Incidence in Clinical Trials of Raltegravir (Isentress)
first-in-class HIV integrase inhibitor, raltegravir
(Isentress), was approved by the U.S. Food and Drug Administration in October
the drug's development, some clinical trials suggested that participants taking
raltegravir had a higher rate of malignancies,
though this was not confirmed in later studies.
a poster presented at the 16th Conference on Retroviruses
and Opportunistic Infections (CROI 2009) this month in Montreal, David Cooper
and colleagues summarized the most recent and complete cancer rate data from 5
randomized, double-blind clinical trials of raltegravir and the open-label expanded
access program (EAP-P023,
also known as EARMRK). Data were collected through the end of August 2008.
The analysis included:
96 week data
from the Phase 3 trial protocols P018 and P019 for treatment-experienced patients,
better known as BENCHMRK 1 and 2;
week data from the Phase 3 treatment-naive study P021, better known as STARTMRK;
120 week data from Phase 2 trials P004 and 005.
the randomized trials, a combined total of 1039 study participants were randomly
assigned to receive raltegravir (total 1454 person-years [PY]), while 605 were
assigned to comparator drugs (656 PY). The BENCHMRK protocols also included an
open-label phase. In the EAP, 5438 patients enrolled through March 2008 received
open-label raltegravir; they were required to report all serious adverse events,
including cancers, whether or not they were thought to be drug-related.
investigators used both a broad definition of cancer that included recurrences,
worsening of pre-existing cancer, non-melanoma skin cancers, and carcinoma in
situ, as well as a narrower definition that excluded these categories. A time-to-first-event
analysis was used to estimate event rates per 100 PY. Relative risk (RR) was determined
for double-blind data only. Cancer rates in the EAP were analyzed separately using
a consistent time-to-first-event approach.
In the double-blind trials, using the broad definition, 29 cancer cases occurred
in the raltegravir arms (1.68 per 100 PY) versus 17 in the comparator arms (2.24
per 100 PY), for a RR of 0.75.
In the double-blind trials, using the narrower definition, there were 13 cancers
in the raltegravir arms (0.75 per 100 PY) and 11 in the comparator arm (1.44 per
100 PY), for a RR of 0.52.
Looking at all clinical trial data combined -- both double-blind and open label
-- using the broad definition, there were 49 cancer cases (2.10 per 100 PY).
Looking at combined clinical trial data using the narrow definition, there were
22 cancers events (0.93 per 100 PY).
In the open-label EAP, using the broad definition, 55 cancer cases were reported
(2.48 per 100 PY).
In the EAP using the narrower definition, there were 32 cancers (1.44 per 100
A majority of cancers observed in raltegravir recipients were types recognized
to occur more often in people with HIV/AIDS:
Kaposi's sarcoma: 12 cases;
Anal squamous cell carcinoma: 7 cases;
Skin squamous cell carcinoma: 7 cases;
Basal cell carcinoma: 7 cases;
B-cell lymphoma: 5 cases.
on these findings, the researchers stated, "cancer rates were slightly lower
for raltegravir, but not significantly different from comparators."
the EAP included some 2200 additional person-years of follow-up in patients with
more advanced HIV disease, cancer rates were similar to those seen in clinical
"Data to date showed no difference in risk of cancer in HIV-infected
patients receiving raltegravir vs other antiretroviral therapy," the investigators
D Cooper, R Steigbigel,
J Lennnox, and others. Review of Cancer Incidence in Raltegravir Clinical Trials.
16th Conference on Retroviruses and Opportunistic Infections (CROI 2009). Montreal,
Canada. February 8-11, 2009. Abstract 859.