Heartbreaking Works of Staggering Genius: Cardiac Safety for Oncology

Heartbreaking Works of Staggering Genius: Cardiac Safety for Oncology

I could give you some of facts and figures about cancer. Like the fact that the American Cancer Society estimates there will be 1,658,370 new cancer cases diagnosed and 589,430 cancer deaths in the US this year. Or that pancreatic cancer has only a 5-year survival rate of 5%.

But, these statistics belie the heartbreaking reality that cancer patients and their families face. Dave Eggers vividly described the experience of losing both his parents to cancer in his memoir, “A Heartbreaking Work of Staggering Genius.” Regarding a surgeon’s ultimately futile attempt at resecting his mother’s metastatic cancer, he writes:

“but when she went in again, and they had ‘opened her up’ — a phrase they used — and had looked inside, it was staring out at them, at the doctors, like a thousand writhing worms under a rock, swarming, shimmering, wet and oily — Good God! — or maybe not like worms but like a million little podules, each a tiny city of cancer, each with an unruly, sprawling, environmentally careless citizenry with no zoning laws whatsoever. When the doctor opened her up, and there was suddenly light thrown upon the world of cancer-podules, they were annoyed by the disturbance, and defiant. Turn off. The [expletive]. Light. They glared at the doctor, each podule, though a city unto itself, having one single eye, one blind evil eye in the middle, which stared imperiously, as only a blind eye can do, out at the doctor. Go. The. [Expletive]. Away.”

While fighting cancer remains a formidable challenge, there is hope. Certara’s talented scientists strive to help biopharmaceutical researchers develop innovative new drugs that kill cancer cells but are safe for the patient. In this post, I’ll discuss some recently published work on model-based approaches for evaluating potential cardiac safety issues associated with novel combination treatments for breast cancer patients.

Ensuring the safety of combination products for the treatment of breast cancer

While increased screening and early treatment have led to a decrease in breast cancer mortality, metastatic breast cancer (MBC) remains incurable. However, new treatments— using combinations of drugs— have the potential to turn MBC into a manageable, chronic disease. This would enable patients to live longer and have a higher quality of life. Examples of cardiac safety analyses of combination products for the treatment of HER2+ MBC and triple negative breast cancer (TNBC) are presented below.

Perjeta®: Targeting HER signaling in breast cancer

Human epidermal growth factor receptor 2 (HER2) is a cell surface receptor that controls cell growth, survival, and differentiation. It frequently becomes amplified and/or over expressed in a significant percentage of breast cancer patients. Patients with a HER+ tumors tend to experience increased tumor aggressiveness, higher rates of recurrence, and increased mortality. Thus, HER2 is an important target for treating HER2+ MBC.

Pertuzumab is a humanized monoclonal anti-HER2 antibody. It blocks the heterodimerization of HER2 to inhibit ligand-activated downstream cell signaling. Combined with trastuzumab and docetaxel, pertuzumab improved both overall and progression-free survival (PFS) in patients with first-line MBC.

Satisfying regulatory requirements for cardiac safety

Cardiotoxicity is a common concern during the development of a novel drugs. Adverse cardiac reactions have resulted in the withdrawal of more drugs from the market than any other adverse reaction in recent times. Therefore, all new drugs with systemic bioavailability are required by regulatory agencies to have an assessment of the drug’s potential to delay cardiac repolarization as measured by the QT/QTc interval on the surface electrocardiogram (ECG).

Our team performed linear mixed-effects modeling to evaluate potential exposure-response relationships between the concentration of pertuzumab (in combination with trastuzumab and docetaxel) and the magnitude of QTc prolongation. Cardiac monitoring and concentration-QTc modeling demonstrated that pertuzumab did not result in clinically relevant effects on QTc or other ECG parameters.

On September 30, 2013, the FDA granted pertuzumab injection (Perjeta) accelerated approval for use in combination with trastuzumab (Herceptin®) and docetaxel for neoadjuvant treatment of patients with HER2+ locally advanced, inflammatory, or early-stage breast cancer. If you want to read more about this work, please check out my colleague, Dr. JF Marier’s article in Cancer Chemotherapy and Pharmacology, “Exposure–response analysis of pertuzumab in HER2‑positive metastatic breast cancer: absence of effect on QTc prolongation and other ECG parameters.”

Onartuzumab: a triple-negative breast cancer treatment

More recently, our team worked with a client— a major pharmaceutical company— to perform similar concentration-QT analyses for the triple combination product of onartuzumab, bevacizumab and paclitaxel for the treatment of TNBC. Onartuzumab is a monoclonal antibody that binds the tyrosine kinase receptor, MET, and inhibits activation of downstream signaling pathways. MET over expression is associated with poor prognosis in a number of cancers, including TNBC.

The study design was as follows:

  1. Triplicate ECG recording was performed at screening, pre- and post-dose on day 1 of cycles 1, 2, and 4, and at the study drug discontinuation visit.
  2. Serum samples for PK analysis of onartuzumab were collected at all these time points, except for the screening visit.
  3. The QT recordings were corrected for heart rate and the change from baseline (ΔQTcF) and time-matched, baseline-adjusted, control arm-corrected measurements (ΔΔQTcF) were calculated.
  4. We performed linear mixed effect modeling to evaluate a potential relationship between onartuzumab concentration and ΔQTcF.

The analyses did not show any evidence that onartuzumab— at the doses tested— significantly prolonged the QTcF interval. Additional information on the concentration-QT analysis was published in my colleague, Dr. Igor Rubet’s article, published last month in Cancer Chemotherapy and Pharmacology, “Onartuzumab with or without bevacizumab in combination with weekly paclitaxel does not prolong QTc or adversely affect other ECG parameters in patients with locally recurrent or metastatic triple‑negative breast cancer.”

All information presented derive from public source materials.

Learn more about modeling and simulation informs oncology drug development

Read this case study to learn how modeling and simulation technology was used to facilitate regulatory approval for a targeted treatment for melanoma.

Michael Eckstut

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Michael Eckstut

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Michael Eckstut is Senior Vice President and the Head of Certara Consulting. He joined Certara in 2014 from Archstone Consulting, a Hackett Group company, where he was head of the Life Sciences Practice and the Managing Partner of the firm’s West Region. Mr. Eckstut holds a BS and MS cum laude in Chemical Engineering from Rensselaer Polytechnic Institute and an MBA (as a Baker Scholar) from the Harvard Graduate School of Business Administration.