Abstract
Contemporary observational cancer research requires associating genomic biomarkers with reproducible end points; overall survival (OS) is a key end point, but interpretation can be challenging when multiple lines of therapy and prolonged survival are common. Progression-free survival (PFS), time to treatment discontinuation (TTD), and time to next treatment (TTNT) are alternative end points, but their utility as surrogates for OS in real-world clinicogenomic data sets has not been well characterized. To measure correlations between candidate surrogate end points and OS in a multi-institutional clinicogenomic data set. A retrospective cohort study was conducted of patients with non-small cell lung cancer (NSCLC) or colorectal cancer (CRC) whose tumors were genotyped at 4 academic centers from January 1, 2014, to December 31, 2017, and who initiated systemic therapy for advanced disease. Patients were followed up through August 31, 2020 (NSCLC), and October 31, 2020 (CRC). Statistical analyses were conducted on January 5, 2021. Candidate surrogate end points included TTD; TTNT; PFS based on imaging reports only; PFS based on medical oncologist ascertainment only; PFS based on either imaging or medical oncologist ascertainment, whichever came first; and PFS defined by a requirement that both imaging and medical oncologist ascertainment have indicated progression. The primary outcome was the correlation between candidate surrogate end points and OS. There were 1161 patients with NSCLC (648 women [55.8%]; mean [SD] age, 63 [11] years) and 1150 with CRC (647 men [56.3%]; mean [SD] age, 54 [12] years) identified for analysis. Progression-free survival based on both imaging and medical oncologist documentation was most correlated with OS (NSCLC: ρ = 0.76; 95% CI, 0.73-0.79; CRC: ρ = 0.73; 95% CI, 0.69-0.75). Time to treatment discontinuation was least associated with OS (NSCLC: ρ = 0.45; 95% CI, 0.40-0.50; CRC: ρ = 0.13; 95% CI, 0.06-0.19). Time to next treatment was modestly associated with OS (NSCLC: ρ = 0.60; 0.55-0.64; CRC: ρ = 0.39; 95% CI, 0.32-0.46). This cohort study suggests that PFS based on both a radiologist and a treating oncologist determining that a progression event has occurred was the surrogate end point most highly correlated with OS for analysis of observational clinicogenomic data.
Highlights
For patients with cancer enrolled in clinical trials, the Response Evaluation Criteria in Solid Tumors, version 1.1,1 are applied to ascertain treatment response and disease progression
Progression-free survival based on both imaging and medical oncologist documentation was most correlated with overall survival (OS) (NSCLC: ρ = 0.76; 95% CI, 0.73-0.79; colorectal cancer (CRC): ρ = 0.73; 95% CI, 0.69-0.75)
Time to treatment discontinuation was least associated with OS (NSCLC: ρ = 0.45; 95% CI, 0.40-0.50; CRC: ρ = 0.13; 95% CI, 0.06-0.19)
Summary
For patients with cancer enrolled in clinical trials, the Response Evaluation Criteria in Solid Tumors, version 1.1,1 are applied to ascertain treatment response and disease progression. Overall survival (OS) constitutes a key outcome in cancer research, end points such as progression-free survival (PFS; time to progression or death), time to treatment discontinuation (TTD), and time to treatment (TTNT) may be relevant in some contexts. TTD, defined as the time from initiation of a systemic therapy regimen to the date of treatment discontinuation or death, can be rapidly extracted from structured pharmacy data and has been proposed as an alternative end point in the observational setting.[4,5] Time to treatment, defined as time from initiation of a systemic therapy to the date of initiation of the first subsequent systemic therapy regimen[6,7,8] or death, can be extracted from pharmacy data
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