This phase II trial compares the effect of chemotherapy (carboplatin and paclitaxel) with versus without cemiplimab given before surgery (neoadjuvant) in patients with sinonasal squamous cell cancer. Carboplatin is in a class of medications known as platinum-containing compounds. Carboplatin works by killing, stopping or slowing the growth of cancer cells. Paclitaxel is in a class of medications called antimicrotubule agents. It stops cancer cells from growing and dividing and may kill them. Immunotherapy with monoclonal antibodies, such as cemiplimab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. The usual approach for patients with sinonasal squamous cell cancer is surgery followed by radiation therapy, with or without chemotherapy. Recently, some patients have also been treated with neoadjuvant chemotherapy before surgery. Adding cemiplimab to chemotherapy before surgery may be more effective at stopping the cancer from growing or spreading, compared to chemotherapy alone.
Patients must have histologically confirmed squamous cell carcinoma of sinonasal origin
Patients must have a T stage (T3, T4a, and select T4b) primary tumor according to American Joint Committee on Cancer (AJCC) 8th edition. Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥ 20 mm (≥ 2 cm) by chest x-ray or as ≥ 10 mm (≥ 1 cm) with CT scan, MRI, or calipers by clinical exam
No evidence of metastatic disease determined by pre-treatment imaging. Metastatic disease to neck nodes is considered locally advanced and therefore allowable. Patients with N0 and N1-3 disease will be eligible
Known HPV status (i.e., HPV negative, p16 immunohistochemistry [IHC] positive, high risk [HR]-HPV in situ hybridization [ISH] positive) from testing performed prior to referral. HPV status data (e.g., date of test, type of test [p16 IHC or HR-HPV ISH] and testing result) must be collected during enrollment. Patients who do not have this information available for collection will not be enrolled on this study
Patients with unresectable disease
Patients presenting with T3 disease without the need for maxillectomy and/or orbital invasion requiring orbital dissection/resection
Patients who have had any previous systemic therapy to the index lesion in the past 12 months. This includes cemiplimab (REGN2810) and/or other immune modulating agents. Previous systemic therapy may alter or affect response
Patients who had palliative RT (< 20 Gy) within 1 week prior to entering the study
Parallel
Biopsy Procedure
Procedure/SurgeryUndergo biopsy
Biospecimen Collection
Procedure/SurgeryUndergo collection of blood samples
Carboplatin
DrugGiven IV
Carboplatin
DrugGiven carboplatin
Cemiplimab
Biological/VaccineGiven IV
Chemoradiotherapy
Other interventionUndergo SOC CRT
Cisplatin
DrugGiven cisplatin
Computed Tomography
Procedure/SurgeryUndergo PET/CT and CT
Magnetic Resonance Imaging
Procedure/SurgeryUndergo MRI
Paclitaxel
DrugGiven IV
Positron Emission Tomography
Procedure/SurgeryUndergo PET/CT
Radiation Therapy
RadiationUndergo radiation therapy
Surgical Procedure
Procedure/SurgeryUndergo surgery
Event free survival (EFS)
Progression will be assessed per Response Evaluation Criteria in Solid Tumors version 1.1. To evaluate EFS, survival functions will be computed using the Kaplan-Meier method and compared between groups using the stratified log-rank test. Adjustment for additional covariates will be performed using Cox proportional hazards regression analysis if numbers allow.
Overall response rate (ORR)
ORR will be defined as complete response + partial response (≥ 30% decrease in tumor volume) per Response Evaluation Criteria in Solid Tumors version 1.1 criteria. ORR will be estimated with a 95% confidence interval using the exact Clopper Pearson method. The ORR will be compared between with neoadjuvant cemiplimab (REGN2810)/carboplatin/paclitaxel (Arm 1) to carboplatin/paclitaxel (Arm 2) using the Cochran-Mantel-Haenszel test, stratified by the same factors used for the primary endpoint. ORR for the aggregate study cohort (Arm 1 + Arm 2) will be compared to historical standard of care using the same analysis plan.
Incidence of adverse events (AEs) associated with neoadjuvant therapy (NAT)
Both acute toxicities and chronic toxicities will be graded by the treating investigator using the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. The frequency of participants experiencing a specific AE will be tabulated by dose level, cycle, seriousness, worst severity, timing of occurrence, outcome, and relationship to study drug. In addition, the number and percentage of participants experiencing a specific toxicity will be tabulated similarly. Accrual will be halted if excessive numbers of unacceptable toxicities are observed. This is defined as \> 30% grade 4 treatment-related AEs, which are directly attributable to NAT.
Changes in T-cell clonality/diversity
The changes in T-cell clonality/diversity will be assessed using ribonucleic acid sequencing (RNAseq) and correlated with NAT response and EFS. RNAseq data will undergo quality control, alignment to the human reference genome, and transcript quantification using standard bioinformatics pipelines. T-cell receptor sequences will be reconstructed using tools such as MiXCR or TRUST4. Measures of T-cell clonality and diversity (e.g., Shannon entropy, clonality index) will be calculated. Changes in T-cell clonality/diversity pre- and post-treatment will be assessed using paired t-tests or Wilcoxon signed-rank tests. Associations with NAT response and EFS will be analyzed using logistic regression and Cox proportional hazards models, adjusting for relevant covariates. Multiple testing correction using the Benjamini-Hochberg method will be applied where appropriate.
Organ preservation rates
Organ preservation in the post-treatment setting is defined as physical and functional preservation of the organ. For example, orbital preservation would imply maintenance of the entirety of the orbit and preservation of vision and motion. Orbital preservation rates will be summarized using descriptive statistics such as mean, standard deviation, median, and range. At the time of enrollment the treating team, with the guidance of the surgical team, will indicate what major anatomic locations would have to be resected if the patient elected initial primary surgical therapy (palate, orbit, and/or skull base). This prospective information will allow concrete subsequent secondary analyses of organ preservation rates without the bias of outcome or recall.
OS
Will correlate human papillomavirus status, combined positive score for PD-L1 expression, and circulating tumor deoxyribonucleic acid (ctDNA) with OS.
EFS
Will correlate human papillomavirus status, combined positive score for PD-L1 expression, and ctDNA with EFS.
NAT response rates
Will correlate human papillomavirus status, combined positive score for PD-L1 expression, and ctDNA with NAT response rates.
ctDNA
ctDNA will be measured at pre-defined timepoints. Sequencing using whole exome sequencing will be conducted on pre-treatment tissue.
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