Multicenter Phase II Trial Supporting Approval of Brentuximab Vedotin in Anaplastic Large-cell Lymphoma

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The study results validate a CD30-targeted approach in a disease with uniform antigen expression.

Systemic anaplastic large-cell lymphoma (ALCL) is an aggressive T-cell lymphoma subtype characterized by uniform expression of CD30. Apart from low- to intermediate-risk patients with ALK-positive disease, patients with ALCL have a poor prognosis when treated with conventional, anthracycline-based front-line chemotherapy and typically have disease that is resistant to multiagent chemotherapy after relapse. Brentuximab vedotin (Adcetris)—a conjugate of an anti-CD30 antibody (brentuximab) and the anti-microtubule agent monomethylauristatin E (vedotin)—was found to produce responses in CD30-positive lymphomas in a phase I study,1 raising hope that the conjugate approach would represent an improvement over the disappointing efficacy results achieved with first-generation anti-CD30 antibodies in early-phase studies.2

In a recent Journal of Clinical Oncology article, Pro and colleagues reported the full results of the multicenter phase II study of brentuximab vedotin in relapsed/refractory ALCL that supported the drug’s approval in 2011 for treatment of patients with ALCL after failure of at least one prior multiagent chemotherapy regimen.3 The trial is the largest prospective trial reported to date in patients with recurrent systemic ALCL.

Study Design

In this trial, 58 patients with systemic ALCL and recurrent disease after at least one prior therapy received brentuximab vedotin at 1.8 mg/kg IV over 30 minutes as an outpatient infusion every 3 weeks.3 Patients had to be aged ≥ 12 years and had to have an ECOG performance status of 0 or 1, measurable disease (> 1.5 cm), absolute neutrophil count > 1,000/µL, and platelet count > 50,000/µL. Patients could not have previously received an allogeneic stem cell transplant. The primary endpoint of the study was objective response rate according to independent central review. Response was assessed by CT scans at cycles 2, 4, 7, 10, 13, and 16 and by PET scans at cycles 4 and 7.

Patients had a median age of 52 years (range, 14–76 years), 57% were male, and 72% had ALK-negative disease. Overall, 50% of patients had relapsed disease, and 50% had refractory disease after their most recent therapy. The median number of prior chemotherapy regimens, excluding autologous stem cell transplant, was two (range, 1–6), and 26% of patients had treatment failure with autologous stem cell transplant; 45% of patients had received radiation therapy. The most recent treatment prior to study enrollment was autologous transplant or multiagent chemotherapy in 91% of patients.

Key Data

Patients received a median of seven cycles of treatment (range, 1–16). The objective response rate was 86%, with complete remission occurring in 57% of patients and partial remission in 29%. Reduction in tumor size was observed in 97% of patients. The median time to objective response was 5.9 weeks (range, 4.3–14 weeks), and the median time to complete remission was 11.9 weeks (range, 5.1–50.3 weeks). These median times approximate the timing of the first CT and PET response assessments, respectively.

Median durations of response were 12.6 months in all responders and 13.2 months in patients with a complete response. Median durations of response were 12.6 months in patients with complete remission who did not undergo subsequent stem cell transplant (n = 22) and 13.2 months in those undergoing allogeneic transplant in complete remission (n = 6), with median duration not being reached in patients undergoing autologous transplant in complete remission (n=5). The median time from the last dose of brentuximab vedotin to initiation of stem cell transplant was 25 days.

ALK protein status did not appear to affect response. Objective response occurred in 88% of patients with ALK-negative disease, including complete remission in 52%, and in 81% of patients with ALK-positive disease, including complete remission in 69%, and there were no differences in median duration of response or progression-free survival between these two subgroups. Other subgroup analyses (eg, according to relapsed vs refractory, primary refractory status, 1 vs > 1 prior treatments, prior autologous stem cell transplant, bone marrow involvement, age, sex, and ECOG performance status) showed clinically meaningful antitumor activity in all subgroups, with no subgroup having a greater likelihood of complete remission.

The estimated median progression-free survival for on independent review was 13.3 months for all patients and 14.6 months for those with complete remission. A prespecified comparison of investigator-assessed progression-free survival and progression-free survival after the most recent prior therapy showed a significant prolongation with brentuximab vedotin treatment (median, 14.3 vs 5.9 months, HR = 0.48, P = .001). Median overall survival had not been reached at the time of the analysis. The estimated 12-month overall survival was 70%.

Major Adverse Events

The most common (≥ 20%) adverse events of any grade were peripheral sensory neuropathy (41%), nausea (40%), fatigue (38%), pyrexia (34%), diarrhea (29%), rash (24%), constipation (22%), and neutropenia (21%). Adverse events of at least grade 3 occurred in 60% of patients, with the most common being neutropenia (21%, including grade 4 in 9%), thrombocytopenia (14%, including grade 4 in 5%), peripheral sensory neuropathy (12%), and anemia (7%).

Adverse events led to discontinuation of treatment in 24% of patients; peripheral sensory neuropathy led to discontinuation in 10%, with no other adverse event leading to discontinuation in more than one patient. Brentuximab vedotin doses were delayed due to adverse events in 40% of patients, most commonly due to peripheral sensory neuropathy (14%) and neutropenia (12%). Overall, 10% of doses were delayed. Doses were reduced in 12% of patients, most commonly due to peripheral sensory neuropathy (7%).

Overall, 53% of patients experienced peripheral neuropathy adverse events, which were grade 3 in 14%. The median times to onset were 13.3 weeks for events of any grade, 16.9 weeks for grade 2 events, and 28.4 weeks for grade 3 events. Improvement or resolution of peripheral neuropathy occurred in 81% of patients, with complete resolution occurring in 48%. The median time to improvement or resolution was 9.9 weeks (range, 0.3–32.9 weeks).

Tumor lysis syndrome occurred in one patient after the first dose of brentuximab vedotin; the patient recovered with supportive care, continued to receive study medication, and achieved complete remission. Four patients experienced palpable, painful enlargement of affected nodes with overlying erythema, which subsequently regressed. These tumor flares were considered to reflect an inflammatory process rather than disease progression. Overall, six patients (10%) died within 30 days of the last dose of brentuximab vedotin, with none of the deaths considered related to study treatment.

It should be noted that early in 2012, a boxed warning for progressive multifocal leukoencephalopathy was added to brentuximab vedotin labeling, as was a contraindication for use of the drug concomitantly with bleomycin due to increased risk of pulmonary toxicity.4

In Conclusion

As stated by the investigators, “The study results validate a CD30-targeted approach in a disease with uniform antigen expression. The [complete remission] rate … and acceptable safety profile achieved in this study demonstrate that brentuximab vedotin could be valuable as a potential treatment strategy for aggressive, CD30-positive, T-cell lymphomas. Clinical evaluation of brentuximab vedotin in newly diagnosed patients with ALCL and other CD30-expressing lymphomas is warranted.”3


1. Younes A, Bartlett NL, Leonard JP, et al: Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl J Med 363:1812-1821, 2010.

2. Forero-Torres A, Leonard JP, Younes A, et al: A phase II study of SGN-30 (anti-CD30 mAb) in Hodgkin lymphoma or systemic anaplastic large cell lymphoma. Br J Haematol 146:171-179, 2009.

3. Pro B, Advani R, Brice P, et al: Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: Results of a phase II study. J Clin Oncol 30:2190-2196, 2012.

4. ADCETRISTM (brentuximab vedotin) for injection prescribing information. Seattle Genetics, Inc, January 2012. Available at Accessed June 13, 2012.