Biomarkers for Predicting Response to PD-1 Inhibitor Therapy in Squamous Cell Carcinoma: A Retrospective-Prospective Cohort Study

1. Study Title Biomarkers for Predicting Response to PD-1 Inhibitor Therapy in Squamous Cell Carcinoma: A Retrospective-Prospective Cohort Study
2. Background and Rationale Squamous Cell Carcinoma (SCC) is a malignancy arising from squamous epithelium, affecting multiple organs including the skin, oral cavity, esophagus, lungs, and cervix. It is characterized by a high incidence rate and significant mortality.

• Epidemiology of SCC Subtypes:

• Esophageal Squamous Cell Carcinoma (ESCC): According to 2022 GLOBOCAN data, esophageal cancer is the 11th most common cancer globally, with ESCC accounting for approximately 90% of cases. China is a high-incidence region for this disease. Despite a decreasing incidence, the five-year survival rate remains low at around 20%.

• Head and Neck Squamous Cell Carcinoma (HNSC): HNSC represents about 90% of all head and neck cancers, with approximately 890,000 new cases and 325,000 deaths globally in 2022. In China, the mortality rate from head and neck cancer has been rising, primarily linked to risk factors like smoking, alcohol consumption, and betel nut use.

• Cervical Squamous Cell Carcinoma (CESC): In 2022, China recorded the highest number of new cervical cancer cases globally, with 150,659 new diagnoses (23% of the global total) and 55,694 deaths (16% of the global total). Disparities in screening and HPV vaccination access contribute to a heavy burden, particularly in lower-income areas.

• Lung Squamous Cell Carcinoma (LUSC): In 2022, China accounted for 42.8% of new global lung cancer cases and 40.3% of deaths. LUSC is a major subtype, strongly associated with smoking, and is characterized by rapid cell proliferation and a high potential for invasion and metastasis.

• Therapeutic Landscape and Unmet Needs: The advent of PD-1 inhibitors over the past decade has offered new hope for patients with SCC. However, clinical trials have shown that the benefits are limited to a subset of patients, and the high cost of treatment places a significant financial burden on healthcare systems. Therefore, there is a critical need to develop accurate and reliable predictive biomarkers to identify patients most likely to respond to immunotherapy.

• Current Biomarkers and Rationale for a Pan-SCC Approach: PD-L1 expression is the most widely studied biomarker, assessed via systems like Tumor Proportion Score (TPS) and Combined Positive Score (CPS). However, these methods have limitations. This study is founded on the principle that SCCs originating from different anatomical sites (esophagus, cervix, head and neck, lung) share significant molecular and immunological similarities. This "pan-cancer" approach allows for the integration of data across tumor types to identify common biological characteristics and universal mechanisms of drug resistance. By expanding from a single cancer type to a pan-SCC analysis, this study aims to accelerate the optimization of immunotherapy strategies and develop a more broadly applicable predictive model. Within this framework, assay-based biomarker features, including blood ELISA and tissue mIF, and pretreatment tissue-pathology features, including PD-L1 assessment, biopsy/H&E-based features, and other clinicopathological features where available, may be evaluated as component scores and/or integrated risk scores to support response prediction and risk stratification.

This innovative retrospective-prospective cohort study will integrate real-world clinical data with biological samples to build and validate a predictive model specifically for Chinese patients with SCC, aiming to guide clinical decision-making and optimize resource allocation. 3. Study Objectives

• Primary Objective: To evaluate the performance of a predictive model or risk-score framework based on blood-based ELISA, tissue-based multiplex immunofluorescence assays, PD-L1 assessment, and available pretreatment biopsy/H&E-based pathology and clinicopathological features, individually or in combination, in forecasting the efficacy of PD-1 inhibitor-based therapy in patients with squamous cell carcinoma.
• Secondary Objectives: