Leukocyte interleukin injection (LI) immunotherapy extends overall survival (OS) in treatment-naive low-risk (LR) locally advanced primary squamous cell carcinoma of the head and neck: The IT-MATTERS study.

6032 Background: The 3-week pre-surgery peritumoral/perilymphatic administration of an investigational proinflammatory cytokine complex biologic (LI) with CIZ (single low dose cyclophosphamide IV-bolus, 300 mg/m 2 ), indomethacin (po 25mg tid) and Zinc as multivitamins (po 15-45mg Zinc) + Standard of Care (SOC) to oral and soft-palate SCCHN subjects, resulted in early response (CRs/PRs) prior to surgery [RECIST] (confirmed at surgery by pathology) significantly prolonged OS in the NCCN-defined LR intent to treat (ITT) population vs SOC alone. Encouraging phase 2 OS and early responders results motivated this pivotal study IT-MATTERS Clinicaltrials.gov NCT01265849. No safety issues were noted for LI in this pivotal study or previous studies. Methods: Subjects (923 ITT; of which 380 LR ITT) meeting protocol entry criteria (including AJCC Stage III/IVa OSCC, soft-palate SCCHN, treatment naive) were randomized 3:1:3 to treatment arms LI (+/- CIZ) + SOC or to Control (SOC alone). LI treated were administered 200IU peritumorally and the same dose peri-lymphatically daily for 3-weeks before surgery. All study subjects were to receive SOC (per NCCN Guidelines). LR for recurrence subjects were to receive RTx while high risk subjects were to receive CRTx post-surgery. Follow-up was comparable (56-57 months median per treatment group). Results: Pre-surgery responders (PSR; CR/PR) in ITT LI treated (+/- CIZ) groups were 8.5% (45/529; overall LI) and 16% (34/212; LR LI) vs no SOC PSRs. Early response lowered death rate to 22.2% (ITT LI treated) vs 54.1% for non-PSRs (two-sided Fisher Exact (2FE) p < 0.0001), for ITT LR LI PSRs with 17.6% vs 42.7% (2FE p = 0.0067), and for ITT LR LI responders (LI+CIZ+SOC) 12.5% vs 41% (2FE p = 0.0101). Proportional hazard (PH) ITT LR LI treated HR = 0.348 (95% CI: [0.152, 0.801]), ITT LR LI+CIZ+SOC HR = 0.246 (95% CI: [0.077, 0.787]). For all ITT LR (n = 380), LI+CIZ+SOC demonstrated significant OS advantage vs SOC (log rank p = 0.0478; Cox HR = 0.68 (95% CI: [0.48-0.95]), Wald p = 0.0236 [controlling for tumor stage, tumor location and geographic region]. The absolute OS advantage in ITT LR LI+CIZ+SOC vs SOC was 4.9%/9.5%/14.1%, at 36/48/60 months (M), representing 72.4% vs 67.5% (36 M); 67.3% vs 57.8% (48 M), and 62.7% vs 48.6% (60 M) with a 46.5 M median OS advantage (101.7 M [LI+CIZ+SOC] vs 55.2 M [SOC]). Percent treatment emergent adverse events (TEAEs) were comparable among all treated groups. No excess safety was reported for LI treatment over SOC alone. Conclusions: LI immunotherapy did not add excess safety issues or TEAEs. Early LI response decreases mortality and is OS prognostic. ITT LR LI+CIZ+SOC absolute OS advantage over SOC alone increased over time; the 0.68 HR corresponds to a 47% prolongation of median survival in a population without any new therapy options in decades. Clinical trial information: NCT01265849.

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