Neoadjuvant LI Improves OS in Low PD-L1–Selected Oral Cancer

Neoadjuvant leukocyte interleukin injection (LI; Multikine) plus cyclophosphamide, indomethacin, and zinc (CIZ) prior to standard of care (SOC) improved overall survival (OS) compared with SOC alone in patients with locally advanced oral squamous cell carcinoma (OSCC) selected by lower tumor PD-L1 expression and lack of lymph node involvement, according to results published in Oral Oncology.¹

The findings come from a histopathology analysis of the phase 3 IT-MATTERS trial (NCT01265849; EudraCT 2010-019952-35), which randomly assigned 928 patients with treatment-naive, resectable, locally advanced stage III/IVa OSCC and soft palate cancer; 387 patients contributed tumor samples adequate for PD-L1 assessment. Among patients selected for no nodal involvement (N0) and tumor proportion score (TPS) of less than 10% (n = 114), OS was significantly improved with LI plus CIZ plus SOC vs SOC alone (HR, 0.34; 95% CI, 0.18-0.66; P =.0012), corresponding to a 28.6% absolute improvement in 5-year OS (73.4% vs 45.8%). Progression-free survival (PFS) was also improved in this population (HR, 0.51; 95% CI, 0.29-0.90; P = .0197).

“Publication of these findings in Oral Oncology represents an important peer-reviewed acceptance of the science behind our Multikine development program,” Geert Kersten, CEO of CEL-SCI Corporation, the study sponsor, stated in a news release. “The results not only confirm the remarkable [OS] and [PFS] benefit observed in the selected population analyzed in our phase 3 trial, but they also provide strong support for the biomarker selection strategy we are implementing for our confirmatory registration study.”²

Study Design and Biomarker Selection

Investigators evaluated 3 treatment groups in IT-MATTERS: LI plus CIZ plus SOC, LI plus SOC, and SOC alone, with OS as the primary end point. The current analysis focused on the comparison between LI plus CIZ plus SOC (n = 196) and SOC alone (n = 191) among the subset of patients with tumor samples suitable for PD-L1 immunohistochemistry using the 22C3 antibody clone diagnostic. Investigators prospectively defined PD-L1 TPS thresholds of high (≥ 20%), medium (≥ 10% to < 20%), and low (< 10%) expression, hypothesizing that tumors with lower PD-L1 expression would be more susceptible to the immune-mediated antitumor activity induced by LI. N0 status was also selected as a marker of lower disease burden, since LI requires 3 weeks of administration before surgery. The SOC included surgery followed by radiotherapy or chemoradiotherapy based on risk of recurrence.

In the full histopathology cohort, TPS of less than 10% was observed in 67.3% of patients treated with LI plus CIZ plus SOC and 62.3% of those who received SOC alone. When patients were further selected for confirmed low-risk status at surgery in addition to N0 and low PD-L1 expression (n = 79), the OS benefit was more pronounced (HR, 0.26; 95% CI, 0.11-0.61; P =.0023), with a 32% absolute OS advantage over SOC alone at 60 months; PFS was also improved in this group (HR, 0.43; 95% CI, 0.21-0.86; P =.0178).

Broader Development Context

According to the study authors, the findings represent the first demonstration of an OS benefit for a neoadjuvant treatment in biomarker-selected, treatment-naive, resectable, locally advanced head and neck squamous cell carcinoma vs SOC in decades. The authors contrasted these results with the neoadjuvant/adjuvant pembrolizumab (Keytruda) regimen evaluated in the KEYNOTE-689 trial (NCT03765918), which showed a significant improvement in event-free survival, predominantly in patients with high PD-L1 combined positive scores, but no significant OS benefit at the time of its FDA approval in this setting.

CEL-SCI is preparing to launch a global, 212-patient confirmatory registration study of LI in newly diagnosed, previously untreated, locally advanced resectable oral cancer, enrolling patients with low or no PD-L1 tumor expression (TPS < 10%) and no lymph node involvement, the same population evaluated in the Oral Oncology publication. According to the news release, the trial is designed with approximately 97% statistical power to confirm the previously observed OS benefit.

“As awareness of the [LI] data grows within the global oncology community, we believe [LI] will become increasingly recognized as a differentiated immunotherapy,” Kersten said in the news release.

REFERENCES

1. Talor E, Lavin P, Cipriano J, Markovic D, Ladányi A, Tímár J; IT-MATTERS Investigators. A novel neoadjuvant immunotherapy confers improved overall survival in oral cancer patients with low tumor PD-L1 expression: the IT-MATTERS clinical trial – prognostic role of tumor PD-L1 expression. Oral Oncol. 2026;181:108092. doi:10.1016/j.oraloncology.2026.108092

2. CEL-SCI Study Published in Peer-Reviewed Oral Oncology Supports Multikine's Biomarker Strategy and Potential Overall Survival Benefit Ahead of Head and Neck Cancer Confirmatory Registration Study. News release. CEL-SCI Corporation. August 4, 2026. Accessed August 4, 2026. https://tinyurl.com/y3t6cm32