2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

TARGETING CD30 IN HODGKIN LYMPHOMA
cycles with brentuximab vedotin was seven (range, one to
16). The median duration of objective response was 13.0
months (range 0.1 month to more than 19.1 months), the
median PFS was 14.6 months, and the median OS had not
yet been reached. Peripheral sensory neuropathy was observed
in 41% of patients, which in 10 patients (17%) was
grade 3. Among the patients with neuropathy of any grade,
26 (79%) had achieved either resolution or improvement in
symptoms with a median time-to-improvement of 13.3
weeks (range 0.3 week to 48.7 weeks).
These results led to the unanimous recommendation of
the Oncology Drug Advisory Committee of the United States
Food and Drug Administration for accelerated approval of
brentuximab vedotin (Adcetris; Seattle Genetics, Inc, Bothell,
WA) for the treatment of relapsed or refractory HL in
patients with progressive disease after either ASCT or two
chemotherapy regimens in patients ineligible for transplantation.
Brentuximab vedotin was also approved for patients
with sALCL who had at least one prior treatment fail.
Brentuximab vedotin is the first new therapy approved for
the treatment of HL in more than 30 years.
Ongoing Trials
Although brentuximab vedotin therapy demonstrated
substantial single-agent activity in patients with relapsed or
refractory HL, one would anticipate that even greater benefits
could be achieved if it is integrated with or substituted
for components of standard treatment. In addition, aspects
of the optimal use of single-agent therapy need clarification.
A variety of planned and ongoing studies are attempting to
answer several key questions:
Can patients who achieved CR with brentuximab vedotin
who then stopped therapy in remission benefit from retreatment
at a time of subsequent relapse? Small case series
suggest that indeed patients may display sensitivity to
retreatment with brentuximab vedotin at the time of relapse.
25 Bartlett and colleagues reported a study of seven
patients retreated after relapse (one patient twice), for a
total of eight retreatment experiences. Responses included
two patients with CR, four with PR, and two with stable
disease. 26
Can brentuximab vedotin be safely combined with and
improve the results of first-line treatment regimens? An
ongoing phase I trial of brentuximab vedotin in combination
with either ABVD (doxorubicin, bleomycin, vinblastine,
and dacarbazine) or AVD (doxorubicin, vinblastine, and
dacarbazine) chemotherapy in untreated patients with
HL is evaluating this issue (ClinicalTrials.gov identifier:
NCT01060904). Interim data for the first 31 patients treated
were presented at ASH 2011. 27 Patient demographics included
an international prognostic index greater than 4 in
29% of patients, stage IV disease in 55%, and a median age
of 35 (range, 19 to 59). Brentuximab vedotin at either 0.6
mg/kg, 0.9 mg/kg, or 1.2 mg/kg was administered with
standard doses of ABVD or at 1.2 mg/kg with AVD, on days
1 and 15 of each 28-day cycle for six cycles. Overall, adverse
events included peripheral neuropathy (48%), fatigue (45%),
and neutropenia (77%). Grades 3 or 4 adverse events included
neutropenia (74%), febrile neutropenia (16%), and
anemia (13%). Importantly, in the ABVD cohort of 25
patients, seven patients (28%) developed pulmonary toxicity,
dyspnea, and interstitial lung disease, which led to the
discontinuation of bleomycin. Of the 10 patients who were
available for response assessment, all achieved CR. Based
on these data, the ABVD/brentuximab vedotin arm has been
closed to further enrollment and AVD/brentuximab vedotin
is undergoing further evaluation.
Does brentuximab vedotin have a role in targeting minimal
residual disease as a maintenance strategy to prevent
relapse in high-risk patients? This question is currently
being investigated in patients who are at high risk after
ASCT in a placebo-controlled, randomized trial of brentuximab
vedotin maintenance, referred to as AETHERA (ADC
Empowered Trial for Hodgkin to Evaluate Progression after
ASCT; ClinicalTrials.gov identifier: NCT01100502).
Future Directions
Determining the optimal timing for brentuximab vedotin
therapy and whether brentuximab vedotin will ultimately
be best used alone as a single agent or as a component of a
novel treatment platform remain ongoing issues. Many of
the patients treated in both of the original phase I studies
and the pivotal phase II study were heavily pretreated, often
with relapse after autologous or allogeneic bone marrow
transplantation. The response rate to brentuximab vedotin
in treatment-naïve patients is not known, but because this is
a patient population with chemotherapy-sensitive disease,
one might expect that the activity of the drug would be
greater as part of initial or second-line treatment. First-line
ABVD continues to be generally well tolerated, based on 30
years of safety data and an extremely high response rate.
Thus an improvement in outcome for low-risk patients
might not be easily discernible without very large studies.
However, a meaningful relapse rate occurs, and morbidity
and (albeit rare) mortality with this regimen is measurable.
Improvements in both efficacy and tolerability may be
achievable. For high-risk patients, the issue of whether
including brentuximab vedotin would obviate the need for
more intensive chemotherapy, such as augmented BEA-
COPP, remains quite relevant.
In addition, the role of brentuximab vedotin as part of a
dose-intensive transplantation approach is important. Maximal
cytoreduction before ASCT is associated with a more
favorable outcome. The current standard salvage chemotherapy
regimens, such as ifosfamide, carboplatin, and etoposide
(i.e., ICE), have a low CR rate (26%) despite a high
ORR. 28 Improving the CR rate might allow more patients
with relapsed or refractory HL to proceed to and have
successful results from ASCT. A retrospective analysis reported
at ASH 2011 suggests that brentuximab vedotin
therapy before reduced-intensity alloSCT for patients with
HL may result in prolonged disease control without an
increase in engraftment delay, post-transplant infectious
complications, acute or chronic graft-versus-host disease, or
nonrelapse-related transplant mortality. 29
The retreatment data, albeit on a small number of patients,
suggest that some patients with relapsed HL may
maintain sensitivity to brentuximab vedotin. This issue
warrants more detailed characterization in larger numbers
of patients to better identify which patients might be most
likely to benefit from retreatment. A phase II retreatment
trial in patients who have previously achieved objective
responses to brentuximab vedotin is currently ongoing
(ClinicalTrials.gov identifier: NCT00947856).
The challenges for this highly active and novel therapy
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