Lead Investigator: David Hsieh, University of Texas Southwestern Medical Center
Title of Proposal Research: Patterns of outcomes and the relevance surrogate endpoints in patients treated with immune checkpoint inhibitors.
Vivli Data Request: 6008
Funding Source: Cancer Prevention and Research Institute of Texas
Potential Conflicts of Interest: None
Summary of the Proposed Research:
Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy because of their ability to induce tolerable and durable responses in advanced cancers. This can be attributed to the unique mechanism by which ICIs trigger a person’s immune system to reject cancer cells. The effects of ICIs in patients are different from those observed with conventional chemotherapies. For instance, while chemotherapy typically causes cancer cell death resulting in detectable shrinkage of cancers, ICIs may stop or slow cancer growth for long periods without evidence of cancer cell death. In several small studies, patients treated with ICIs have also been noted to have prolonged lives despite their cancers growing during ICI treatment. The different patterns of responses observed in patients treated with ICIs are important to recognize as they guide expectations of treatment outcomes for patients and may inform the design of clinical trials studying ICIs. However, atypical responses to ICIs have not been consistently defined in past studies or only assessed at the level of trials. This is also of clinical relevance as surrogate endpoints, substitute measures of overall survival, are frequently used in ICI trials to determine the advancement of treatment testing or for FDA approval.
Our primary objective is to assess how objective response categories, progression-free survival (PFS), duration of response (DUR), time to best response (TTBR), and depth of response (DepOR) are associated/correlated with overall survival (OS) in patients treated with ICIs.
Statistical Analysis Plan:
To explore different patterns of clinical outcomes after ICIs, we will perform K-means unsupervised clustering of patients using objective response categories, overall survival (OS), progression-free survival (PFS), duration of response (DUR), time to best response (TTBR), and depth of response (DepOR) as features. This will allow us to determine how overall survival and different surrogate outcomes may be related and characterize the frequency of patients with a specific outcome profile. For instance, we may identify a cluster of patients with stable disease but prolonged OS, and the number of patients within this cluster would allow us to gauge the prevalence of this outcome profile.
To specifically assess the association between PFS, DUR, TTBR, and DepOR with OS, we will determine the Pearson correlation coefficient and coefficient of determination to assess the linear relationship and the proportion of variance in OS that is explained by surrogate endpoints. The Kruskal-Wallis test will be used to test for differences in the length of OS between objective response categories.
To assess whether surrogate endpoints and patient characteristics (age, sex, and body mass index) are predictive of OS, we will use time-dependent univariable and multivariable Cox regression analyses of OS.
Analyses will be done in collaboration with Dr. Yang Xie, Director of the Quantitative Biomedical Research Center at UTSW.
Data is requested from phase 2 as well as phase 3 comparative trials, as non-ICI treated patients will be similarly assessed to determine whether outcome categories observed with ICIs are also seen among patients treated with chemotherapies and other anti-cancer agents.
Requested Studies:
A Phase II, Multicenter, Single-Arm Study of Atezolizumab in Patients With Locally Advanced or Metastatic Urothelial Bladder Cancer
Data Contributor: Roche
Study ID: NCT02951767
Sponsor ID: GO29293 (Cohort 1)
A Phase III, Open-Label, Randomized Study of Atezolizumab (Anti-PD-L1 Antibody) in Combination With Bevacizumab Versus Sunitinib in Patients With Untreated Advanced Renal Cell Carcinoma
Data Contributor: Roche
Study ID: NCT02420821
Sponsor ID: WO29637
A Phase III, Open-Label, Multicenter, Randomized Study to Investigate the Efficacy and Safety of Atezolizumab (Anti-PD-L1 Antibody) Compared With Chemotherapy in Patients With Locally Advanced or Metastatic Urothelial Bladder Cancer After Failure With Platinum-Containing Chemotherapy
Data Contributor: Roche
Study ID: NCT02302807
Sponsor ID: GO29294
A Phase II, Multicenter, Single-Arm Study of Atezolizumab in Patients With Locally Advanced or Metastatic Urothelial Bladder Cancer
Data Contributor: Roche
Study ID: NCT02108652
Sponsor ID: GO29293 (Cohort 2)
A Phase II, Multicenter, Single-Arm Study OF Atezolizumab In Patients With PD-L1-Positive Locally Advanced Or Metastatic Non-Small Cell Lung Cancer
Data Contributor: Roche
Study ID: NCT02031458
Sponsor ID: GO28754
A Phase III, Open-Label, Multicenter, Randomized Study to Investigate the Efficacy and Safety of Atezolizumab (Anti-PD-L1 Antibody) Compared With Docetaxel in Patients With Non-Small Cell Lung Cancer After Failure With Platinum Containing Chemotherapy
Data Contributor: Roche
Study ID: NCT02008227
Sponsor ID: GO28915
A Phase II, Randomized Study of Atezolizumab (Anti-PD-L1 Antibody) Administered as Monotherapy or in Combination With Bevacizumab Versus Sunitinib in Patients With Untreated Advanced Renal Cell Carcinoma
Data Contributor: Roche
Study ID: NCT01984242
Sponsor ID: WO29074
A Phase II, Open-label, Multicenter, Randomized Study to Investigate the Efficacy and Safety of MPDL3280A (Anti−PD-L1 Antibody) Compared With Docetaxel in Patients With Non−Small Cell Lung Cancer After Platinum Failure
Data Contributor: Roche
Study ID: NCT01903993
Sponsor ID: GO28753
A Phase II, Multicenter, Single-arm Study of MPDL3280A in Patients With PD-L1-Positive Locally Advanced or Metastatic Non-small Cell Lung Cancer
Data Contributor: Roche
Study ID: NCT01846416
Sponsor ID: GO28625
Public Disclosures:
- Espinoza, M., Muiquith, M., Lim, M., Zhu, H., Singal, A. G., & Hsiehchen, D. (2023). Disease etiology and outcomes after atezolizumab plus bevacizumab in hepatocellular carcinoma: Post-hoc analysis of IMbrave150. Gastroenterology. doi: 10.1053/j.gastro.2023.02.042
- Lim, M., Muquith, M., Miramontes, B., Lee, C.J., Espinoza, M., Huang, Y.H. and Hsiehchen, D., 2023. Surrogate and modified endpoints for immunotherapy in advanced hepatocellular carcinoma. Hepatology, pp.10-1097. Doi: 10.1097/HEP.0000000000000494