2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

TARGETING CD30 IN HODGKIN LYMPHOMA
protein may be shed into a soluble form in the serum
(sCD30). Elevated levels of sCD30 have been detected in the
serum of patients with CD30-positive malignancies, and
there is some suggestion that this might correlate with
tumor burden, clinical outcome, or both. 9 CD30 expression is
present in many conditions of dysregulated immunity, including
cutaneous T-cell lymphoma, diffuse large B-cell
lymphomas, follicular lymphoma, post-transplantation lymphoproliferative
disorder, and virally infected T cells (e.g.,
HIV). 10-12
Unconjugated CD30-Directed Monoclonal Antibodies
Several groups have evaluated unconjugated monoclonal
antibodies against CD30 as therapeutic agent. Recent advances
in antibody engineering have optimized two unconjugated
antibodies: SGN-30 (cAC10), a chimerized
immunoglobulin G1 (IgG1) monoclonal antibody, and MDX-
060, a fully human monoclonal antibody that has shown
enhanced antibody-dependent cell-mediated cytotoxicity
(ADCC) compared with SGN-30. SGN-30 was evaluated in a
phase II trial of patients with HL and systemic CD30positive
anaplastic large-cell lymphoma (sALCL) (Table
1). 13 The treatment was well tolerated, however objective
responses were not observed in patients with HL. Yet, seven
of the 41 patients with sALCL (17%) attained therapeutic
KEY POINTS
Table 1. Summary of Clinical Response Data to CD30-Targeted Antibody Therapy
Drug Investigated
n
Treatment Dosage
ORR (%)
(reference) Clinical trial HL ALCL Total (mg/kg body weight)
HL ALCL Overall
SGN-30 (13) Phase II 38 41 79 6–12 weekly 0 17 (CR 5, PR 12) 9
MDX-060 (14) Phase I/II 63 7 72* 0.1–15 weekly 6 (CR 3, PR 3) 29 (CR 29) 8*
Brentuximabvedotin
(19)
Brentuximabvedotin
(20)
Brentuximabvedotin
(21,22)
Brentuximab vedotin
(23)
Initial phase I 42 2 45† 0.1–3.6 every 3 wk 36 (CR 21) 100 (CR 100) 38† (CR 24; ORR 50 for
patients treated at the
MTD)
Phase I 44 5 38 0.4–1.4 weekly 59 (CR 34)
Pivotal phase II, in
patients with HL
Phase II, in patients
with sALCL
● CD30 expression is characteristic of Reed-Sternberg
cells in Hodgkin lymphoma.
● Efforts to target CD30 with unconjugated or “naked”
monoclonal antibodies have had limited therapeutic
success.
● Brentuximab vedotin is a CD30-directed antibody
conjugated to a synthetic taxane (MMAE) with substantial
therapeutic activity in recurrent Hodgkin
lymphoma.
● The toxicity profile of brentuximab vedotin suggests
that it may be combined successfully with several
standard chemotherapeutic agents.
● Ongoing efforts are directed toward integrating brentuximab
vedotin into Hodgkin lymphoma therapeutic
regimens to maximally improve outcomes.
102 – 102 1.8 every 3 wk 75 (CR 34) – –
– 58 58 1.8 every 3 wk – 86 (CR 53) –
Abbreviations: ALCL: anaplastic large-cell lymphoma; CR: complete remission; HL: Hodgkin lymphoma; MTD: maximum-tolerated dose; ORR: overall response rate;
PR: partial remission.
* Including two patients with CD30 � T cell lymphoma. † Including one patient with CD30 � angioimmunoblastic T cell lymphoma. ‡ Including one patient with peripheral
T cell lymphoma.
responses: two (5%) attained complete response (CR) and
five (12%) attained partial remission (PR), which provides
some proof of concept. A phase I/II trial of MDX-060 was
performed in 72 patients with relapsed or refractory CD30positive
lymphomas. 14 The overall response rate (ORR) was
6% in the patients with HL and 29% in the patients with
ALCL. With preclinical data suggesting synergy between
cytotoxic chemotherapy and SGN-30, this agent was combined
with GVD (gemcitabine, vinorelbine, and liposomal
doxorubicin) chemotherapy by the Cancer and Leukemia
Group B (CALGB) in a phase II trial for patients with
relapsed HL. 15 This trial was prematurely closed because of
grades 3 to 5 pneumonitis that occurred in five of the 30
patients enrolled. Interestingly, all five patients with pneumonitis
were noted to have a valine/phenylalanine (V/F)
polymorphism in the FcgammaRIIIa gene, suggesting a
possible immune component. These pulmonary issues, including
the potential for worsened risk of lung toxicity in
combination with bleomycin (which can cause lung injury
itself) are of importance as the development of CD30directed
agents moves forward. Given the relatively low
response rate seen with both SGN-30 and MDX-060 (i.e.,
unconjugated anti-CD30 antibodies), their continued development
has been limited, and the assessment of novel,
conjugated agents has taken higher priority.
Brentuximab-Vedotin: A Novel CD30-Targeted
Antibody-Drug Conjugate
Antibody-drug conjugates (ADC) can provide specific,
preferential targeting of potent chemotherapeutic agents or
toxins to differentially expressed antibody targets. Regarding
binding to cell-surface targets, ADCs are generally
internalized primarily via clathrin-mediated endocytosis
and subsequent lysosomal proteolysis. This feature allows
the therapeutic agent to be delivered into the target cell,
ideally without affecting bystander and normal cells because
they lack the antigen providing specificity. By allowing more
of the drug or toxin to reach the target cell, therapeutic
benefit should result, and because normal cells would be
spared, toxicity should be minimized. In addition, if the
antibody itself and the drug conjugated to it both have
antitumor activity, multiple mechanisms of therapeutic action
may be in effect.
Brentuximab vedotin is a CD30-targeted ADC composed
of the chimeric antibody cAC10 (SGN-30) modified by the
addition of a valine-citrulline peptide linker to monomethyl
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