Abstract
PurposeClassical clinical endpoints [e.g., objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS)] may not be appropriate for immune checkpoint blockers (ICBs). We evaluated correlations between these endpoints and overall survival (OS) for surrogacy.MethodsRandomized controlled trials (RCTs) of solid tumors patients treated with ICBs published between 01/2005 and 03/2017, and congress proceedings (2014–2016) were included. Arm-level analyses measured 6-month PFS rate to predict 18-month OS rate. Comparison-level analyses measured ORR odds ratio (OR), DCR OR, and 6-month PFS hazard ratio (HR) to predict OS HR. A pooled analysis for single-agent ICBs and ICBs plus chemotherapy vs chemotherapy was conducted. Studies of single-agent ICBs vs chemotherapy were separately analyzed.Results27 RCTs involving 61 treatment arms and 10,300 patients were included. Arm-level analysis showed higher 6- or 9-month PFS rates predicted better 18-month OS rates for ICB arms and/or chemotherapy arms. ICB arms had a higher average OS rate vs chemotherapy for all PFS rates. Comparison-level analysis showed a nonsignificant/weak correlation between ORR OR (adjusted R2 = − 0.069; P = 0.866) or DCR OR (adjusted R2 = 0.271; P = 0.107) and OS HR. PFS HR correlated weakly with OS HR in the pooled (adjusted R2 = 0.366; P = 0.005) and single-agent (adjusted R2 = 0.452; P = 0.005) ICB studies. Six-month PFS HR was highly predictive of OS HR for single-agent ICBs (adjusted R2 = 0.907; P < 0.001), but weakly predictive in the pooled analysis (adjusted R2 = 0.333; P = 0.023).ConclusionsPFS was an imperfect surrogate for OS. Predictive value of 6-month PFS HR for OS HR in the single-agent ICB analysis requires further exploration.
Highlights
Immune checkpoint blockers (ICBs), and the use of antibodies against programmed cell death-1 (PD-1), programmed cell death ligand-1 (PD-L1), and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) have been approved for use in several cancer types and demonstrated improved overall survival (OS) compared with the standard therapy (AstraZeneca Pharmaceuticals 2017; Bristol-Myers Squibb 2013; Bristol-Myers Squibb 2017; Genentech 2017; Merck and Company Inc. 2017; Pfizer 2017)
We identified relevant randomized controlled trials (RCTs) of ICBs over the past 12 years and analyzed both arm- and comparisonlevel data to explore the relationship between OS and clinical endpoints (ORR, disease control rate (DCR), and progression-free survival (PFS)) in patients with solid tumors treated with single-agent ICBs or ICBs in combination with chemotherapy, compared with patients treated with chemotherapy
Most of these studies were conducted in patients with melanoma (52%; 14/27), followed by non-small-cell lung cancer (NSCLC) (33%; 9/27); 2 trials were conducted in patients with urothelial carcinoma (UC), one study in patients with renal-cell carcinoma (RCC), and one study in patients with head and neck squamous-cell carcinoma (HNSCC)
Summary
Immune checkpoint blockers (ICBs), and the use of antibodies against programmed cell death-1 (PD-1), programmed cell death ligand-1 (PD-L1), and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) have been approved for use in several cancer types and demonstrated improved overall survival (OS) compared with the standard therapy (AstraZeneca Pharmaceuticals 2017; Bristol-Myers Squibb 2013; Bristol-Myers Squibb 2017; Genentech 2017; Merck and Company Inc. 2017; Pfizer 2017). Improvement in OS is generally the most desirable endpoint in oncology clinical trials, there is an ongoing interest in identifying and validating surrogate endpoints that can better predict the likelihood of OS to improve the design of clinical studies and potentially expedite the approval of novel agents (Booth and Eisenhauer 2012; Foster et al 2011; Kemp and Prasad 2017) Correlations between endpoints such as progression-free survival (PFS), ORR, disease control rate (DCR), and time to progression and OS have been investigated, but correlations between these endpoints and OS have not been thoroughly investigated for ICBs (Flaherty et al 2014; Prasad et al 2015). Unlike other cancer therapies that act directly on tumor cells, ICBs act indirectly by enhancing antitumor immune responses and eliciting lymphocyte infiltration into the tumor, thereby frequently resulting in an initial tumor enlargement of varying degrees depending on the tumor type, and possibly the appearance of new lesions, with subsequent reduction in tumor size and number of lesions mediated by ongoing immunologic mechanisms (Hersh et al 2011; Hodi et al 2016b; Seymour et al 2017; Wolchok et al 2009)
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