Abstract 4779
Background
Despite the application of PD-1 inhibitors in clinical practice in SCCHN, only a fraction of patients shows durable responses to monotherapy. Numerous combinatorial strategies have been utilized to attempt to augment immunotherapy efficacy. While dysregulated tumour metabolism (TM) is a critical feature of the tumour microenvironment (TME) and impacts immune function within the TME, much remains to be done to bridge these areas and explore therapeutic opportunities. Recent murine xenograft and clinical translational data suggests that metformin alters TM, and preclinical data suggests possible potentiation of PD-1 axis inhibition by metformin.
Methods
This is a single-center, randomized trial for patients with all stages of resectable SCCHN, with planned enrollment of 38 patients. Part 1, which has been completed, was a safety run-in with 6 patients treated with metformin (met) + durvalumab (durva) for safety evaluation. Part 2 will enroll 32 additional patients with a 3:1 randomization to treatment arm A (met 1000 mg BID Day 1-31 + durva 1500 mg IV x 1 on Day 3) and treatment arm B (durva 1500 mg IV x 1). Tumor and blood will be collected pre and post treatment with analysis of immune cell composition. The primary endpoint is the combined effect of metformin and durvalumab on the immune TME, specifically with respect to alterations in T cell and macrophage polarization. Secondary endpoints include safety and tolerability, alterations in immunohistochemical markers of the TME, transcriptome and circulating DNA analysis, and objective response rate.
Results
Six patients were enrolled in Part 1. All were males with a mean age of 65.7 ± 6.8 years. All patients had grade 1 adverse events (AE) consisting mainly of gastrointestinal (diarrhea, nausea, or abdominal cramps) and constitutional (anorexia, fatigue, or sleep disturbance) symptoms. No patient experienced AE > = grade 2. All patients were able to proceed to surgery without unanticipated delays.
Conclusions
The combination of met and durva was safe in the first cohort of patients. Enrollment for Part 2 is ongoing.
Clinical trial identification
NCT03618654.
Editorial acknowledgement
Legal entity responsible for the study
Sidney Kimmel Cancer Center at Thomas Jefferson University Sidney Kimmel Cancer Center at Thomas Jefferson University Sidney Kimmel Cancer Center at Thomas Jefferson University Sidney Kimmel Cancer Center at Thomas Jefferson University.
Funding
Sidney Kimmel Cancer Center at Thomas Jefferson University.
Disclosure
J.M. Johnson: Research grant / Funding (self): Bristol-Myers Squibb. A. Argiris: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Merck Serono; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy: Roche; Advisory / Consultancy: Debiopharm Group; Advisory / Consultancy: Aspyrian Therapeutics; Research grant / Funding (self): Genentech/Roche. A. Luginbuhl: Research grant / Funding (self): Bristol-Myers Squibb. R. Zinner: Research grant / Funding (institution), Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment, An Immediate Family Member: Merck; Research grant / Funding (institution), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Travel / Accommodation / Expenses: Lilly. U. Rodeck: Shareholder / Stockholder / Stock options: Akriveia Therapeutics; Research grant / Funding (self): Advaxis; Licensing / Royalties: Several Patents. J.M. Curry: Research grant / Funding (self): AstraZeneca. All other authors have declared no conflicts of interest.
Resources from the same session
1908 - Androgen Receptor (AR) Aberrations in Patients (Pts) With Metastatic Castration-Sensitive Prostate Cancer (mCSPC) Treated With Apalutamide (APA) Plus Androgen Deprivation Therapy (ADT) in TITAN
Presenter: Kim Chi
Session: Poster Display session 3
Resources:
Abstract
4058 - 68Ga-PSMA guided bone biopsies for molecular diagnostics in metastatic castration resistant prostate cancer patients
Presenter: Anouk de Jong
Session: Poster Display session 3
Resources:
Abstract
2226 - Spatial-Temporal Change in Quantitative Total Bone Imaging (QTBI) and Circulating Tumor Cells (CTCs) in Metastatic Castration-Resistant Prostate Cancer (mCRPC) Treated With Enzalutamide (ENZA)
Presenter: Glenn Liu
Session: Poster Display session 3
Resources:
Abstract
5795 - Efficacy of Enzalutamide in Hormone-sensitive Metastatic Prostate Cancer: Clinical Utility of 18F-Choline PET and Whole Body MRI.
Presenter: Susanne Osanto
Session: Poster Display session 3
Resources:
Abstract
899 - Urine extracellular vesicle GATA2 mRNA alone and in a multigene test predicts initial prostate biopsy result
Presenter: Jungreem Woo
Session: Poster Display session 3
Resources:
Abstract
3094 - Circulating tumor cell (CTC) genomic landscape in neuroendocrine prostate cancer (NEPC) by single cell copy number analysis
Presenter: Vincenza Conteduca
Session: Poster Display session 3
Resources:
Abstract
2527 - Circulating Tumor Cells (CTC) count and Prostate-Specific Antigen (PSA) response measures in metastatic Castration-Resistant Prostate Cancer (mCRPC) patients (pts) treated with Docetaxel (Doc)
Presenter: Rebeca Lozano Mejorada
Session: Poster Display session 3
Resources:
Abstract
6106 - Assessing the clinical relevance of drug–drug interactions (DDI) with darolutamide (DARO)
Presenter: Christian Zurth
Session: Poster Display session 3
Resources:
Abstract
2237 - KEYNOTE-921: phase 3 study of pembrolizumab (pembro) plus docetaxel and prednisone for enzalutamide (enza)- or abiraterone (abi)-pretreated patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Presenter: Daniel Petrylak
Session: Poster Display session 3
Resources:
Abstract
2241 - KEYNOTE-641: Phase 3 Study of Pembrolizumab (pembro) Plus Enzalutamide for Metastatic Castration-Resistant Prostate Cancer (mCRPC)
Presenter: Julie Graff
Session: Poster Display session 3
Resources:
Abstract