Vienna, Austria

ESTRO 2023

Session Item

Head and neck
6005
Poster (Digital)
Clinical
Biomarkers of neoadjuvant Multikine (LI) treatment outcome in locally advanced head & neck carcinoma
József Timar, Hungary
PO-1231

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.