- L. Fong (San Francisco, United States of America)
- J. Haanen (Amsterdam, Netherlands)
DOI session
91O - A multi-center phase IIa trial to assess the safety and efficacy of BL-8040 (a CXCR4 inhibitor) in combination with pembrolizumab and chemotherapy in patients with metastatic pancreatic adenocarcinoma (PDAC)
- M. Hidalgo (Madrid, Spain)
- M. Hidalgo (Madrid, Spain)
- V. Semenisty (Haifa, Israel)
- B. Bockorny (Boston, AL, United States of America)
- E. Borazanci (Scottsdale, United States of America)
- D. Von Hoff (Scottsdale, AZ, United States of America)
- J. Feliu (Madrid, Spain)
- M. Ponz Sarvise (Pamplona, Spain)
- D. Gutierrez Abad (, Spain)
- A. Peled (Jerusalem, Israel)
- O. Bohana-Kashtan (Modi'in-Maccabim-Re'ut, Israel)
- Y. Gozlan (Modi'in-Maccabim-Re'ut, Israel)
- E. Sorani (Modi'in-Maccabim-Re'ut, Israel)
- M. Chaney (North Wales, United States of America)
- S. Kadosh (Nesher, Israel)
- A. Vainstein (Modi'in-Maccabim-Re'ut, Israel)
- T. Macarulla (, Spain)
Abstract
Background
Current treatment options for PDAC are limited. While PD-1/PD-L1 antagonists have shown promising results in other cancer types, this approach has been ineffective in PDAC. In Cohort 1 of the COMBAT study, the dual combination of BL-8040 (a CXCR4 inhibitor) and Pembrolizumab was safe and showed a promising 7.5 mo OS in 2L patients. BL-8040 modified the TME by promoting infiltration of effector T cells and decreasing immune suppressor cells. Based on these encouraging results, as well as preclinical data supporting the combination of BL-8040, Pembrolizumab and chemotherapy, the study was expanded to include a combination arm (Cohort 2) composed of BL-8040, Pembrolizumab and chemotherapy (Onivyde/5-FU/LV). Here we report the preliminary safety and efficacy of BL-8040 in this expansion cohort.
Methods
Phase IIa study, Cohort 2, treatment regimen consists of 5 days BL-8040 priming monotherapy followed by combination treatment of Onivyde/5-FU/LV every 2 weeks, Pembrolizumab every 3 weeks and BL-8040 twice a week. Eligibility criteria includes metastatic PDAC subjects with measurable disease by RECIST1.1 that have progressed following first-line treatment with gemcitabine-based chemotherapy.
Results
This is a snapshot of Cohort 2 of the COMBAT study. As of September 2019, 22 patients have been enrolled, of which 15 are evaluable (i.e. received at least 1 dose of combination and have post-baseline CT). Median age 68, ECOG≤1 and 60% males. 15 SAEs were reported by 10 patients. 2 subjects were discontinued due to SAEs. Best Response by RECISTv1.1 for the evaluable population showed 4 partial response (PR) and 8 stable disease (SD) patients, a total of 12 subjects with disease control (DC) out of 15. Median PFS and OS were not reached. Notably all patients with PR and SD had an initial increase in CA 19-9 followed by a decrease. Tumor shrinkage began during the transient increase of CA 19-9.
Conclusion
Preliminary data from the ongoing COMBAT study Cohort 2 with the triple combination of BL-8040, Pembrolizumab and chemo, show promising ORR (4/15) and DC (12/15) results. Median PFS and OS have not yet been reached.
Clinical trial identification
NCT02826486.
Legal entity responsible for the study
The authors.
Funding
Biolinerx.
Disclosure
M. Hidalgo: Full / Part-time employment: Beth Israel Deaconess Medical Center; Full / Part-time employment: Harvard Medical School; Full / Part-time employment: Weill Cornell Medical College. V. Semenisty: Full / Part-time employment: Rambam Health Care Campus. B. Bockorny: Full / Part-time employment: Beth Israel Deaconess Medical Center; Research grant / Funding (institution): NanoView Biosciences. E. Borazanci: Full / Part-time employment: Honor-Health/TGen. D.D. von Hoff: Full / Part-time employment: Honor-Health/TGen. J. Feliu: Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Roche; Advisory / Consultancy: Novartis; Advisory / Consultancy: Eisai; Advisory / Consultancy: Merck; Travel / Accommodation / Expenses: Seriver. M. Ponz Sarvise: Full / Part-time employment: Clinica Universidad de Navarra. D. Gutierrez Abad: Full / Part-time employment: Grupo Oncologia Fuenlabrada. A. Peled: Full / Part-time employment: Goldyne Savad Institute of Gene Therapy; Leadership role: Biokine Therapeutics Ltd. O. Bohana-Kashtan: Full / Part-time employment: Biolinerx. Y. Gozlan: Full / Part-time employment: Biolinerx. E. Sorani: Honoraria (self), Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Biolinerx. M. Chaney: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc. S. Kadosh: Full / Part-time employment: StatExcellence. A.V. Vainstein: Honoraria (self), Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Biolinerx. T. Macarulla: Full / Part-time employment: Vall d´Hebron University Hospital.
