135: Methods to Assess QT/QTc Prolongation in Oncology Clinical Development: A Landscape Analysis of Approved Oncology Therapeutics

Statement of Purpose: The ICH E14 guideline was published in 2005 addressing thorough QT/QTc (TQT) studies to determine if a drug has QT/QTc prolongation risk. However, some of the design elements of these TQT studies are not feasible for oncology drugs. Revisions to the guideline in 2015 addressed the use of exposure-response modeling of QTc data. Due to a lack of published guidance and standards for QT prolongation risk evaluation for oncology drug development, a more robust understanding of what has been conducted in recent years helps provide insight for future oncology drug development.

Description of Methods & Materials: Small molecule agents used for oncology indications were searched for using Drugs@FDA, filtered for original NDA approval with a submission classification of “Type 1 - New Molecular Entity” between January 2018 and December 2022. Information including label warnings, study design elements and analysis type for QT prolongation risk assessment were extracted from USPIs and FDA Application Review Files such as the Interdisciplinary Review Team for QT Studies Consultation Reviews (QT-IRT) in the Drugs@FDA database. For this analysis, NMEs with QT prolongation risk are defined as those with labels containing language about QT prolongation in the Warnings and Precautions section.

Data & Results: A total of 48 small molecule NMEs with NDA approvals for oncology indications between January 2018-December 2022 were identified. Ten of these drugs had QT prolongation risk, one of which included a drug class warning despite TQT study results demonstrating no clinically meaningful QTcF prolongation. Data from FIP dose escalation and/or dose expansion studies were most frequently used to assess change in QTc (21/48 (44%)). By-timepoint (central tendency) analyses were conducted for all of these NMES. Exposure-response analysis could not be conducted for only one NME due to a lack of a direct relationship between drug concentration and QTc effects (i.e. temporal effects). The majority of these NMEs (17/21 (81%)) had no QT prolongation risk. Of the programs that conducted studies with primary objectives to assess change in QTc (18/48 (38%)), 11/18 (61%) had both positive and negative control arms, 2/18 (11%) had only a placebo control and 5/18 (28%) had no control arms. Nine (50%) included arms for supratherapeutic doses ranging from 1.25-9x the therapeutic dose. Fourteen (78%) of these NMEs had no QT prolongation risk. Of the remaining programs, 7/9 (78%) utilized QT data from Phase 2 or Phase 3 trials and 2/9 (22%) analyzed both FIP and Phase 3 data. One NME conducting a Phase 2 sub-study and one NME analyzing both FIP and Phase 3 data had QT prolongation risk.

Interpretation, Conclusion or Significance: Though heterogeneity exists in assessment of drug effect on QT prolongation in oncology, the increase in exposure-response assessments following ICH E14 revisions in 2015 have persisted in recent years. Considering the challenges of conducting QT-focused studies for anticancer drugs, data produced from FIP escalation and expansion studies have proven valuable due to the wide range of exposures achieved. The availability of such data may warrant evaluation of the necessity of conducting QT-focused studies in oncology drug development.

Disclosures: All authors are or were Pfizer contractors or employees.