2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

auristatin E (MMAE), a synthetic analog of the naturally
occurring antimitotic agent dolastatin 10. Brentuximab vedotin
appears to have a multistep mechanism of action that
is initiated by binding to CD30 on the cell surface, followed
by clathrin-mediated endocytosis. MMAE is released in the
lysosome from its conjugate through proteolytic degradation
of the peptide linker. 16 The binding of released MMAE to
tubulin disrupts the microtubule network, leading to G2/M
phase cell-cycle arrest and apoptosis. 17 Overall efficacy of
the ADC may be enhanced by the fact that a small fraction
of drug diffuses out of the targeted tumor cell and exerts
cytotoxic effects on the surrounding tumor microenvironment.
Preclinical in vitro and in vivo studies demonstrated that
brentuximab vedotin was highly selective for its target
CD30, was highly potent, and had low toxicity. 18 Brentuximab
vedotin displayed a half maximal inhibitory concentration
(IC 50) of less than 10 ng/mL against CD30-positive
tumor cell lines, but was 300-fold less active against CD30negative
cells. In severe combined immunodeficiency (SCID)
mouse xenograft models of HL, brentuximab vedotin was
efficacious at doses as low as 1 mg/kg. SCID mice treated
with doses as high as 30 mg/kg showed no evidence of
toxicity. Enhanced in vitro antitumor activity against HL
was reported for the combination of brentuximab vedotin
with cytotoxic chemotherapy agents such as bleomycin,
dacarbazine, vinblastine, doxorubicin, or gemcitabine. Collectively,
these experiences suggested that brentuximab
vedotin has the potential to be a highly effective agent
against CD30-expressing malignancies.
Clinical Data
In the initial phase I trial of brentuximab vedotin in
patients with relapsed or refractory CD30-positive malignancies,
45 patients were enrolled with histologies including
HL (42 patients), sALCL (two patients), and CD30-positive
angioimmunoblastic T-cell lymphoma (one patient). 19 The
primary objective of the study was to determine the maximum
tolerated dose (MTD), and the secondary objectives
were to evaluate overall response rate (ORR) and pharmacokinetics.
Patients had a median age of 36 (range, 20 to 87),
had Eastern Cooperative Oncology Group (ECOG) performance
status of 0 or 1 (93%), and were heavily pretreated,
with a median of three prior chemotherapy regimens (range,
one to seven). Seventy-three percent had recurrent disease
after prior ASCT. Brentuximab vedotin was administered as
outpatient intravenous infusions at doses ranging from 0.1
mg/kg to 3.6 mg/kg, every 21 days.
Brentuximab vedotin was well tolerated at doses less than
1.8 mg/kg, with the most common adverse events being
fatigue (16 patients [36%]), pyrexia (15 patients [33%]), and
diarrhea, nausea, neutropenia, or peripheral neuropathy (10
patients [l22%] for each). No grade 3 or 4 adverse events
occurred at the 1.2-mg/kg dose level (one level below the
MTD). Grade 3 neutropenia, limb pain, and back pain each
occurred in one patient of the 12 receiving the 1.8-mg/kg
dose. At doses higher than 1.8 mg/kg, grade 3 neutropenia
and pyrexia were seen in two of the 12 patients (17%)
receiving the 2.7-mg/kg dose. One patient receiving the
3.6-mg/kg dose developed febrile neutropenia and died of
infectious complications. Besides the low level of hematologic
toxicity, the most important side effect was peripheral
neuropathy, which occurred in 16 patients (36%), 13 of
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DIEFENBACH AND LEONARD
whom were receiving the 1.8-mg/kg or 2.7-mg/kg doses. This
observation was typically characterized by grade 1 or 2
parasthesias in the hands or feet and prompted the discontinuation
of treatment in three patients. Importantly, subsequent
resolution of peripheral neuropathy was noted in 10
of the 16 patients (63%) at the last safety assessment for the
study.
Of greatest note in this initial trial was that 17 patients
demonstrated objective responses, including 11 CRs. Six of
the 12 patients (50%) treated at the MTD of 1.8 mg/kg had
an objective response with a median response duration of 9.7
months (ranging from 0.6 month to more than 19.5 months).
Some reduction of tumor size was noted in 36 of the 42
evaluable patients (86%), and 13 of the 16 patients (81%)
with disease-related symptoms at baseline (e.g., pruritis and
night sweats) had their symptoms resolve upon receiving
therapy, irrespective of their antitumor response status. 19
To explore a weekly dosing schedule (compared with the
3-week schedule in the prior study), a second phase I trial
was conducted in a similar patient population. 20 A total of 44
patients—38 with HL, five with sALCL, and one with
peripheral T-cell lymphoma—were enrolled. Patients had a
median age of 33 (range, 12 to 82) with a median of three
prior therapies (range, one to eight). Sixty-eight percent of
patients had received prior ASCT. Patients received weekly
brentuximab vedotin for 3 of 4 weeks, with doses ranging 0.4
mg/kg to 1.4 mg/kg. The most common treatment-related
adverse events again included peripheral neuropathy, nausea,
fatigue, neutropenia, diarrhea, and dizziness. The MTD
for weekly dosing was 1.2 mg/kg. The ORR evaluated across
all dose levels was 59%, with 34% achieving CR. The median
duration of response had not been reached at the follow-up
at 45 weeks. Data from the phase 1 trials demonstrated
that across the dosing range of 1.2 to 2.7mg/kg ADC exposures
were dose proportional, and steady state levels were
achieved within 21 days on an every 3 week dosing schedule.
On this schedule there was minimal to no accumulation of
ADC observed with multiple treatments.
Given the high response rates in both of these phase I
trials, a pivotal phase II trial was conducted in patients with
relapsed or refractory HL, and outcomes were reported at
the 2010 American Society of Hematology (ASH) annual
meeting 21 with updates presented at the 2011 American
Society of Clinical Oncology (ASCO) annual meeting. 22 In
the study, 102 patients with relapsed or refractory HL were
treated every 3 weeks with brentuximab vedotin at a dose of
1.8 mg/kg. Demographics of the study population included a
median age of 31 and a median of four prior therapies. All
participants had undergone ASCT. The ORR was 75% with
a CR rate of 34%, and reductions in tumor volume were
reported in up to 95% of patients. The median duration of
response for patients achieving CR had not been reached at
the time of the presentation.
The data from a second phase II clinical trial of patients
with sALCL were also reported at ASH 2011. 24 A total of 58
patients with sALCL were treated with the same dose of
brentuximab vedotin (1.8 mg/kg) on the 3-week schedule.
The spectrum of toxicity was similar to that observed in
patients with HL. The ORR was 86% with a CR rate of 53%,
and response duration also had not been reached at the time
of the presentation. The study was updated at ASH 2011. 24
At the time of the updated analysis, all but two patients had
discontinued therapy, and the median number of treatment