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CD30-Positive Lymphoma Table 1. Clinical Trials and/or Observational Studies Evaluating the Antitumor Activity of Brentuximab Vedotin in Relapsed/Refractory CD30-Positive Lymphoma Author
Study Design
Patient Population
Response
PFS/OS/DR
Younes et al
Phase I dose escalation; SGN-35 given at dosages ranging from 0.1 mg/kg to 3.6 mg/kg every 21 days
Relapsed/refractory CD30+ hematologic malignancies (N = 45)
ORR = 54% CRR = 39% PRR = 14%
DR = 9.7 mo PFS = 5.9 mo
Younes et al23
Phase II; SGN-35 1.8 mg/kg every 21 days
Relpsed/refractory HL (N = 102)
ORR = 75% CRR = 34%
PFS = 5.6 mo DR = 20.5 mo
Pro et al24
Phase II; SGN-35 1.8 mg/kg every 21 days
Relapsed/refractory ALCL (N = 50)
ORR = 86% CRR = 57%
PFS = 13.3 mo DR = 12.6 mo
Fanale et al25
Phase I, dose escalation; SGN-35 given at doses ranging from 0.4 mg/kg to 1.4 mg/kg every 28 days on days 1, 8, and 15
Relapsed/refractory CD30+ hematologic malignancies (N = 44)
ORR = 59% CRR = 34%
DR = NR at 45 wk
Chen et al26
Case series; patients treated with SGN-35 standard-dose schedule
Relapsed/refractory HL (N = 18)
ORR = 77% CRR = 33% RR reported prior to RIC allo BMT
1-yr PFS = 92.3% 1-yr OS = 100%
22
HL = Hodgkin lymphoma; ALCL = anaplastic large cell lymphoma; SGN-35 = brentuximab vedotin; ORR = overall response rate; CRR = complete response rate; PRR = partial response rate; RR = response rate; RIC allo BMT = reduced-intensity conditioning allogeneic bone marrow transplant; PFS = progression-free survival; DR = duration of response; mo = months; OS = overall survival.
of evaluable patients (36/42); objective clinical responses were noted in 17 patients (including 12 patients achieving a complete response [CR]). The median duration of response was 9.7 months for the entire group of patients and 17.3 months for patients with objective responses. The median progressionfree survival (PFS) was 5.9 months for all patients.22 Subsequently, a pivotal phase II study of brentuximab vedotin in patients with relapsed/refractory HL reported similar results.23 All patients (N = 102) had failed HDC-ASCT and had a median of 3.5 prior treatments. Patients received brentuximab vedotin at 1.8 mg/kg intravenously every 3 weeks until disease progression, prohibitive toxicity, or up to a maximum of 16 infusions. The ORR was 75% (76/102) with 34% of the patients achieving a CR (35/102). Partial response (PR) was observed in 40% of the patients. The median time to objective response was 5.7 weeks, and the median time to achieve a CR was 12 weeks. The median PFS was only 5.6 months for all patients and 20.5 months for those patients who achieved a CR. For the most part, brentuximab vedotin was well tolerated. The toxicity profile was similar to other brentuximab vedotin studies (Table 2). The median number of cycles administered was 9 (range, 1-16). The most common treatment-related adverse events were peripheral sensory neuropathy, nausea, neutropenia, diarrhea, and fatigue. The only clinically relevant grade 3 or higher adverse event noted was neuropathy (8%). Only two patients discontinued treatment due to adverse events, and treatment delay due to neutropenia was observed in 16% of patients. Parallel to the HL pivotal study, brentuximab vedotin was formally evaluated in patients with relapsed/refractory ALCL. Pro et al24 reported the results of a phase II study. A total of 58 patients with pretreated ALCL (median number of previous treatments was 2) received brentuximab vedotin at the standard dose of 1.8 mg/kg every 21 days for up to 16 cycles, until disease progression, or until unacceptable toxicity. Objective response was observed in 86% of the patients, and 57% of the patients achieved a CR. The median duration of response was 12.6 months. Toxicity was similar to what had been observed in prior clinical trials, with only 24% of patients discontinuing treatment due to adverse events. The most common grade 46 / 11.12
3-4 adverse events were peripheral neuropathy, neutropenia, and thrombocytopenia (Table 2). Based on these three clinical studies, brentuximab vedotin received FDA approval for the treatment of relapsed/refractory HL and ALCL. While the overall response rates (ORRs) and CR rates for brentuximab vedotin are higher than second- or third-line chemotherapy agents, historical controls, or other novel agents tested in clinical studies, the duration of response is rather short, further stressing the need to develop strategies to optimize this agent in the management of relapsed/refractory HL or ALCL. Two strategies have been tested recently with various degrees of success. Fanale et al25 conducted a phase I study to determine the MTD and DLT of brentuximab vedotin administered on a weekly dosing schedule in hematologic malignancies. A total of 44 patients (38 HL patients) with relapsed/refractory CD30-positive hematologic malignancies received weekly brentuximab vedotin at dosages ranging between 0.4 mg/kg to 1.4 mg/kg. The MTD was observed at the 1.2-mg/kg dose level, and grade 3 peripheral neuropathy was found to be the DLT. Clinically significant neuropathy was observed in 66% of the patients. In contrast to prior clinical studies with brentuximab vedotin administered on a 21-day cycle, the median time to onset of neuropathy was shorter, and its severity was higher in the weekly dosing schedule. On the other hand, the response rate was similar to prior brentuximab vedotin studies (ORR = 59%). Based on this study, it appears that the standard 21-day schedule of administration confers the best antitumor activity with the lowest incidence of grade 3 hematologic and nonhematologic toxicities. Given the higher incidence of CR rates, brentuximab vedotin has been evaluated as a therapeutic strategy in preparation for reduced-intensity conditioning (RIC) allogeneic bone marrow transplant in patients with relapsed/refractory HL who had previously failed HDC-ASCT. Chen et al26 reported the clinical outcome of 18 patients with relapsed/refractory HL treated with brentuximab vedotin followed by RIC allogeneic bone marrow transplant. All but one patient had failed HDC-ASCT prior to enrollment and received brentuximab vedotin 1.8 mg/kg every 21 days. The duration The International Journal of TargetedTherapies in Cancer