CSRC Think Tank: CV Safety in Oncology Clinical Trials: Providing Clarity for a New Era of Cancer Therapeutics

December 1, 2021

Welcome and Introductions

Jonathan Seltzer, MD, MBA, MA (Executive Director, Cardiac Safety Research Consortium)

Session 1: There is a problem with CV endpoints in oncology trials

  • Pros: Marc Bonaca, MD, MPH (CPC Clinical Research – University of Colorado)
  • Cons: Leslie Lipka, MD, PhD (Merck & Co, Inc.)

Session 2: Perspectives, CV endpoints in oncology trials

  • Regulatory Perspective: Laleh Amiri-Kordestani, MD (US FDA)
  • CTCAE Perspective: Alice Chen, MD (US NIH)
  • Over- and under-counting of CV events: experience of miscalculation of CV events in oncology trials– James Januzzi, Jr, MD (Harvard Medical)

Session 3: Problems with Current Methods of Endpoint Capture

  • Problems with current methods of endpoint capture: Ninian Lang, MBChB, PhD (University of Glasgow, UK)

Archival Context: This article summarizes key insights from the CSRC Think Tank session “Cardiovascular Safety in Oncology Clinical Trials.” The following analysis, derived from the presentation by Dr. James L. Januzzi Jr. (Harvard Medical School), addresses the critical discrepancies in reporting cardiovascular adverse events in oncology trials.

Executive Summary

As the landscape of cancer therapy shifts towards targeted therapies, the precision of safety monitoring must evolve. A recurring challenge in modern oncology trials is the “Over- and Under-counting” of cardiovascular (CV) events5.

Without standardized adjudication, the true safety profile of potent Kinase Inhibitors can be obscured. This article examines real-world data versus clinical trial data for two landmark drugs—Ibrutinib and Ponatinib—to illustrate the necessity of rigorous cardiovascular monitoring and the role of pre-clinical selectivity profiling in predicting these risks.

Case Study 1: Under-Reporting of CV Events (Ibrutinib)

Ibrutinib, a first-in-class BTK inhibitor, has revolutionized the treatment of hematologic malignancies. However, post-market analysis suggests its cardiovascular liability may have been underestimated in initial reports.

Signal Detection in VigiBase

Dr. Januzzi highlighted an analysis of the WHO VigiBase regarding Cardiovascular Adverse Drug Reactions (CV-ADR) associated with Ibrutinib6. The data revealed significant odds ratios (OR) for serious events:

  • Atrial Fibrillation / SVT: OR 23.1 ($P < 0.001$) 7
  • Ventricular Arrhythmia: OR 4.7 ($P < 0.001$) 8
  • Heart Failure: OR 3.5 ($P < 0.001$) 9

Implication for Discovery: The high incidence of arrhythmias suggests potential off-target effects on cardiac ion channels or signaling pathways. This underscores the importance of screening new BTK inhibitors against a broad panel of kinases and ion channels using high-purity reference standards to minimize cardiotoxicity.

Case Study 2: Over-Reporting and “Broad Terms” (Ponatinib)

Conversely, some safety signals may be amplified by non-specific coding. Ponatinib, a potent BCR-ABL inhibitor used in resistant leukemia, was originally reported to have a high rate of Arterial Occlusive Events (AOE)10.

The Impact of Adjudication

In the PACE trial, events were initially captured using broad MedDRA terms11. When a retrospective, independent adjudication was performed, the “true” rate of serious AOEs dropped significantly:

  • Pre-adjudication: 24.7% of patients flagged with $\ge 1$ AOE12.
  • Verified AOE: Only 17.4% confirmed after adjudication13.

This discrepancy highlights that while Ponatinib carries vascular risks, precise definitions are required to avoid overestimating toxicity, which could unnecessarily limit patient access to life-saving therapy14.

The Need for Standardized Definitions

The variability in reporting—whether it is Ibrutinib-associated arrhythmias or Ponatinib-associated vascular events—stems from a lack of universal definitions.

As noted by the International Cardio-Oncology Society, standardized criteria are essential for:

  1. Cardiac Dysfunction: Moving beyond simple LVEF drops to include Global Longitudinal Strain (GLS)15.
  2. Myocarditis: Specifically for Immune Checkpoint Inhibitors, defined by major and minor diagnostic criteria16.
  3. Vascular Toxicity: Distinguishing transient hypertension from sustained vascular occlusive disease17.

Conclusion: From Clinical Data to Bench Science

The findings presented at the CSRC Think Tank confirm that “Safety” is not a static checkbox. It is a dynamic assessment that requires:

  • In the Clinic: Independent Adjudication Committees (IACs) to verify events18.
  • In the Lab: Robust Target Safety Profiling during drug discovery.

By utilizing annotated Kinase Inhibitor Libraries to screen for off-target binding (e.g., VEGFR inhibition causing hypertension, or BTK off-targets causing arrhythmia), developers can anticipate these clinical signals years before the first patient is dosed.

References

  1. Januzzi, J. L. “Over- and under-counting of CV events: experience of miscalculation of CV events in oncology trials.” CSRC Think Tank Presentation, 202119.
  2. Salem, J. E., et al. “Cardiovascular toxicities associated with Ibrutinib.” J Am Coll Cardiol, 201920.
  3. Herrmann, J., et al. “Defining cardiovascular toxicities of cancer therapies: an International Cardio-Oncology Society (IC-OS) consensus statement.” Eur Heart J, 202221.