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An investigational drug known as brentuximab vedotin (SGN-35) achieved dramatic responses in a pivotal phase II study involving younger patients with relapsed or refractory Hodgkin lymphoma.
An investigational drug known as brentuximab vedotin (SGN-35) achieved dramatic responses in a pivotal phase II study involving younger patients with relapsed or refractory Hodgkin lymphoma (HL) who had no other treatment options, investigators reported at the meeting. Based on results from this trial, Seattle Genetics and Millennium announced that they will apply to the regulatory agencies in the United States and Europe for approval of brentuximab as a treatment for HL and anaplastic large cell lymphoma (ALCL) during the first quarter of 2011.
In the single-arm study, 75% of patients demonstrated response (defined as tumor shrinkage >50%) and 34% achieved complete remission (CR). Overall, 94% of patients experienced some degree of tumor reduction, said Robert Chen, MD, assistant professor, Hematology and Hematopoietic Cell Transplantation at City of Hope, Duarte, California. In an interview with Oncology & Biotech News, Chen said the response rate of 75% was “surprisingly high” for a singleagent therapy in HL. “This is comparable to multiagent combination chemotherapy,” he added.
At a press conference, Chen explained that nearly 30% of patients with HL will experience a relapse. “These patients have limited treatment options beyond autologous stem cell transplantation and represent a significant unmet medical need,” Chen said. “Based on these data, brentuximab vedotin has the potential to change the treatment paradigm for relapsed or refractory HL patients and could be the first treatment approved for these patients in more than 20 years.”
Brentuximab vedotin is an antibody-drug conjugate that uses an enzyme-cleavable linker to join SGN-30, a humanized anti-CD30 monoclonal antibody, with the cytotoxic monomethyl auristatin E (MMAE), a potent tubulin inhibitor. The drug targets tumor necrosis factor CD30 receptors; MMAE is not released until after the drug has been taken into the tumor cells; this should theoretically protect non-CD30 cells from toxicity.
Investigators enrolled 102 patients who had relapsed or had refractory HL following autologous stem cell transplantation. The median age of the patients was 31 years (range, 15 to 77 y), and slightly more than half (53%) were female. More than 70% had primary refractory disease, having failed to achieve CR or having progressed within 3 months of completing frontline therapy. In addition, 39% had disease refractory to the most recent salvage therapy (excluding autologous transplantation). Patients received a median of 4 prior treatment regimens (range, 1-13). The study’s primary endpoint was objective response rate (ORR) by independent central review.
All patients received 1.8 mg/kg of brentuximab vedotin every 3 weeks for ≤16 doses. Median duration of brentuximab vedotin treatment was 29 weeks (range, 3-54 wk) by independent central review and 47 weeks by investigator assessment; the median number of cycles delivered was 9 (range, 1-16). Among patients achieving CR, the median duration had still not been reached after a median follow-up of approximately 1 year.
In addition to a 75% ORR and a 34% rate of CR, Chen said 22% of patients had stable disease and 3% had progressive disease. Investigators defined stable disease as a “reduction in tumor size of <50% and no growth in tumor size of >50%,” said Chen. Median progression-free survival (PFS) was 25 weeks according to independent review and 39 weeks based on investigator assessment. At the time of the meeting, PFS for the subgroup of patients who achieved CR had not yet been reached.
Peripheral sensory neuropathy was the most common adverse effect, followed by fatigue, nausea, upper respiratory tract infection, and diarrhea (Figure). The most common adverse events ≥grade 3 included neutropenia, peripheral sensory neuropathy, thrombocytopenia, and anemia. Chen said 20% of patients in the study discontinued brentuximab because of treatmentrelated adverse effects, but none of the deaths in the study were attributable to the drug.
“This promising drug offers a new treatment option for patients with relapsed/refractory HL who have no other options,” stated Ginna Laport, MD, Stanford University School of Medicine, Stanford, California, who moderated the press conference where these data were released.
Asked how he sees brentuximab vedotin being used at the practice level, Chen told Oncology & Biotech News that “Brentuximab vedotin definitely will be used for patients who relapse after autologous stem cell transplantation.” And, depending on what type of FDA approval the drug receives, Chen said, “[It] can also be used for some patients before autologous stem cell transplantation.”
Investigators are currently conducting an ongoing phase II clinical trial that is evaluating the efficacy and safety of brentuximab vedotin as maintenance therapy after stem cell transplant versus the current standard of care, which, Chen pointed out, is “nothing.” He said the takeaway message for community oncologists from this study is that “brentuximab vedotin has a high response rate, and side effects are very manageable…many are reversible.” In addition, patients taking the drug were able to continue with their daily routines.
Chen R, Gopal AK, Smith SE, et al. Results of a pivotal phase 2 study of brentuximab vedotin (SGN-35) in patients with relapsed or refractory Hodgkin lymphoma. Presented at: 52nd ASH Annual Meeting and Exposition; December 4-7, 2010; Orlando, Florida.
Shustov AR, Advani R, Brice P, et al. Complete remissions with brentuximab vedotin in patients with relapsed or refractory systemic anaplastic large cell lymphoma. Presented at: 52nd ASH Annual Meeting and Exposition; December 4-7, 2010; Orlando, Florida.