Risk for Fatal Adverse Events With Anti-Angiogenic Drugs

[Bonni Hess]

Dear ASPS Community Friends,
There is a concerning new article published on February 13th on the Medscape web site (http://www.medscape.org) titled
"Risk for Fatal Adverse Events Linked With Certain Cancer Drugs". This article documents the increased risk and occurrence of fatal events in patients who are treated with Sorafenib, Sunitinib, and Pazopanib. The study doesn't include Cediranib or Dasatanib, but since Cediranib or Dastanib are both anti-angiogenic tyrosine kinase inhibitors (TKI's) in the same class of drugs as Sorafenib, Sunitinib, and Pazopanib, I assume that there may also be/is an increased risk of fatal hemorrhage, myocardial ischemia, liver failure, or congestive heart failure with Cediranib and Dasatanib.
I will be discussing the obvious concerns raised by this article and the documented data with Brittany's Clinical Trial oncologist, and would strongly encourage everyone who is currently taking any of these drugs/considering taking these drugs to read this article, research this important matter, and discuss it with your oncologist.
With special concern, and continued Hope,
Bonni

The text of the Medscape article is as follows:

Risk for Fatal Adverse Events Linked With Certain Cancer Drugs CME/CE Clinical Context

Vascular endothelial growth factor (VEGF) is an important mechanism for the growth of solid tumors, and inhibition of VEGF receptors has emerged as a major pathway to treat cancer. The authors of the current study perform a review of tumors approved for treatment by the US Food and Drug Administration with sorafenib, sunitinib, or pazopanib. These tumors include renal cell cancer, hepatocellular carcinoma, and gastrointestinal stromal tumor.

A previous meta-analysis of the anti-VEGF monoclonal antibody bevacizumab demonstrated that this therapy was associated with a 33% increase in the risk for fatal adverse events vs traditional chemotherapy alone. The current meta-analysis by Choueiri and colleagues queries the risk for fatal adverse events associated with VEGF receptor tyrosine kinase inhibitors (VEGFR TKIs) from clinical trials of patients with cancer.

Study Synopsis and Perspective
New details on the risk for fatal adverse events associated with several targeted cancer drugs have come from a large meta-analysis of clinical trials, which was published online February 6 in the Journal of Clinical Oncology.

The drugs investigated were pazopanib (Votrient, GlaxoSmithKline), which is approved for use in renal cell carcinoma; sorafenib (Nexavar, Bayer & Onyx), which is approved for use in renal cell carcinoma and hepatocellular cancer; and sunitinib (Sutent, Pfizer), which is approved for use in hepatocellular cancer and gastrointestinal stromal tumors. All 3 products are VEGFR TKIs.

The meta-analysis, which examined data on 4679 patients from 10 clinical trials, found that these 3 drugs were associated with fatal adverse events at a rate that was about twice that seen in the placebo groups. The crude incidence of fatal adverse events was 1.5% in patients taking these drugs, compared with 0.7% in patients in the placebo or control groups (relative risk [RR], 2.23; P = .023).

The most common cause of death was hemorrhage; the second most common was myocardial ischemia. Liver failure and congestive heart failure were also reported.

Senior author Toni Choueiri, MD, from the Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, said that clinicians need to be aware of the risks associated with these drugs.

"There is no doubt that for the average patient, these drugs have benefits," Dr. Choueiri said in a statement. In fact, these drugs represent a major step forward in the treatment of several malignancies, and they have led to significant improvements in patient outcomes.

However, they are associated with a significant increase in the risk of developing fatal drug-related events, and "practitioners must be aware of the risks associated with their use and must provide rigorous monitoring to continue to improve patient outcomes," the researchers note.

"While the absolute incidence of these fatal side effects is very small, the relative risks are higher," Dr. Choueiri noted. In addition, the patients in this meta-analysis were participating in clinical trials and all had adequate organ function at study entry, so the overall incidence and risk for unreported fatal adverse events could be higher in common medical practice.

Similar Data on Bevacizumab

An increase in the risk for fatal adverse events has also been reported for bevacizumab (Avastin, Genentech/Roche), which inhibits VEGF but by another mechanism; it is a monoclonal antibody that binds to VEGF. The data on bevacizumab, reported last year, came from a meta-analysis of clinical trials involving 10,217 patients, which found a significantly higher rate of fatal adverse events associated with bevacizumab than with chemotherapy alone (2.5% vs 1.7%; RR, 1.46; P = .01).

This increased risk and incidence of fatal adverse events reported for bevacizumab "are on the same scale" as those described in this meta-analysis looking at pazopanib, sorafenib, and sunitinib, note Dr. Choueiri and colleagues. In both cases, hemorrhage was the cause of death in the majority of patients.

When the bevacizumab data were published (JAMA. 2011;305;487-494), an accompanying editorial questioned the overall benefit of adding bevacizumab to chemotherapy (JAMA. 2011;305:506-508). Editorialist Daniel Hayes, MD, from the University of Michigan Comprehensive Cancer Center in Ann Arbor, speculated that the increased rate of fatal adverse events "might negate any survival benefit."

Medscape Medical News asked Dr. Hayes to comment on the findings of an increased rate of fatal adverse events with pazopanib, sorafenib, and sunitinib.

