Low PD-L1 expression and node-negative status identified oral cancer patients most likely to benefit from neoadjuvant leukocyte interleukin injection.
Neoadjuvant leukocyte interleukin injection (LI; Multikine) plus cyclophosphamide, indomethacin, and zinc (CIZ) prior to standard of care (SOC) produced a significant overall survival (OS) benefit over SOC alone in patients with locally advanced oral squamous cell carcinoma (OSCC) or soft-palate cancer who had tumor PD-L1 expression below 10% and no nodal involvement (N0), according to a biomarker analysis of the phase 3 IT-MATTERS trial (NCT01265849) published in Oral Oncology.¹
In the histopathology intention-to-treat (ITT) population selected for N0 and PD-L1 tumor proportion score (TPS) below 10% (n = 114), the OS HR was 0.34 (95% CI, 0.18-0.66; P = .0012; Kaplan-Meier log-rank P = .0015) favoring LI plus CIZ plus SOC over SOC alone. Among patients confirmed as low risk for recurrence at surgery within this biomarker-selected cohort (n = 79), the OS HR improved to 0.26 (95% CI, 0.11-0.63; P = .0023; log-rank P = .0013), supported by a progression-free survival (PFS) HR of 0.43 (95% CI, 0.21-0.86; P = .0178), with a 32% absolute OS advantage over SOC at 60 months.
IT-MATTERS randomly assigned 928 treatment-naive patients with resectable, stage III or IVa OSCC or soft-palate cancer to LI plus CIZ plus SOC, LI plus SOC, or SOC alone; this analysis focused on the LI plus CIZ plus SOC and SOC-alone comparator arms. LI was administered as 2 mL total daily dose (400 IU as interleukin-2 equivalent) split between peritumoral and perilymphatic injection, five times weekly for three consecutive weeks, with CIZ comprising a single low-dose intravenous cyclophosphamide plus oral indomethacin and zinc multivitamins, all administered prior to SOC surgery and adjuvant radiotherapy or chemoradiotherapy.
Of 387 ITT histopathology (HP) subjects with tumor samples adequate for PD-L1 assessment by the 22C3 immunohistochemistry assay (n = 196 LI plus CIZ plus SOC; n = 191 SOC), PD-L1 expression was prospectively categorized as high (TPS ≥20%), medium (TPS 10%-<20%), or low (TPS <10%), with baseline demographics comparable between treatment arms. Median time from random assignment to surgery was 35 days for LI plus CIZ plus SOC versus 12 days for SOC, and participants were followed for a median of 59.5 months.
Without incorporating PD-L1 as a selection variable, the HP ITT low-risk cohort (n = 177) showed an OS HR of 0.64 (95% CI, 0.40-1.01; P = .0545; log-rank P = .0411) favoring LI plus CIZ plus SOC. Adding PD-L1 TPS below 10% and N0 status as selection criteria improved the OS HR to 0.34 in the overall biomarker-selected HP cohort (n = 114) and to 0.26 in the subset also confirmed as low risk at surgery (n = 79), with 5-year absolute OS advantages of 28.6% and 32%, respectively, favoring LI plus CIZ plus SOC.
Among ITT subjects meeting only the cN0 entry criterion regardless of PD-L1 status (n = 170), the OS HR was 0.55 (95% CI, 0.33-0.91; P = .0200). Investigators reported that low PD-L1 expression (TPS <10%) was observed in 67.3% of LI plus CIZ plus SOC–treated ITT patients and 62.3% of SOC-treated patients, and that similar findings were obtained using a TPS cutoff below 1%. Bias assessments comparing the 453 HP-evaluable subjects with the remaining ITT population identified no differences in baseline characteristics or outcomes.
Investigators noted that the PD-L1 and N0 selection criteria were developed based on the proposed mechanism of action of LI rather than confirmed prospectively as a primary trial hypothesis, and that the SOC control arm had a 9% higher proportion of stage III disease and 9% lower proportion of stage IVa disease than the LI-treated cohort within the biomarker-selected population.
The authors concluded that these findings represent the first demonstration of an OS advantage for a biomarker-selected (N0, PD-L1 TPS <10%), short-term neoadjuvant immunotherapy in treatment-naive, resectable, locally advanced HNSCC, complementing existing ICI approvals that apply to high PD-L1 expression, and proposed that these selection criteria could guide future neoadjuvant treatment trials in this population.
