Brentuximab regimen effective for younger patients with advanced-stage Hodgkin lymphoma
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CHICAGO — Combining brentuximab vedotin with a chemotherapy regimen as first-line therapy conferred an objective response in 88% of younger patients with newly diagnosed advanced-stage classical Hodgkin lymphoma, study results show.
Data from the phase 1/phase 2 study presented at ASCO Annual Meeting suggest that the regimen — already FDA-approved for the same indication as first-line therapy in adults — is safe and effective for younger patients, as well.
Background
The cure rates for younger patients with Hodgkin lymphoma are typically higher than other pediatric cancers, with OS rates of better than 90% for children, adolescents and young adults who develop the disease, according to Robin E. Norris, MD, MS, MPH, associate professor in the department of pediatrics at University of Cincinnati School of Medicine and director of oncology clinical research at Cincinnati Children's Hospital Medical Center.
“But those cure rates come at a cost,” she said during a presentation.
“They come with the risk of potentially serious sequelae, including cardiovascular disease, pulmonary toxicity, [avascular necrosis], decreased fertility and secondary malignancies,” she added. “Therefore, there is a clear need to incorporate novel therapies with the goal of replacing cornerstone agents and, thus, decreasing the associated toxicity while maintaining — if not improving — efficacy.”
Brentuximab vedotin (Adcetris, Seagen), a CD30-directed antibody-drug conjugate, is one of the newer agents “that appears to be changing the treatment landscape for pediatric and adult Hodgkin lymphoma,” Norris noted.
The drug in combination with doxorubicin, vinblastine and dacarbazine (AVD) was already approved for first-line use in adults with classical Hodgkin lymphoma based on results of the ECHELON-1 study, which led her group to evaluate for the first time its potential as a less toxic and more effective replacement for current therapies in younger patients.
Methodology
Norris and colleagues presented combined updated data from an ongoing phase 1/phase 2 open-label, multicenter trial of brentuximab vedotin in combination with AVD for younger patients with newly diagnosed, advanced stage CD30-positive classical Hodgkin lymphoma. The study included patients aged 5 to 18 years with stage III or stage IV disease.
Phase 1 of the study included eight patients (median age, 13 years; range, 6-17; 50% male) who received up to six cycles of brentuximab vedotin 48 mg/m2 plus AVD on days 1 and 15 of a 28-day cycle. The first portion of the study aimed to evaluate the regimen’s safety and tolerability while establishing 48 mg/m2 as the recommended phase two dose of brentuximab vedotin.
No dose-limiting toxicities occurred during the phase 1 portion of the study, which showed an objective response rate of 100% and a complete response (CR) rate of 88%
Phase 2 of the study included 51 additional patients who received the same treatment regimen.
Efficacy measurements by independent review, including ORR, CR and partial response rates at the end of treatment, served as phase 2 portion’s primary objectives.
A total of 59 patients (median age, 14 years; range 6-17; 53% male) from the combined phase 1 and phase 2 portions of the study completed six cycles of the treatment regimen and were eligible for the safety and efficacy analyses.
Median follow-up was 28.7 months, with a data cutoff date of Sept. 24, 2021. All patients had been enrolled in the study for at least 2 years as of the data cutoff date.
Key findings
Combined phase 1/phase 2 results showed an ORR per independent review facility of 88% (95% CI, 77-95), with a CR rate of 76% (95% CI, 63-86) and a partial response rate of 12% (95% CI, 5-23).
Seven patients (12%) had progressive disease, with 14 (24%) going on to receive radiation therapy at the end of treatment.
Median OS and duration of response could not be estimated as of the data cutoff point. However, independent review facility assessment showed an estimated 24-month OS rate of 100%.
Median PFS has not yet been reached, with estimated PFS per independent review facility for all patents at 24 months of 72.6% (95% CI, 58.1-82.8).
All 59 patients had at least one treatment-related adverse event, including 92% who had at least one grade 3 or higher event.
The most common hematologic treatment-related adverse events included neutropenia (58%), decreased white blood cell count (42%) and decreased neutrophil count (37%).
The most common nonhematologic treatment-related adverse events included vomiting (85%), nausea (75%) and pyrexia (42%).
Twenty-four percent of patients developed treatment-related peripheral neuropathy that took a median of 1.6 weeks to resolve.
No patients died during the study.
Clinical implications
Norris said she was encouraged by the results thus far and that “brentuximab plus AVD was well tolerated” in younger patients.
“These safety and efficacy data are consistent with those seen in adult patients,” she said, referring to the similar findings in the ECHELON-1 trial.
Norris also noted the number of patients requiring subsequent radiation therapy was much lower for the regimen her group evaluated than what has been observed in previous studies of similar patients.
“These findings support the use of brentuximab plus AVD as a reasonable option for pediatric patients with newly diagnosed, advanced-stage classical Hodgkin lymphoma,” she said.
Perspective
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Navin R. Pinto, MD
The work done by Norris and colleagues demonstrates progress in the field of pediatric cancer treatment.
The data they present suggest there is a lower rate of treatment-related toxicity in the acute setting for the brentuximab-plus-chemotherapy regimen they examined. More importantly, they have eliminated drugs like cyclophosphamide and prednisone from the chemotherapy backbone, in addition to the elimination of subsequent external-beam radiation therapy in many patients.
We will likely see the true benefit of this combination in a reduction of the late effects, which are often quite daunting for patients with Hodgkin lymphoma, so I eagerly await results from the long-term follow-up of this study.
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Franklin AR, et al. Abstract 10000. Presented at: ASCO Annual Meeting; June 3-7, 2022; Chicago.
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