"I really don't have much to add. The data are as they are," he said. "All drugs have benefits and risks, and it is up to caregivers, patients, and society to decide if the benefits outweigh the risks."

"It seems like we sometimes throw out one or the other side of this equation when reviewing therapeutic strategies," Dr. Hayes explained. "Regardless, certainly one cannot determine the benefit/risk ratio if we don't have a legitimate estimate of the latter, so this is an important paper."

Breakdown of the New Findings

Of the 4679 patients in this meta-analysis, 2856 were involved in sorafenib clinical trials, 1388 were involved in sunitinib trials, and 435 were involved in pazopanib trials.

Although there were more fatal adverse events reported for sorafenib than for the other 2 drugs, there was no statistically significant difference in the RR for the 3 drugs, the researchers note. All 3 products have a similar mechanism of action (antagonizing the intracellular domain of VEGF and blocking downstream signaling), and all 3 drugs have similar class-effect toxicity profiles, they add.

Half of the 19 study deaths (47.5%) that occurred in patients taking pazopanib, sorafenib, or sunitinib were due to hemorrhage. The majority of these deaths from hemorrhage (79%) occurred in patients with non–small-cell lung cancer (NSCLC). This is not surprising, the researchers note, because NSCLC lesions are known to be highly necrotic and have a propensity to bleed, even without the inhibition of the VEGF pathway.

The second most common reason for death was myocardial ischemia (n = 6), the researchers note. Other causes were abnormal hepatic function or failure (n = 40), sepsis (n = 3), congestive heart failure (n = 2), ischemic stroke (n = 1), pulmonary embolism (n = 1), dehydration (n = 1), and sudden death (n = 1).

The findings of myocardial infarction and other cardiovascular events is consistent with previous analyses, the researchers note. Dr. Choueiri and colleagues have previously reported a significant increase in the risk for arterial thromboembolic events and in the risk for bleeding associated with sorafenib and sunitinib. They have also reported an increase in the risk for congestive heart failure with bevacizumab.

Dr. Choueiri previously told Medscape Medical News that the adverse events are a result of these drugs inhibiting VEGF, which is a class effect. In a tumor, blocking VEGF inhibits angiogenesis and an anticancer effect, but in the body, the inhibitory effects of VEGF can disrupt the hemostatic balance, he explained. If the balance is tipped toward clotting, arterial thromboembolic events, such as stroke and myocardial infarction, can occur; if it goes the other way, bleeding can occur.

Dr. Choueiri reports serving as a consultant for Pfizer, Bayer/Onyx, Novartis, GlaxoSmithKline, Abbott, Genentech, AVEO Pharmaceuticals, and Agennix. Dr. Hayes reports stock ownership in Oncimmune LLC and Halcyon Diagnostics Inc; and receiving honoraria for consulting from Compendia Bioscience, Chugai Pharmaceuticals, and Biomarker Strategies.

J Clin Oncol. Published online February 6, 2012. Abstract

Study Highlights

Researchers examined MEDLINE databases for randomized clinical trials of sorafenib, sunitinib, or pazopanib. Studies that compared different VEGFR TKIs were excluded from analysis.
The main study outcome was the relationship between treatment with VEGFR TKIs and incident fatal adverse events. Researchers compared results from trials that included a placebo vs an active treatment group, and they also examined the quality of included research.
Of 15 studies carefully reviewed for eligibility, 10 trials with a total of 4679 participants were included in the current meta-analysis. 6 of these studies focused on sorafenib, and 3 examined sunitinib. Only 1 study tested pazopanib.
In general, patients eligible for participation in the included research were free of other serious illness. Types of tumors included in the research were renal cell cancer, hepatocellular carcinoma, melanoma, NSCLC, breast cancer, and pancreatic neuroendocrine tumor.
Most studies were placebo controlled, and nearly all were double blinded. Overall, study quality was found to be very good, and there was no evidence of publication bias.
The rate of fatal adverse events ascribed to treatment with VEGFR TKIs was 1.5%. There was no significant difference between individual VEGFR TKIs in promoting fatal adverse events.
Hemorrhage was the most common cause of death in cases of fatal adverse events, accounting for 47.5% of all deaths in the meta-analysis. Myocardial infarction was the next most common cause of fatal adverse events, but it represented only 15% of all deaths.
The overall risk for fatal adverse events associated with treatment with VEGFR TKIs was 2.23 (95% confidence interval, 1.12 - 4.44). Again, the relative risk for fatal adverse events in comparing the 3 individual VEGFR TKIs was similar.
There was also no difference in comparing the risk for fatal adverse events associated with treatment with VEGFR TKIs among patients with renal cell cancer or other types of cancer.
VEGFR TKIs were associated with higher risks of fatal adverse events in placebo-controlled trials as well as in studies with an active comparator treatment.

Clinical Implications

Tumors approved for treatment with VEGFR TKIs by the US Food and Drug Administration include renal cell cancer, hepatocellular carcinoma, and gastrointestinal stromal tumor.
The current study by Choueiri and colleagues suggests that the VEGFR TKI inhibitors sorafenib, sunitinib, and pazopanib can promote a higher rate of fatal adverse events among patients with cancer. This risk was similar in comparing individual VEGFR TKIs, and hemorrhage was the leading cause of death.