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Multicenter Study
. 2021 Jul 1;4(7):e2117547.
doi: 10.1001/jamanetworkopen.2021.17547.

Correlation Between Surrogate End Points and Overall Survival in a Multi-institutional Clinicogenomic Cohort of Patients With Non-Small Cell Lung or Colorectal Cancer

Kenneth L Kehl  1 , Gregory J Riely  2 , Eva M Lepisto  1 , Jessica A Lavery  2 , Jeremy L Warner  3   4 , Michele L LeNoue-Newton  5 , Shawn M Sweeney  6 , Julia E Rudolph  2 , Samantha Brown  2 , Celeste Yu  7 , Philippe L Bedard  7   8 , Deborah Schrag  1   9 , Katherine S Panageas  2 ; American Association of Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) Consortium
Collaborators, Affiliations
Multicenter Study

Correlation Between Surrogate End Points and Overall Survival in a Multi-institutional Clinicogenomic Cohort of Patients With Non-Small Cell Lung or Colorectal Cancer

Kenneth L Kehl et al. JAMA Netw Open. .

Abstract

Importance: 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.

Objective: To measure correlations between candidate surrogate end points and OS in a multi-institutional clinicogenomic data set.

Design, setting, and participants: 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.

Exposures: 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.

Main outcomes and measures: The primary outcome was the correlation between candidate surrogate end points and OS.

Results: 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).

Conclusions and relevance: 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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Kehl reported receiving grants from Wong Family Foundation, American Association of Cancer Research (AACR), Simeon J. Fortin Foundation, Doris Duke Foundation, and the National Cancer Institute during the conduct of the study; grants from IBM; and personal fees from Aetion and Roche outside the submitted work. Dr Riely reported receiving grants from AACR during the conduct of the study; grants from Novartis, Pfizer, Merck, Mirati, Takeda, and Roche; and nonfinancial support from Pfizer and Merck outside the submitted work. Ms Lepisto reported receiving grants from AACR during the conduct of the study. Ms Lavery reported receiving grants from AACR during the conduct of the study. Dr Warner reported receiving grants from AACR during the conduct of the study; grants from the National Institutes of Health; consulting fees from Westat and IBM; and having equity in HemOnc.org LLC. Dr LeNoue-Newton reported receiving research funding from AACR during the conduct of the study; and research funding from GE Healthcare outside the submitted work. Dr Sweeney reported receiving grants from Amgen Inc, AstraZeneca UK Ltd, Bristol Myers Squibb, Bayer Healthcare Pharmaceuticals Inc, Boehringer Ingelheim, Genentech, Janssen Pharmaceuticals Inc, Merck Sharp & Dohme Corp, Novartis, and Pfizer Inc during the conduct of the study. Ms Brown reported receivng grants from AACR during the conduct of the study. Dr Bedard reported receiving grants from AACR during the conduct of the study; consulting fees from Seattle Genetics, Eli Lilly and Co, Amgen Inc, Merck Sharp & Dohme Corp, Bristol Myers Squibb, Sanofi, and Pizer; serving on the advisory boards for Bristol Myers Squibb, Eli Lilly and Co, Amgen, Seattle Genetics, Merck, Pfizer, and Gilead; and receiving research funding directed to his institution from Bristol Myers Squibb, Sanofi, AstraZeneca, Genentech, Servier, GlaxoSmithKline, Novartis, SignalChem, PTC Therapeutics, Nektar, Merck Sharp & Dohme Corp, Seattle Genetics, Mersana, Immunomedics, and Eli Lilly and Co. Dr Schrag reported receiving fees from JAMA for editorial services; speaking fees from Pfizer; research funding given directly to the institution from AACR, Patient-Centered Outcomes Research Institute, GRAIL, and the National Cancer Institute (NCI). Dr Panageas reported receiving grants from NCI Cancer Center Support Grant and research funding from AACR Project Genomics Evidence Neoplasia Information Exchange (GENIE) Consortium during the conduct of the study. AACR Project GENIE receives funding from Amgen Inc, Bristol Myers Squibb Co, Merck Sharp & Dohme Corp, AstraZeneca UK Ltd, Genentech, Novartis, Bayer Healthcare Pharmaceuticals Inc, H3 Biomedicine, Puma Biotechnology, Boehringer Ingelheim, and Janssen Pharmaceuticals Inc. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Kaplan-Meier Curves for Candidate Outcome Measures After First-Line Systemic Therapy for Recurrent or Metastatic Non–Small Cell Lung Cancer
OS indicates overall survival; PFS, progression-free survival; PFS-I, PFS based on imaging reports only; PFS-I-and-M, PFS defined by a requirement that both imaging and medical oncologist ascertainment have indicated progression; PFS-I-or-M, PFS based on either imaging or medical oncologist ascertainment, whichever came first; PFS-M, PFS based on medical oncologist ascertainment only; TTD, time to treatment discontinuation (or death); and TTNT, time to next treatment (or death).
Figure 2.
Figure 2.. Kaplan-Meier Curves for Candidate Outcome Measures After First-Line Systemic Therapy for Recurrent or Metastatic Colorectal Cancer
OS indicates overall survival; PFS, progression-free survival; PFS-I, PFS based on imaging reports only; PFS-I-and-M, PFS defined by a requirement that both imaging and medical oncologist ascertainment have indicated progression; PFS-I-or-M, PFS based on either imaging or medical oncologist ascertainment, whichever came first; PFS-M, PFS based on medical oncologist ascertainment only; TTD, time to treatment discontinuation (or death); and TTNT, time to next treatment (or death).
See this image and copyright information in PMC

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