ES20.02 Charting a New Path: Defining Better Endpoints in Immune Therapy Trials in Lung Cancer

Abstract

The use of immune checkpoint inhibitor therapy has transformed the face of lung cancer management. Trials of such agents for metastatic and locally advanced disease have used the traditional endpoint of overall survival (OS) by time-to-event analysis. However, obtaining this endpoint in a randomized trial takes some time and other endpoints are being considered, particularly for the radical or operable setting. To consider the most appropriate endpoint to use for immunotherapy, we must consider the aims of our treatment of lung cancer. For radically treatable disease through surgery is the aim always to improve the cure rate, or is another aim such as delaying recurrence (e.g., disease-free survival) just as clinically meaningful, if it doesn’t correlate with OS? We must also consider the magnitude of the effect size we wish to observe, particularly when using a surrogate endpoint of OS. Here, hazard ratios of 0.85 may not be clinically meaningful anymore, and we need to consider if we are prepared to accept uncertainty in effect by using a surrogate (earlier) endpoint for more rapid regulatory approval. If using a surrogate endpoint, will this give enough information to be able to pass HTA reimbursement value thresholds? We have clear guidance from the regulatory agencies on endpoints to be used for clinical trials. EMA give different definitions of endpoints for phase 1 and 2 trials from confirmatory phase 3 trials, giving a different stance for trials of cytotoxics to those non-cytotoxic based1. They recognize that immunomodulatory treatments may work most effectively where tumour bulk is low, and may take time to generate an defect, indeed with effect occurring post progression, and for phase 3 trials, progression-free survival remains acceptable. In the curative setting, EMA is clear that if event-free survival (EFS) is being used then this is justified under certain conditions and they give clear direction on using surrogates for the (neo)adjuvant setting1. The FDA also gives clear guidance on endpoints, with OS as the gold standard, but may allow other endpoints, recognizing that non-small cell lung cancer (NSCLC) is a heterogeneous disease, and the effects of different subsets should be explored2. When immunotherapy is being considered as the investigational medical product, endpoints such as progression-free survival (PFS), objective response rate (ORR) and even OS can have several benefits and risks. Measuring the benefit from immunotherapy can be difficult due to different patterns of benefit, and altered kinetics of benefit from cytotoxic therapy, alongside the heterogenous nature of NSCLC. Several surrogate endpoints e.g., ORR, duration of response, relapse-free survival, major pathological response or complete pathological response can be considered, but each give several benefits, but are prone to biases that need accounting for. The latter pathology-based endpoints have unclear definitions and the IASLC have proposed a structure for their definition3. When considering such surrogate endpoints, we should consider if such surrogates really to result in earlier approval or whether OS-based randomized trials are the main strategy- giving the example of extensive-stage small cell lung cancer4. Finally, if considering disease-free survival (DFS), multiple considerations need to be given. There are multiple emerging endpoints such as minimal residual disease in myeloma and the field of surrogate endpoints continues to evolve5. 1. EMA. Guideline on the clinical evaluation of anticancer medicinal products. https://www.ema.europa.eu/en/documents/scientific-guideline/draft-guideline-evaluation-anticancer-medicinal-products-man-revision-6_en.pdf 2. FDA. Clinical Trial Endpoints for the Approval of Non- Small Cell Lung Cancer Drugs and Biologics. Published 2015. https://www.fda.gov/media/116860/download 3. Travis WD, Dacic S, Wistuba I, et al. IASLC Multidisciplinary Recommendations for Pathologic Assessment of Lung Cancer Resection Specimens After Neoadjuvant Therapy. Journal of Thoracic Oncology. 2020;15(5):709-740. doi:10.1016/j.jtho.2020.01.005 4. Gill J, Cetnar JP, Prasad V. A Timeline of Immune Checkpoint Inhibitor Approvals in Small Cell Lung Cancer. Trends in Cancer. 2020;6(9):736-738. doi:10.1016/j.trecan.2020.05.014 5. EMA. Guideline on the use of minimal residual disease as a clinical endpoint in multiple myeloma studies. https://www.ema.europa.eu/en/documents/scientific-guideline/draft-guideline-use-minimal-residual-disease-clinical-endpoint-multiple-myeloma-studies_en.pdf endpoint, Clinical trials, immunotherapy