Abstract 4062
Background
M9241 is a tumor-targeting immunocytokine composed of IL-12 heterodimers fused to a monoclonal antibody targeting DNA in necrotic tumor regions. Avelumab is a human anti–PD-L1 IgG1 monoclonal antibody with clinical activity in various tumor types. Preclinical data predicted a potential drug-drug interaction (DDI) between M9241 and avelumab. We report an interim analysis of safety and PK/PD from the dose-escalation part of JAVELIN IL-12 (NCT02994953), a phase Ib study of M9241 and avelumab in pts with locally advanced, unresectable, or metastatic solid tumors.
Methods
At data cutoff (20 Aug 2018), 29 pts in dose levels (DLs) 1-4 received M9241 4, 8, 12, or 16.8 μg/kg SC every 4 weeks (Q4W) and avelumab 10 mg/kg IV every 2 weeks (Q2W). Three pts in DL5 received 12-week induction with avelumab 800 mg IV once weekly (Q1W) and M9241 16.8 μg/kg SC Q4W and then continuation treatment with avelumab 800 mg IV Q2W and M9241 16.8 μg/kg SC Q4W. The primary endpoint was overall safety and dose-limiting toxicities (DLTs).
Results
DLs 1-4 were well tolerated. One DLT occurred at DL3 (grade 3 autoimmune hepatitis), but no DLTs occurred at other DLs. Maximum tolerated dose was not reached. PK analyses suggested a DDI at DLs 1-4, evidenced by decreased avelumab exposure concurrent with increased IFN-γ levels; therefore, DL5 was introduced. At DL5, PK data showed no evidence of a DDI. DL5 was also well tolerated and showed a similar safety profile to DL4, with treatment-emergent adverse events limited to grade 1/2. Prolonged clinical responses (CR/PR) were seen, including in a checkpoint inhibitor–refractory pt.
Conclusions
Combining avelumab 800 mg IV Q1W and M9241 16.8 μg/kg SC Q4W as 12-week induction followed by avelumab 800 mg IV Q2W and M9241 16.8 μg/kg SC Q4W as continuation treatment had an acceptable safety and tolerability profile and was therefore declared as recommended phase II dose (RP2D). The observed DDI is likely driven by M9241-mediated IFN-γ induction, causing PD-L1 upregulation in the periphery and tumor and target-mediated clearance of avelumab. Based on available data, this DDI mechanism is likely saturated at the RP2D. This trial continues recruitment into expansion cohorts at the RP2D.
Clinical trial identification
NCT02994953.
Editorial acknowledgement
ClinicalThinking, funded by Merck Healthcare KGaA and Pfizer Inc.
Legal entity responsible for the study
Merck Healthcare KGaA.
Funding
Merck Healthcare KGaA and Pfizer Inc.
Disclosure
J. Strauss: Research grant / Funding (institution): EMD Serono; Licensing / Royalties, Patent: dual blockade of PD-L1 and TGF beta for HPV+ cancer: Not applicable. Y. Vugmeyster: Full / Part-time employment: EMD Serono; Shareholder / Stockholder / Stock options: EMD Serono; Shareholder / Stockholder / Stock options: Alexion; Licensing / Royalties: EMD Serono; Licensing / Royalties: Wyeth; Licensing / Royalties: Pfizer. M. Sznol: Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Genentech/Roche ; Advisory / Consultancy: AstraZeneca/MedImmune ; Advisory / Consultancy: Kyowa Hakko Kirin ; Advisory / Consultancy: Nektar; Advisory / Consultancy: Novartis; Advisory / Consultancy: Lilly; Advisory / Consultancy: Merck Sharp & Dohme; Advisory / Consultancy: Biodesix; Advisory / Consultancy: Adaptimmune; Advisory / Consultancy: Theravance; Advisory / Consultancy: Modulate Pharma; Advisory / Consultancy: Omniox; Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy: Inovio Pharmaceuticals; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Torque; Shareholder / Stockholder / Stock options: Amphivena Therapeutics; Shareholder / Stockholder / Stock options: Intensity Therapeutics; Shareholder / Stockholder / Stock options: Adaptive Biotechnologies ; Shareholder / Stockholder / Stock options: Actym Therapeutics; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Newlink Genetics; Advisory / Consultancy: Molecular Partners; Advisory / Consultancy: Genmab; Advisory / Consultancy: AbbVie; Advisory / Consultancy: Allakos; Advisory / Consultancy: Hinge; Advisory / Consultancy: Symphogen; Advisory / Consultancy: Pieris Pharmaceuticals; Advisory / Consultancy: Gritstone Oncology; Advisory / Consultancy: Innate Pharma; Advisory / Consultancy: Celldex; Advisory / Consultancy: Incyte; Advisory / Consultancy: Almac Diagnostics; Advisory / Consultancy: immunocore; Advisory / Consultancy: Array BioPharma. R.K. Pachynski: Advisory / Consultancy: EMD Serono; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Jounce Therapeutics; Speaker Bureau / Expert testimony: Dendreon; Speaker Bureau / Expert testimony: Merck; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Genentech/Roche; Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Sanofi; Speaker Bureau / Expert testimony: Genomic Health; Research grant / Funding (institution): Janssen Oncology. K. Trang: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck KGaA/EMD Serono. S. Chennoufi: Full / Part-time employment: Merck KGaA. J.L. Gulley: Research grant / Funding (institution): EMD Serono; Research grant / Funding (institution): Bavarian Nordic; Research grant / Funding (institution): Astellas Medivation; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): NantBioScience, Inc.; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Merck.
Resources from the same session
5043 - Comprehensive results of a Phase Ib study with a HER2/neu B-cell peptide vaccine administered with cisplatin and 5-fluorouracil or capecitabine chemotherapy show safety, immunogenicity and clinical response in patients with HER2/Neu overexpressing advanced gastric cancer
Presenter: Ursula Wiedermann
Session: Poster Display session 3
Resources:
Abstract
4506 - Single intravenous preoperative administration of the oncolytic virus Pexa-Vec to prime anti-tumor immunity
Presenter: Adel Samson
Session: Poster Display session 3
Resources:
Abstract
1631 - Randomized phase 2 clinical trial of NY-ESO-1 protein vaccine combined with cholesteryl pullulan (CHP-NY-ESO-1) in resected esophageal cancer patients
Presenter: Shinichi Kageyama
Session: Poster Display session 3
Resources:
Abstract
4244 - T cell repertoire sequencing reveals dynamics of response to dendritic cell vaccine plus dasatinib for checkpoint blockade resistant metastatic melanoma
Presenter: Luca Quagliata
Session: Poster Display session 3
Resources:
Abstract
5791 - Ixovex, a novel oncolytic E1B-mutated adenovirus
Presenter: Mohiemen Anwar
Session: Poster Display session 3
Resources:
Abstract
4170 - Anti-CSPG4 DNA vaccination as a promising strategy for the treatment of CSPG4+ tumors: a comparative oncology trial
Presenter: Federica Riccardo
Session: Poster Display session 3
Resources:
Abstract
5780 - Antitumor activity, immunogenicity and safety of a novel PD-1 vaccine in combination with two chimeric HER-2 peptide vaccine in syngeneic Balb/c, C57Bl/6 models and in beagle dogs
Presenter: Pravin Kaumaya
Session: Poster Display session 3
Resources:
Abstract
5860 - Maternal immunization against ALK as a weapon to fight neuroblastoma
Presenter: Giuseppina Barutello
Session: Poster Display session 3
Resources:
Abstract
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
Presenter: Jason Luke
Session: Poster Display session 3
Resources:
Abstract
5717 - Anti-PD-L1/IL-15 fusion protein generates robust adaptive immune gene signatures in tumors leading to tumor inhibition and memory responses
Presenter: Stella Martomo
Session: Poster Display session 3
Resources:
Abstract