Maraviroc (Selzentry) Not Associated with Elevated Cancer Risk in Clinical Development Program

		SUMMARY: The CCR5 antagonist maraviroc (Selzentry) was not linked to cancer risk in a retrospective review of Phase 2b and 3 trials of treatment-naive and treatment-experienced HIV patients in the drug's clinical development program, according to a poster presented last month at the XVIII International AIDS Conference (AIDS 2010) in Vienna.

By Liz Highleyman

Selzentry maraviroc) • News Articles • Full US Prescribing Information

Some non-AIDS-defining malignancies have infectious causes; since maraviroc interferes with CCR5 binding, and CCR5-mediated signaling plays a role in immune surveillance, there is a theoretical concern that maraviroc might increase the risk of infections or cancers. Some early maraviroc study data suggested a potential cancer safety signal, leading investigators to look carefully at cancer rates in larger clinical trials of the drug.

Sharon Walmsley from the University of Toronto and colleagues investigated the incidence of and risk factors for malignancies across trial included in the maraviroc Phase 2b/3 development program.

For this retrospective analysis, researchers collected information about treatment-emergent (occurring while on therapy) malignancies in clinical trials with both treatment-experienced and previously untreated participants, including MOTIVATE 1 and 2, MERIT, and A4001029 (patients with non-CCR5-tropic virus). The analysis included data from the randomized blinded study period, as well as open-label extended follow-up.

Overall, 1499 participants in the development program received maraviroc, contributing 2333 person-years of data (median 82 weeks use). In addition, 361 people received efavirenz (Sustiva) as a comparison first-line drug, contributing 768 person-years of data (median exposure 139 weeks) and 270 treatment-experienced patients received placebo with optimized background therapy, contributing 196 person-years (median exposure 20 weeks).

The researchers looked at overall cancer rates, rates of AIDS-defining malignancies (Kaposi's sarcoma, non-Hodgkin lymphoma, and cervical cancer), and non-AIDS cancers, including those associated with infectious pathogens (e.g., anal cancer caused by human papillomavirus, Hodgkin lymphoma linked to Epstein-Barr virus, liver cancer due to chronic hepatitis B or C) and those with no known infectious cause.

Results

	Overall, the most commonly observed malignancies were anal cancer, lymphoma, and basal cell carcinoma.
	Malignancy incidence rates were generally numerically lower among maraviroc recipients versus those in the comparison arms.
	This was the case overall and for both AIDS-defining and non-AIDS malignancies.
	Among treatment-experienced patients in the MOTIVATE trials, cancer incidence rates were significant lower with maraviroc than with placebo (although exposure to maraviroc was considerably longer):
	Cancer overall: exposure-adjusted risk ratio 0.49; AIDS-defining malignancies: risk ratio 1.04; Non-AIDS malignancies: risk ratio 0.38; Infection-related cancers: risk ratio 0.68; Non-infectious cancers: 0.27.
	Among treatment-naive participants in MERIT, the incidence rate of non-AIDS malignancies was lower with maraviroc than with efavirenz, but the difference was not statistically significant.
	MERIT participants who developed cancer while on treatment had smaller prior CD4 gains than those without cancer.
	There were too few new malignancies to draw meaningful conclusions in study A4001029.
	In a multivariate analysis, larger CD4 cell increases and HIV suppression to < 50 copies/mL were associated with decreased cancer risk:
	Every increase of 25 cells/mm3 was associated with an approximate 10% decrease in cancer risk; Nevertheless, a large proportion of patients who developed malignancies did so after achieving undetectable viral load.
	Older age, in contrast, was associated with increased overall cancer risk.

In this retrospective analysis of nearly 1500 people, "maraviroc-treated patients had a low incidence of malignancies, regardless of virus tropism or degree of antiretroviral treatment experience," the researchers concluded. "Long-term blinded and open-label treatment with maraviroc did not reveal any increased incidence of malignancies, compared to published rates at 48 weeks."

"The exposure-adjusted incidence of malignancies was generally numerically lower in the maraviroc group compared to placebo or efavirenz," they continued. "Across the 3 cohorts, the incidence of non-AIDS-defining malignancies was generally greater than that of AIDS-defining malignancies."

Investigator affiliations: University of Toronto, Toronto, Canada; University of Miami, Miami, FL; ViiV Healthcare, Research Triangle Park, NC; Pfizer Global Research and Development, New London, CT; Pfizer Inc, New York, NY.

8/17/10

Reference
S Walmsley, R Campo, J Goodrich, and others. Low risk of malignancy with maraviroc in treatment-experienced and treatment-naive patients across the maraviroc clinical development program. XVIII International AIDS Conference (AIDS 2010). Vienna, July 18-23, 2010. Abstract TUPE0157.

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