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Purpose: The utility of real-world data (RWD) for use as external controls in drug development is informed by studies that replicate trial control arms for different endpoints. The purpose of this study was to replicate control arms from four non–small cell lung cancer (NSCLC) randomized controlled trials (RCT) to analyze overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) using RWD. Patients and Methods: This study used RWD from a nationwide de-identified database and a clinico-genomic database to replicate OS, PFS, and ORR endpoints in the chemotherapy control arms of four first-line NSCLC RCTs evaluating atezolizumab [IMpower150–wild-type (WT), IMpower130-WT, IMpower131, and IMpower132]. Additional objectives were to develop a definition of real-world PFS (rwPFS) and to evaluate the real-world response rate (rwRR) endpoint. Results: Baseline demographic and clinical characteristics were balanced after application of propensity score weighting methods. For rwPFS and OS, RWD external controls were generally similar to their RCT control counterparts. Across all four trials, the hazard ratio (HR) point estimates comparing trial controls with external controls were closer to 1.0 for the PFS endpoint than for the OS endpoint. An exploratory assessment of rwRR in RWD revealed a slight but nonsignificant overestimation of RCT ORR, which was unconfounded by baseline characteristics. Conclusions: RWD can be used to reasonably replicate the OS and PFS of chemotherapy control arms of first-line NSCLC RCTs. Additional studies can provide greater insight into the utility of RWD in drug development.

Purpose: Chk1 inhibition potentiates DNA-damaging chemotherapy by overriding cell-cycle arrest and genome repair. This phase I study evaluated the Chk1 inhibitor GDC-0425 given in combination with gemcitabine to patients with advanced solid tumors. Experimental Design: Patients received GDC-0425 alone for a 1-week lead-in followed by 21-day cycles of gemcitabine plus GDC-0425. Gemcitabine was initially administered at 750 mg/m2 (Arm A), then increased to 1,000 mg/m2 (Arm B), on days 1 and 8 in a 3 + 3 + 3 dose escalation to establish maximum tolerated dose (MTD). GDC-0425 was initially administered daily for three consecutive days; however, dosing was abbreviated to a single day on the basis of pharmacokinetics and tolerability. TP53 mutations were evaluated in archival tumor tissue. On-treatment tumor biopsies underwent pharmacodynamic biomarker analyses. Results: Forty patients were treated with GDC-0425. The MTD of GDC-0425 was 60 mg when administered approximately 24 hours after gemcitabine 1,000 mg/m2. Dose-limiting toxicities included thrombocytopenia (n = 5), neutropenia (n = 4), dyspnea, nausea, pyrexia, syncope, and increased alanine aminotransferase (n = 1 each). Common related adverse events were nausea (48%); anemia, neutropenia, vomiting (45% each); fatigue (43%); pyrexia (40%); and thrombocytopenia (35%). The GDC-0425 half-life was approximately 15 hours. There were two confirmed partial responses in patients with triple-negative breast cancer (TP53-mutated) and melanoma (n = 1 each) and one unconfirmed partial response in a patient with cancer of unknown primary origin. Conclusions: Chk1 inhibition with GDC-0425 in combination with gemcitabine was tolerated with manageable bone marrow suppression. The observed preliminary clinical activity warrants further investigation of this chemopotentiation strategy. Clin Cancer Res; 23(10); 2423–32. ©2016 AACR.

Background: Hormone receptor-positive (HR+) breast cancer (BC) comprises 60-65% of all BC. Activating mutations in PIK3CA are the most common oncogenic alteration in HR+ BC, yet little is known about the prognostic utility of single (SM) and multiple (MM) PIK3CA mutations. A novel database with next-generation sequencing (NGS) data from Foundation Medicine, Inc. (FMI) linked to electronic health records-derived clinical data from Flatiron Health allows investigation of the prognostic utility of genomic alterations including PIK3CA. Using this database, this study seeks to understand HR+/human epidermal growth factor receptor 2-negative (HER2-) metastatic BC (mBC) patient (pt) testing behavior, characteristics, and survival according to PIK3CA mutation status. Methods: Pt-level data from US pts diagnosed with HR+/HER2- mBC from January 1, 2011 to December 31, 2018 were selected from the de-identified Flatiron Health-FMI Clinico-Genomic Database (CGDB). Kaplan-Meier methods were used to estimate median (95% confidence interval [CI]) survival time, defined as time from mBC diagnosis to death. Multivariable Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% CIs. Index date was mBC diagnosis date, but adjustments were made in survival analyses to account for delayed dataset entry due to FMI results date occurring after mBC diagnosis date. Descriptive statistics and chi-square and Kruskal-Wallis tests for significance were used to compare pt characteristics. Results: Of 1349 HR+/HER2- mBC pts included in this study, 807 pts (60%) were wild-type (WT) for PIK3CA, 436 (32%) were SM, and 106 (8%) were MM. Only 2% of pts had an FMI results date before mBC diagnosis date. Most pts had an FMI results date either during (26%) or after (59%) first-line treatment. Median time from mBC diagnosis to FMI results date was longer for MM (19 mo) vs. SM (13 mo) and WT (13 mo) pts (p=0.15). SM and MM pts were older than WT pts at mBC diagnosis (median: 59.9 yr [MM] vs. 59.6 yr [SM] vs. 56.2 yr [WT], p Conclusions: These data showed that PIK3CA mutations were not associated with survival in this patient population and underscore the utility of linked clinical and genomics data for understanding the relationship between genetic alterations and patient outcomes. The majority of HR+/HER2- mBC pts received FMI results more than a year after mBC diagnosis, suggesting that NGS testing is used to guide decisions after pts have failed standard therapy. Additional studies with larger sample sizes and longer follow-up are needed to confirm these observations. Citation Format: Mary K. Downer, Peter Lambert, Sami Mahrus, Katherine E. Hutchinson, Patricia Luhn, Jennifer L. Schutzman. Utility of novel clinico-genomic data to understand patient characteristics, treatments, and outcomes according to PIK3CA mutation status among hormone receptor-positive metastatic breast cancer patients [abstract]. In: Proceedings of the AACR Special Conference on Advancing Precision Medicine Drug Development: Incorporation of Real-World Data and Other Novel Strategies; Jan 9-12, 2020; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_1):Abstract nr 29.