Invited Discussant 91O
- L. Fong (San Francisco, United States of America)
- L. Fong (San Francisco, United States of America)
129O - Resistance to immunotherapy is associated with high parenchymal PD1+CD8+/CD8+ T cells (PD1tR) driven by tumour CD155
- A. Lepletier de Oliveira (Brisbane, Australia)
- A. Lepletier de Oliveira (Brisbane, Australia)
- J. Madore (Brisbane, QLD, Australia)
- J. S. O’donnell (Brisbane, Australia)
- R. L. Johnston (Brisbane, QLD, Australia)
- M. Eastgate (Brisbane, QLD, Australia)
- D. Mallardo (Napoli, Italy)
- P. Ascierto (Napoli, Italy)
- D. Massi (Florence, Italy)
- B. Merelli (Bergamo, Italy)
- M. Mandala (Bergamo, Italy)
- J. S Wilmott (Sydney, NSW, Australia)
- T. Bald (Brisbane, QLD, Australia)
- J. Stagg (Montreal, QC, Canada)
- B. Routy (Montreal, QC, Canada)
- G. V. Long (Sydney, QLD, Australia)
- R. A. Scolyer (Sydney, Australia)
- N. Waddell (Brisbane, ACT, Australia)
- W. C. Dougall (Brisbane, QLD, Australia)
- M. W. L. Teng (Brisbane, QLD, Australia)
- M. Smyth (Brisbane, QLD, Australia)
Abstract
Background
We have previously shown that a possible complementary target to PD1-based immune-checkpoint blockade (ICB) is the adhesion molecule CD155, which promotes tumor growth and metastasis in mouse models. To date, it is unclear to what extent tumor CD155 expression impacts the immune infiltrate contexture or if expression of CD155 by human tumors affects sensitivity to ICB.
Methods
We assessed pretreatment tumor FFPE specimens from 146 metastatic melanomas patients treated with immune checkpoint blockade (ICB) and 41 patients that have received 1st line BRAF/MEK targeted therapy and no ICB. CD155 expression was defined by immunohistochemistry (IHC) H-score. The immune infiltrate was separately analysed in stroma and parenchymal (intratumor) regions using multiplex immunohistofluorescence (IHF) for CD8, PD1 and SOX10. Associations were made between IHC analyses, bulk tumor RNA-seq results, and immunotherapeutic response (RECIST, PFS, and disease specific OS). Key findings were functionally validated in a relevant mouse melanoma model.
Results
Melanoma patients with high levels of tumor CD155 (score 3+) frequently had progressive disease or shorter PFS through promotion of dysfunctional PD1+CD8+ T cells. Further, the intratumor ratio of PD1+CD8+ to total CD8+ T cells (PD1tR) is a strong predictor of ICB refractory patients. Importantly, outcome correlations appeared specific to ICB therapy and were not present in melanoma patients treated with BRAF/MEK targeted therapy. In humans, CD155 high tumors show reduced Interferon-gamma and cytotoxic gene signatures. In PD1 resistant mouse tumor models, deletion of CD155 prevented accumulation of intratumor PD1hiCD8+ T cells. Additionally, therapeutic blockade of the CD155 cognate receptors TIGIT and CD96 restored IFNγ production and improved anti-PD1 tumor control.
Conclusion
Our findings are the first to demonstrate that tumor CD155 underpins the accumulation of dysfunctional PD1hiCD8+ T cells in human tumors and propose pretreatment PD1tR as a potential biomarker of response to ICB.
Legal entity responsible for the study
The Council of the Queensland Institute of Medical Research.
Funding
Bristol-Myers Squibb.
