Association of Patient Characteristics and Tumor Genomics With Clinical Outcomes Among Patients With Non-Small Cell Lung Cancer Using a Clinicogenomic Database
Gaurav Singal, Peter G Miller, Vineeta Agarwala, Gerald Li, Gaurav Kaushik, Daniel Backenroth, Anala Gossai, Garrett M Frampton, Aracelis Z Torres, Erik M Lehnert, David Bourque, Claire O'Connell, Bryan Bowser, Thomas Caron, Ezra Baydur, Kathi Seidl-Rathkopf, Ivan Ivanov, Garrett Alpha-Cobb, Ameet Guria, Jie He, Shannon Frank, Allen C Nunnally, Mark Bailey, Ann Jaskiw, Dana Feuchtbaum, Nathan Nussbaum, Amy P Abernethy, Vincent A Miller, Gaurav Singal, Peter G Miller, Vineeta Agarwala, Gerald Li, Gaurav Kaushik, Daniel Backenroth, Anala Gossai, Garrett M Frampton, Aracelis Z Torres, Erik M Lehnert, David Bourque, Claire O'Connell, Bryan Bowser, Thomas Caron, Ezra Baydur, Kathi Seidl-Rathkopf, Ivan Ivanov, Garrett Alpha-Cobb, Ameet Guria, Jie He, Shannon Frank, Allen C Nunnally, Mark Bailey, Ann Jaskiw, Dana Feuchtbaum, Nathan Nussbaum, Amy P Abernethy, Vincent A Miller
Abstract
Importance: Data sets linking comprehensive genomic profiling (CGP) to clinical outcomes may accelerate precision medicine.
Objective: To assess whether a database that combines EHR-derived clinical data with CGP can identify and extend associations in non-small cell lung cancer (NSCLC).
Design, setting, and participants: Clinical data from EHRs were linked with CGP results for 28 998 patients from 275 US oncology practices. Among 4064 patients with NSCLC, exploratory associations between tumor genomics and patient characteristics with clinical outcomes were conducted, with data obtained between January 1, 2011, and January 1, 2018.
Exposures: Tumor CGP, including presence of a driver alteration (a pathogenic or likely pathogenic alteration in a gene shown to drive tumor growth); tumor mutation burden (TMB), defined as the number of mutations per megabase; and clinical characteristics gathered from EHRs.
Main outcomes and measures: Overall survival (OS), time receiving therapy, maximal therapy response (as documented by the treating physician in the EHR), and clinical benefit rate (fraction of patients with stable disease, partial response, or complete response) to therapy.
Results: Among 4064 patients with NSCLC (median age, 66.0 years; 51.9% female), 3183 (78.3%) had a history of smoking, 3153 (77.6%) had nonsquamous cancer, and 871 (21.4%) had an alteration in EGFR, ALK, or ROS1 (701 [17.2%] with EGFR, 128 [3.1%] with ALK, and 42 [1.0%] with ROS1 alterations). There were 1946 deaths in 7 years. For patients with a driver alteration, improved OS was observed among those treated with (n = 575) vs not treated with (n = 560) targeted therapies (median, 18.6 months [95% CI, 15.2-21.7] vs 11.4 months [95% CI, 9.7-12.5] from advanced diagnosis; P < .001). TMB (in mutations/Mb) was significantly higher among smokers vs nonsmokers (8.7 [IQR, 4.4-14.8] vs 2.6 [IQR, 1.7-5.2]; P < .001) and significantly lower among patients with vs without an alteration in EGFR (3.5 [IQR, 1.76-6.1] vs 7.8 [IQR, 3.5-13.9]; P < .001), ALK (2.1 [IQR, 0.9-4.0] vs 7.0 [IQR, 3.5-13.0]; P < .001), RET (4.6 [IQR, 1.7-8.7] vs 7.0 [IQR, 2.6-13.0]; P = .004), or ROS1 (4.0 [IQR, 1.2-9.6] vs 7.0 [IQR, 2.6-13.0]; P = .03). In patients treated with anti-PD-1/PD-L1 therapies (n = 1290, 31.7%), TMB of 20 or more was significantly associated with improved OS from therapy initiation (16.8 months [95% CI, 11.6-24.9] vs 8.5 months [95% CI, 7.6-9.7]; P < .001), longer time receiving therapy (7.8 months [95% CI, 5.5-11.1] vs 3.3 months [95% CI, 2.8-3.7]; P < .001), and increased clinical benefit rate (80.7% vs 56.7%; P < .001) vs TMB less than 20.
Conclusions and relevance: Among patients with NSCLC included in a longitudinal database of clinical data linked to CGP results from routine care, exploratory analyses replicated previously described associations between clinical and genomic characteristics, between driver mutations and response to targeted therapy, and between TMB and response to immunotherapy. These findings demonstrate the feasibility of creating a clinicogenomic database derived from routine clinical experience and provide support for further research and discovery evaluating this approach in oncology.
Conflict of interest statement
Conflict of Interest Disclosures: Dr P. G. Miller reported receiving personal fees from Foundation Medicine Inc during the conduct of the study. Drs Singal, Li, Kaushik, Frampton, Lehnert, Alpha-Cobb, He, and V. A. Miller; Mr Bourque; Mr Guria; and Mr Bailey are employees at Foundation Medicine. Drs Agarwala, Backenroth, Gossai, Torres, O’Connell, Seidl-Rathkopf, and Nussbaum; Mr Bowser; Mr Caron; Mr Baydur; Mr Ivanov; Ms Frank; Ms Jaskiw; and Ms Feuchtbaum are employees of Flatiron Health. Both Flatiron Health and Foundation Medicine are owned by the Roche Group. Dr Agarwala is also an employee of Google Ventures. Dr Seidl-Rathkopf also reported being an inventor for 2 patents for technology to generate and monitor cohort models for Flatiron Health. At the time of this work, Dr Abernethy was chief medical officer, chief scientific officer, and senior vice president of oncology at Flatiron Health, a member of the Roche Group, and had stock ownership in Roche. At that time, Dr Abernethy also declared the following: serving on the board of directors and stock ownership of athenahealth and CareDx; owner of Orange Leaf Associates LLC; senior advisor of Highlander Partners; advisor of SignalPath Research, RobinCare, and KelaHealth Inc; special advisor of The One Health Company; receiving honoraria from Roche/Genentech (<USD$10 000/year); and having a patent pending for a technology that facilitates the extraction of unstructured information from medical records. With the exception of Orange Leaf Associates LLC, all of these relationships ended on or before January 2019, predating her joining the US Food and Drug Administration (FDA). Since joining the FDA, Dr Abernethy has complied with applicable ethics laws. Dr V. A. Miller is chief medical officer of Foundation Medicine, a board member of Revolution Medicines from which he receives an honorarium and equity, and a patent holder for T790M for which he receives royalties from Memorial Sloan Kettering Cancer Center. No other disclosures were reported.
Figures
Source: PubMed