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
4900 - Molecular profiling and prognostic significance of TP53 mutations in Diffuse Large B Cell Lymphoma: identifying a high-risk subgroup
Presenter: Yuan-Kai Shi
Session: Poster Display session 3
Resources:
Abstract
3809 - Differential expression of various miRNAs in Pediatric Cytogenetically Normal Acute Myeloid Leukemia (CN-AML)
Presenter: Vikas Gaur
Session: Poster Display session 3
Resources:
Abstract
4750 - Circulating tumour cells in head and neck and non-small cell lung cancer
Presenter: Kenneth O'Byrne
Session: Poster Display session 3
Resources:
Abstract
3704 - OX40/OX40L protein expression in Non-small cell lung cancer and its role in clinical outcome and relationships with other immune biomarkers
Presenter: Xiaoshen Zhang
Session: Poster Display session 3
Resources:
Abstract
2235 - Effect of Serum Survivin on Survival among Non-Small Cell Lung Cancer Patients; NCI Experience
Presenter: Reham Rashed
Session: Poster Display session 3
Resources:
Abstract
2788 - Enhanced performance of prognostic estimation from TCGA RNAseq data using transfer learning.
Presenter: Helene Vanacker
Session: Poster Display session 3
Resources:
Abstract
4689 - Analysis of Circulating Tumor DNA for Early Relapse Detection in Stage III Colorectal Cancer After Adjuvant Chemotherapy
Presenter: Samuel Jacobs
Session: Poster Display session 3
Resources:
Abstract
1454 - Ascites-derived circulating microRNAs as potential diagnostic biomarkers of gastric cancer-associated malignant ascites
Presenter: Hye Sook Han
Session: Poster Display session 3
Resources:
Abstract
5574 - Results from TRIO030, a Pre-Surgical Tissue-Acquisition Study to Evaluate Molecular Alterations in Human Breast Cancer Tissue Following Short-Term Exposure to the Androgen Receptor Antagonist Darolutamide
Presenter: Hsiao-Wang Chen
Session: Poster Display session 3
Resources:
Abstract
1787 - JMJD2A is a novel epigenetic factor of chemotherapeutic susceptibility in gastric cancer
Presenter: Yasushi Sato
Session: Poster Display session 3
Resources:
Abstract