Biomarkers of neoadjuvant Multikine (LI) treatment outcome in locally advanced head & neck carcinoma
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Abstract
Biomarkers of neoadjuvant Multikine (LI) treatment outcome in locally advanced head & neck carcinoma
Authors: József Timar1, Philip Lavin2, Andrea Ladanyi3, Istvan Kenessey4, Andras Kiss4, Dusan Markovic5, John Cipriano6, Eyal Talor6
1Semmelweis University, Dept of Pathology and Forensic and Insurance Medicine, Budapest, Hungary; 2Boston Biostatistics Research Foundation, Biostatistics, Farmingham, USA; 3National Institute of Oncology, Surgical Pathology, Budapest, Hungary; 4Semmelweis University, Department of Pathology and Forensic and Insurance Medicine, Budapest, Hungary; 5ERGOMED, PLC, Novisad, Serbia; 6CelSci, Corp, Vienna, USA
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Purpose or Objective
In a Phase 3, randomized, controlled study, neoadjuvant administration of investigational proinflammatory biologic Multikine (LI,Leukocyte interleukin injection) with CIZ (single low dose cyclophosphamide IV, indomethacin (po tid) and Zinc (po, daily) multivitamins + Standard of Care (SOC) to oral and soft-palate squamous cell carcinoma (SCCHN) subjects, resulted in significantly prolonged overall survival (OS) in the NCCN defined low risk (LR) intent to treat (ITT) population vs SOC alone (IT-MATTERS Study, NCT01265849).
Material and Methods
Available HPP (histopathology population) ITT subjects (453 ITT; 210 LR ITT) meeting entry criteria (AJCC Stage III/IVa oral, soft-palate SCCHN, Tx (therapy) naïve randomized 3:1:3 to Tx arms LI (+/- CIZ) + SOC or SOC alone. LI was injected 200IU peritumorally and 200IU peri-lymphatically daily, 3-weeks before surgery. All patients were to receive SOC (per NCCN, LR RTx, high risk CRTx post-surgery). Follow-up was comparable (56-57 months median per Tx group). Tumor samples were stained/quantitated for 20 biomarkers (5 tumor cell, 15 tumor microenvironment); 2 ratios; 14 combinations were prospectively defined, including low/high thresholds for each biomarker, ratio; combinations defined as +ve or -ve. Defined prospective interactions models (all subjects) allowed three-way interactions assessment for risk groups, biomarker level to analyze Tx efficacy for OS, PFS, LRC hazard ratio (HR) outcomes using proportional hazard models.
Results
The HPP (n=453) and the LR HPP (n=210) were representative of the overall population (n=923). LR efficacy was favorable for LI+CIZ+SOC vs SOC as shown below
LR HPP (n=210) Overall Survival Prog-Free Survival Local Regional Control
HR (95% CI) 0.64 (0.41 - 1.01) 0.67 (0.44 - 1.02) 0.62 (0.35 - 1.09)
Cox p-value 0.0569 0.0632 0.0961
5-year success 63.9% vs 44.4% 56.9% vs 41.1% 73.1% vs 63.6%
Efficacy for the 36 marker sets analysis favored LI+CIZ+SOC vs SOC (FLI) significantly more often than favoring SOC (FSOC) (conditional binomial; p<0.0001); see below
Proportion Statistically Significant, one-sided p<0.025
Overall (n=453) LR (n=210)
Overall Survival 26/93 (FLI) vs 1/93 (FSOC) 21/93 (FLI)
Prog-Free Survival 17/93 (FLI) vs 2/93 (FSOC) 16/93 (FLI)
Local Reg Control 18/93 (FLI) vs 2/93 (FSOC) 17/93 (FLI)
Totals 61/279 (21.9%>>2.5%) vs 5/279 (1.9%) 54/279 (19.4%>>2.5%)
All LR advantages favored LI+CIZ+SOC vs SOC (FLI)
Conclusion
LI neoadjuvant Tx followed by surgery and NCCN-directed RTx confirmed efficacy (OS, PFS, LRC) in the HPP subset. Multiple biomarkers (tumor: p16, PDL1, TME: CD4, CD8, CD3, FOXP3, CD20, CD68, CD163, CD1A, immune cells: PD1, CTLA4, PDL1, and CD25), ratios (CD4/CD8, CD8/FOXP3), and combinations proved to be predictive. LI + Surgery + RTx prolongs OS in SCCHN patients with no new Tx options in decades.