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
5218 - Elevated driver mutational burden or number of perturbed pathways and poor response to abiraterone or enzalutamide in metastatic castration-resistant prostate cancer
Presenter: Bram De Laere
Session: Poster Display session 3
Resources:
Abstract
2452 - High proportion of multiple KRAS mutations in circulating tumor DNA and tumor tissue of pancreatic ductal adenocarcinoma
Presenter: Min Kyeong Kim
Session: Poster Display session 3
Resources:
Abstract
3328 - Biological difference of tumor mutational burden (TMB) and microsatellite instability (MSI) status in patients (pts) with somatic vs. germline BRCA1/2-mutated advanced gastrointestinal (GI) cancers using cell-free DNA (cfDNA) sequencing analysis in the GOZILA study
Presenter: Yasuyuki Kawamoto
Session: Poster Display session 3
Resources:
Abstract
3022 - Cell-Free DNA to Detect Focal Versus Non-Focal MET Amplification in Metastatic Colorectal Cancer Patients: Combined Analysis from Japan and the United States
Presenter: Mishima Saori
Session: Poster Display session 3
Resources:
Abstract
2833 - Presence of circulating tumor DNA in surgically resected renal cell carcinoma is associated with advanced disease and poor patient prognosis
Presenter: Andres Correa
Session: Poster Display session 3
Resources:
Abstract
1376 - Combined genomic and epigenomic assessment of cell-free circulating tumor DNA (cfDNA) for cancer diagnosis and recurrence-risk assessment in early-stage lung cancer
Presenter: Junghee Lee
Session: Poster Display session 3
Resources:
Abstract
4050 - DEMo: a prospective evaluation of a prognostic clinico-molecular composite score in NSCLC patients treated with immunotherapy.
Presenter: Arsela Prelaj
Session: Poster Display session 3
Resources:
Abstract
4727 - Bespoke circulating tumor DNA (ctDNA) analysis as a predictive biomarker in solid tumor patients (pts) treated with single agent pembrolizumab (P)
Presenter: Cindy Yang
Session: Poster Display session 3
Resources:
Abstract
3662 - Dynamic changes in whole-genome cell-free DNA (cfDNA) to identify disease progression prior to imaging in advanced solid tumors
Presenter: Andrew Davis
Session: Poster Display session 3
Resources:
Abstract
3817 - Evaluation of Microsatellite Instability Testing Through cell-free DNA sequencing
Presenter: Shile Zhang
Session: Poster Display session 3
Resources:
Abstract