Investigator-initiated Phase II Study of Pembrolizumab Immunological Response Evaluation (INSPIRE)

Aim/goals:

1. Evaluate the changes in genomic, transcriptomic and immune landscapes in patients with various advanced solid tumors during pembrolizumab treatment
2. Assess the feasibility of utilizing circulating tumor DNA analysis as a monitoring tool
3. Explore the potential value of radiomic imaging analysis as a predictive biomarker to pembrolizumab and investigate whether there is any correlation or relationship between tumor genomic profiles and radiomic imaging signatures
4. Explore changes in immune cell subsets in the peripheral circulation and tumor microenvironment during treatment with pembrolizumab
5. Evaluate the positive and negative predictive values of an in vitro predictive assay in distinguishing responders from non-responders among patients receiving pembrolizumab
6. Evaluate the distribution on tumor penetration of pembrolizumab using mass spectrometry based monitoring assay
7. Contribute to data sharing initiatives to maximize the understanding of predictive biomarkers of response or resistance to immune checkpoint blockade

Summary:

INSPIRE (NCT02644369) is a flagship, investigator-initiated phase II study conducted by the Tumor Immunotherapy Program (TIP) at the Princess Margaret, which enrolled 106 patients with advanced solid tumors from March 21, 2016 to May 9, 2018. INSPIRE had 5 patient cohorts: (A) squamous cell carcinoma of the head and neck (n=19), (B) triple negative breast cancer (n=22), (C) high grade serous ovarian cancer (n=21), (D) malignant melanoma (n=12), (E) mixed solid tumors (n=32), all treated with single agent pembrolizumab given intravenously every 3 weeks. INSPIRE is considered a ‘gold standard’ for investigator-initiated therapeutic studies at the Princess Margaret. It comprises data-rich cohorts that collected pre-treatment and on-treatment tumor and blood samples to enable the investigations to evaluate multi-omic predictive and pharmacodynamic biomarkers of sensitivity or resistance to immune checkpoint blockade. Multiple publications have emerged from data generated from the INSPIRE study and additional research are ongoing (Clouthier et al, JITC 2018 PMID 30867072; Bratman, Yang et al. Nat Cancer 2020; Yang et al. Nat Comm 2021 PMID 34446728).