / Funding (institution): Blueprint Medicines; Research grant / Funding (institution): Loxo; Research grant / Funding (institution): Vegenics; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): Alfasigma; Research grant / Funding (institution): Agensys; Research grant / Funding (institution): Idera; Research grant / Funding (institution): Boston Biomedical; Research grant / Funding (institution): InhibRx; Research grant / Funding (institution): Exelixis. S. Kao: Honoraria (self), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (self): Roche; Research grant / Funding (institution): Merck Sharp & Dohme; Travel / Accommodation / Expenses: Boehringer Ingelheim. P. Cassier: Honoraria (self), Travel / Accommodation / Expenses: Amgen; Honoraria (self), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: SERVIER; Research grant / Funding (institution): Celgene ; Research grant / Funding (institution): Bristol-Myers Squibb ; Research grant / Funding (institution): Lilly . M. Khasraw: Honoraria (self): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): AbbVie; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy: Lilly; Research grant / Funding (institution): Specialised Therapeutics . H. Fang: Shareholder / Stockholder / Stock options, Full / Part-time employment: AbbVie. M. Patel: Shareholder / Stockholder / Stock options, Full / Part-time employment: AbbVie. W. Henner: Shareholder / Stockholder / Stock options, Full / Part-time employment: AbbVie. J. Hayflick: Shareholder / Stockholder / Stock options, Full / Part-time employment: AbbVie. M. McDevitt: Shareholder / Stockholder / Stock options, Full / Part-time employment: AbbVie. F. Barlesi: Honoraria (self), Honoraria (institution), Personal/Institutional financial interests : AstraZeneca ; Honoraria (self), Honoraria (institution), Personal/Institutional financial interests : Bayer; Honoraria (self), Honoraria (institution), Personal/Institutional financial interests : Bristol-Myers Squibb; Honoraria (self), Honoraria (institution), Personal/Institutional financial interests : Boehringer Ingelheim; Honoraria (self), Honoraria (institution), Personal/Institutional financial interests : Eli Lilly Oncology; Honoraria (self), Honoraria (institution), Personal/Institutional financial interests : F. Hoffmann-La Roche Ltd; Honoraria (self), Honoraria (institution), Personal/Institutional financial interests : Novartis; Honoraria (self), Honoraria (institution), Personal/Institutional financial interests : Merck ; Honoraria (self), Honoraria (institution), Personal/Institutional financial interests : MSD; Honoraria (self), Honoraria (institution), Personal/Institutional financial interests : Pierre Fabre; Honoraria (self), Honoraria (institution), Personal/Institutional financial interests : Pfizer; Honoraria (self), Honoraria (institution), Personal/Institutional financial interests : Takeda; Honoraria (institution), Institutional financial interests : AbbVie; Honoraria (institution), Institutional financial interests : Amgen; Honoraria (institution), Institutional financial interests : ACEA; Honoraria (institution), Institutional financial interests : Eisai; Honoraria (institution), Institutional financial interests : Genentech; Honoraria (institution), Institutional financial interests : Ipsen; Honoraria (institution), Institutional financial interests : Ignyta; Honoraria (institution), Institutional financial interests : Innate Pharma; Honoraria (institution), Institutional financial interests : Loxo; Honoraria (institution), Institutional financial interests : MedImmune; Honoraria (institution), Institutional financial interests : Sanofi-Aventis. All other authors have declared no conflicts of interest.