Neoadjuvant immunochemotherapy for locally advanced resectable oral squamous cell carcinoma: a prospective single-arm trial (Illuminate Trial)

Abstract

Background: Locally advanced oral squamous cell carcinoma (LAOSCC) is associated with a high rate of recurrence and poor survival. Given the recent successes of neoadjuvant immunochemotherapy (NAICT) in solid tumors, it is promising to use this treatment modality to achieve a better pathological response and improve the survival of LAOSCC, and clinical evidence is needed to assess its safety and efficacy.

Patients and methods: A prospective trial of NAICT with toripalimab (PD-1 inhibitor) and albumin paclitaxel/cisplatin (TTP) was conducted in patients with clinical stage III and IVA OSCC. Intravenous albumin paclitaxel (260 mg/m 2 ), cisplatin (75 mg/m 2 ), and toripalimab (240 mg) were given in sequence on day 1 of each 21 day cycle for two cycles, followed by radical surgery and risk-adapted adjuvant (chemo)radiotherapy. The primary endpoints were safety and major pathological response (MPR). Targeted next generation sequencing and multiplex immunofluorescence were performed to assess clinical molecular characteristics and the tumor immune microenvironment in the pre-NAICT and post-NAICT tumor samples.

Results: Twenty patients were enrolled. NAICT was well-tolerated with a low incidence of grades 3-4 adverse events in three patients. The completion rates of NAICT and subsequent R0 resection were 100%. The MPR rate was 60%, including a 30% pathological complete response. MPR was achieved in all four patients with a combined positive score of PD-L1>10. The density of tertiary lymphatic structure in post-NAICT tumor samples predicted the pathological response to NAICT. During the median 23-month follow-up, the disease-free survival was 90%, and the overall survival was 95%.

Conclusions: NAICT with the TTP protocol in LAOSCC is feasible and well tolerated, with a promising MPR and no obstruction on subsequent surgery. This trial is supportive of further randomized trials using NAICT in LAOSCC.

Trial registration: ClinicalTrials.gov NCT04473716.

Figure 1

Patient screening and disposition flow diagram.

Figure 2

Pathological and radiographical response to NAICT. (A) Tumor regression in a 31-year-old man with clinical stage III tongue cancer (T3N0M0, Patient No. 10). Pre-NAICT image showed a crateriform lesion on left lingual margin (left, white arrow); Post-NAICT image showed tumor shrank significantly (right, white arrow). (B) MR imaging showed the longest diameter of lesion was 2.72 cm in pre-NAICT (left) and 1.38 cm in post-NAICT (right). (C) Pathological findings of the biopsy specimen with hematoxylin–eosin staining, magnifications, 100 and 200 confirmed squamous cell carcinoma (left). Histopathologic images of the post-NAICT resection specimen showed pathological tumor bed (area marked by yellow line) with necrosis (black arrow), residual cornified pearl (white arrow), multinucleated giant cell infiltration (red arrow) and proliferative fibrosis (lower right), with no residual viable tumor (pathological complete response). (D) Waterfall plots showed pathological response and radiographical response to NAICT of individual patients who completed NAICT and surgery (n=20). Asterisks represents patients with CPS>1. (E) The pathological and radiographical response to NAICT was consistent in linear regression analysis (P<0.001).

Figure 3

Biomarker analysis of pathological response to NAICT. (A) Oncoplot showing mutations as assessed with a customized NGS panel targeting 733 cancer-related genes of baseline primary tumor samples (n=19; 5 pCR, 6 MPR, 8 non-MPR); A column represents a patient. Top bar chart represents tumor mutational burden (TMB). Percentages listed right represent the proportion of samples harboring a mutation in the gene listed left. Patients No. are listed at bottom. Bottom bars show pathological response and radiographical response. (B) The difference of TMB between the MPR and non-MPR groups is not statistically significant in unpaired t test (P=0.26). (C) The relationship between CPS and pathological response to NAICT is analyzed, based on the different CPS cutoffs (1, 10), all four patients with CPS>10 achieved MPR, and patients in the CPS>1 group had a higher MPR rate (6/8, 75%) than those in the CPS<1 group (6/12, 50%), but the difference between the two groups is not statistically significant in the Fisher’s exact test (P=0.423). (D) The post-NAICT sample with MIF for TILs staining showing TLS formation, which is composed of CD8+ T cell (pink fluorescent) and CD20+ B cell (green fluorescent) (the sample from patient No.18; left, 100×; right, 200×; DAPI, blue fluorescent). (E) More TLS was found in the post-NAICT samples compared with the pre-NAICT samples (P=0.0028), the difference is statistically significant in the MPR group (P=0.0092), not in the non-MPR group in Wilcoxon signed-rank test (P=0.20).