‘Real World’ Outcomes Show Possible Protective Effect
By Annette M. Boyle
SALT LAKE CITY — The U.S. Food and Drug Administration approval of several tyrosine kinase inhibitors (TKIs) over the last decade has substantially improved outcomes for patients with metastatic renal cell carcinoma. The good news has been muted, however, by concerns raised in a number of clinical trials about increased risk for cardiovascular events associated with TKIs.
VA researchers sought to determine whether the therapy increased the risk of congestive heart failure, stroke and thromboembolic events in a real world setting with veterans. Those are the conditions associated with TKI use in clinical trials, but, in a study presented at the American Society of Clinical Oncology 2017 annual meeting this summer, results indicated that TKIs did not impair cardiovascular health.1
“Our results contradict all the published literature on this,” said co-author Julie A. Lynch, PhD, RN, a research scientist at the VA Salt Lake City Healthcare System. “TKIs have a protective effect in our study.”
The first TKI, sorafenib, gained approval for use in patients with advanced renal cell carcinoma in 2005, followed by sunitinib (2006), pazopanib (2009), axitinib (2012) and cabozantinib (2016). Current guidelines recommend sunitinib and pazopanib for first-line treatment of advanced RCC. TKIs have extended progression-free survival rates significantly for patients and somewhat increased median overall survival, according to a recent review of treatment options for metastatic renal cell carcinoma in the Journal of Hematology & Oncology. 2
Because they have higher rates of known risk factors such as obesity, smoking, diabetes and hypertension, veterans have a more than doubled risk of renal cell carcinoma compared to non-veterans, 38.1 per 100,000 vs. 15.1 per 100,000, according to lead author Kristine Lynch, PhD, of the Salt Lake City VAMC and her co-authors.
Demographics also contribute to higher rates. RCC typically occurs in older patients, is slightly more common in blacks than whites and affects men twice as often as women.
About 2,250 veterans will be diagnosed with RCC this year. Of those, about 15% will be diagnosed with metastatic RCC. Stage 3 RCC has a median five-year survival rate of 53%. For Stage 4 disease, the median five-year survival rate is only 8%.
The VA researchers conducted a retrospective cohort study of veterans diagnosed with RCC between Jan. 1, 2006, and Dec. 31, 2015. They found 3,510 patients eligible for treatment who had no history of prior cardiac events and analyzed the data to find out whether patients had congestive heart failure, cardiomyopathy, acute myocardial infarction, stroke or cardiovascular-related death following treatment with a TKI.
Of those study subjects, 1,840 received at least one TKI prior to any cardiac event, with 27% receiving sunitinib, 5% sorafenib, 8% pazopanib and 12% treated with a combination of TKIs. Of the 909 veterans who experienced a cardiac event, just 29% were treated with a TKI.
A multivariable analysis identified two significant predictors of a cardiac event—dyslipidemia, which doubled the risk, and diabetes, which increased the risk 150%.
Veterans’ Risk Greater
For veterans, “the risk factors associated with obesity, diabetes and dyslipidemia are greater” than the risks that might be associated with TKIs, Lynch told U.S. Medicine.
“The real story is that real world evidence is needed” when making treatment decisions, she added. “Clinical trials tend to get ‘healthy’ patients because many potential participants with comorbidities are excluded from enrolling. They don’t get real-world results.”
The VA offers a tremendous opportunity to test the findings of clinical trials because its electronic health record enables researchers to do analyses not generally found in clinical trials and because of the large population it serves, she noted. “We need to do research like this in the VA because veterans, with all their comorbidities, are more representative of community cancer patients.”
Co-author Dan Becker, MD, chief of the hematology/oncology section at the Manhattan campus of the New York VA, concurred regarding the value added by conducting studies at the VA. “You can gather valuable information on safety in a real-world population. In this case, it offers reassurance that these drugs can be safely used in our VA population. That was evidence that could not be ascertained by clinical trial data alone.”
Another study presented by many of the same researchers at ASCO looked at utilization of specific TKIs over time at the VA. They found that of 2,410 RCC patients exposed to TKIs between 2006 and 2015, 40% received more than one of the agents. Almost three-quarters of patients (73%) received sunitinib, while 32% were prescribed pazopanib and 25% were treated with sorafenib.3
Sorafenib’s share of patients dropped sharply over the study period from 37% of veterans diagnosed with metastatic RCC in 2006 to just 2% in 2015. Pazopanib saw the reverse trend, increasing from 8% to 38% of eligible patients.
Patients who received TKIs tended to be younger than those who did not. The researchers found no notable differences in TKI use by gender or racial or ethnic group, though patients with higher body mass indices were more likely to receive TKIs than those that did not.
- Lynch KE, Lynch JA, Efimova O, Chang J, Berse B. Cardiotoxicity of tyrosine kinase inhibitors among veterans diagnosed with renal cell carcinoma. Journal of Clinical Oncology 35 (15), Suppl. Published online before print.
- Zarrabi K, Fang C, Wu S. New treatment options for metastatic renal cell carcinoma with prior anti-angiogenesis therapy. J Hematol Oncol. 2017 Feb 2;10(1):38.
- Lynch JA, Lynch KE, Filipski KK, Berse B, Rivera D, et al. Equity in access to tyrosine kinase inhibitors among veterans diagnosed with renal cell carcinoma. Journal of Clinical Oncology 35 (15), Suppl. Published online before print.