Disclosure
P.A. Ascierto: Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (self): Roche-Genentech; Advisory / Consultancy, Research grant / Funding (self): Array; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy: Novartis; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Incyte; Advisory / Consultancy: Genmab; Advisory / Consultancy: Newlink Genetics; Advisory / Consultancy: Medimmune; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Syndax; Advisory / Consultancy: Sun Pharma; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Idera; Advisory / Consultancy: Ultimovacs; Advisory / Consultancy: Sandoz; Advisory / Consultancy: Immunocore. G. V. Long: Advisory / Consultancy: Aduro; Advisory / Consultancy: Amgen; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Merck MSD; Advisory / Consultancy: Novartis; Advisory / Consultancy: Roche. R. A. Scolyer: Advisory / Consultancy: Merck Sharp Dohme; Advisory / Consultancy: Novartis; Advisory / Consultancy: Myriad; Advisory / Consultancy: NeraCare. W. C. Dougall: Research grant / Funding (self): Bristol-Myers Squibb; Advisory / Consultancy: Omeros Corporation ; Advisory / Consultancy: Cascadia Drug Development Group. M. W. L. Teng: Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert testimony: MSD; Speaker Bureau / Expert testimony: Bristol-Myers Squibb. M. Smyth: Research grant / Funding (self): Bristol-Myers Squibb; Research grant / Funding (self): Aduro Biotech; Research grant / Funding (self): Tizona Pharmaceuticals. All other authors have declared no conflicts of interest.
1O - Harmonization and standardization of panel-based tumour mutational burden (TMB) measurement: Real-world results and recommendations of the QuIP study
- A. Stenzinger (Heidelberg, Germany)
- A. Stenzinger (Heidelberg, Germany)
- V. Endris (Heidelberg, Germany)
- J. Budczies (Heidelberg, Germany)
- S. Merkelbach-Bruse (Köln, Germany)
- W. Dietmaier (Regensburg, Germany)
- U. Siebolts (Halle, Germany)
- J. Maas (Berlin, Germany)
- D. Merino (Washington, AL, United States of America)
- M. Stewart (Washington, DC, United States of America)
- J. Allen (Washington, United States of America)
- H. Glimm (Dresden, Germany)
- M. Thiemann (Hamburg, Germany)
- D. Aust (Dresden, Germany)
- M. Hummel (Berlin, Germany)
- H. Moch (Zürich, Switzerland)
- A. Jung (München, Germany)
- F. Haller (Erlangen, Germany)
- W. Weichert (München, Germany)
- M. Dietel (Berlin, Germany)
Abstract
Background
TMB is a novel predictive biomarker that can identify patients who may benefit from immunotherapy. NSCLC trial data suggest that whole exome sequencing (WES) and panel-sequencing are suitable to determine TMB, and that centralized and decentralized/lab-developed testing models for panel-based measurements are acceptable. In strategic partnership with the effort led by Friends of Cancer Research, the Quality in Pathology (QuIP) study was designed to analyze performance and specifications of TMB panels in a wet-lab setting.
Methods
20 FFPE samples (NSCLC, HNSCC, CRC, including MSI, mutant POLE) that cover the full spectrum of TMB (2 to 200 muts/Mb) were analyzed by 11 pathology centers and 4 assay providers using 6 different major panels. WES data served as reference standard. Each tumor sample was tested > 20 times across several panels and institutions resulting in 580 datasets. Using raw sequencing data, processed file formats, and reported TMB values, we dissected specifications of each panel result, identified panel-specific requirements, and analyzed Pearson correlations of TMB data between assays, labs, and vs WES.
Results
Each panel had different requirements regarding library preparation (hybridization vs PCR) and input material (range: 20-200 ng). We identified tumor cell content and DNA quality/quantity as crucial preanalytic factors that require integration with coverage data, VAF cut-points, and assay-specific features (eg, molecular barcodes) to obtain reliable TMB results. Control of C>T artifacts was important for assays not using molecular identifiers. Correlations between panel-TMB estimates (R = 0.93 ± 0.1; mean ± sd) and with WES (R > 0.9 for 18 and R > 0.95 for 14 of 20 panel tests) were strong and improved after optimization of pipelines.
Conclusion
The QuIP study demonstrated that all TMB panels work under real-world conditions and strongly correlate with WES data, with low variability across sites. Further, we identified both common and panel-specific parameters that influence TMB results in daily practice. Recommendations will be provided that support standardization and enable implementation of TMB testing in routine diagnostics.
Legal entity responsible for the study
The authors.
Funding
Bristol-Myers Squibb, Roche, Illumina, Thermo Fisher, Neo Oncology, Qiagen.
Disclosure
A. Stenzinger: Advisory / Consultancy, Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony: Illumina; Advisory / Consultancy, Speaker Bureau / Expert testimony: Thermo Fisher; Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy: Seattle Genomics; Speaker Bureau / Expert testimony: MSD. All other authors have declared no conflicts of interest.
Invited Discussant 129O and 1O
- J. Haanen (Amsterdam, Netherlands)
- J. Haanen (Amsterdam, Netherlands)