New results from a trial in pediatric Hodgkin lymphoma have been described as a “paradigm shift” that will change practice, and have just led to approval by the US Food and Drug Administration (FDA) for a new indication for brentuximab vedotin (Adcetris).
In the trial, adding brentuximab vedotin to standard chemotherapy provided superior efficacy versus chemotherapy alone for first-line treatment of pediatric high-risk Hodgkin lymphoma.
The combination approach was associated with a nearly 10% improvement in event-free survival and a 59% reduction in the risk of relapse, death, or second malignant neoplasm, with no increase in the incidence of toxic effects at 3 years, the Children’s Oncology Group (COG) investigators report.
This 10% improvement in event-free survival is “a real breakthrough,” commented senior author Kara Kelly, MD, division chief of hematology/oncology, Department of Pediatrics, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, New York.
“That’s quite a big gain, especially in this field,” she stated in a press release. “We expect that this treatment regimen will soon become standard of care for pediatric patients with high-risk Hodgkin lymphoma.”
First author Sharon Castellino, MD, professor of pediatrics at Emory University School of Medicine in Atlanta, Georgia, and a research member at Winship Cancer Institute of Emory University described the findings as “a paradigm shift for advanced-stage Hodgkin lymphoma in children and an introduction of the first targeted approach for initial therapy in pediatric Hodgkin lymphoma and the first new regimen in two decades.”
“We are optimistic that this trial will set the stage for [FDA] approval of this targeted antibody-drug conjugate for children and adolescents,” Castellino commented when the trial was published online on November 3 in the New England Journal of Medicine.
That FDA approval came just a week later and was announced on November 10.
Brentuximab vedotin is already approved for use in Hodgkin and several other lymphomas. The new approval is specifically for use in pediatric patients 2 years and older with previously untreated high-risk classical Hodgkin lymphoma in combination with doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide.
“We are excited about the approval of Adcetris for children and adolescents with high-risk classical Hodgkin lymphoma because this medicine, which has become part of standard of care for adults with previously untreated advanced stage Hodgkin lymphoma, will now be accessible to young patients as well,” Castellino said in a press release by the manufacture announcing the approval.
Concern About the Late Effects of Treatment
Approached for comment about the new results, Angela M. Feraco, MD, attending physician and associate pediatric hematology/oncology fellowship program director at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Massachusetts, said the findings are “intriguing.”
“These results are highly compelling and suggest that young patients with high-risk disease benefit from the incorporation of brentuximab vedotin into a backbone of dose-dense multi-agent chemotherapy,” Feraco told Medscape Medical News.
However, concerns remain about life-altering treatment effects that can occur later in life for patients exposed to potentially toxic therapies during childhood and adolescence, she commented.
More than 50% of patients in both treatment groups received radiotherapy, she pointed out.
That is a concern also cited in an accompanying editorial by Mark Roschewski, MD, of the National Cancer Institute, Bethesda, Maryland, and Catherine M. Bollard, MD, MBChB, of George Washington University, Washington, DC. They highlight the long-term toxicity effects of current therapies, particularly the risk of second cancers, which “continues to increase for at least 40 years after therapy, reaching a cumulative incidence of nearly 50%.”
“Although chemotherapy contributes, radiation therapy confers the greatest risk of second cancers,” they point out, and so, “limiting the radiation dose, reducing exposure to normal tissue, and omitting radiation therapy altogether remain important goals.”
In this trial, the substitution of brentuximab vedotin for bleomycin with chemotherapy in children with Hodgkin lymphoma improved disease control at 3 years, but did not improve overall survival and appeared not to reduce reliance on radiation therapy, the editorialists point out.
“Future clinical trials should explore strategies to omit radiation therapy altogether in children who have a complete metabolic response, including in those with initial bulky tumors,” they add.
“Given the potential for life-altering health conditions in adults who receive radiation early in life, reducing the number of children and young adults who receive radiation therapy remains a major priority for the field,” Feraco agreed. “Furthermore, the chemotherapy backbone utilized in this study included moderate doses of anthracycline and alkylator medications, each of which can produce lasting health problems.”
In total, 587 eligible patients from 153 institutions were included the randomized, open-label COG trial. Patients were aged 2 to 21 years and had previously untreated Hodgkin lymphoma of stage IIB with bulk tumor or stage IIIB, IVA, or IVB.
Patients were randomized to receive either standard care chemotherapy with doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide, or a new combination in which bleomycin was replaced by brentuximab vedotin and added to doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide. Both groups received five 21-day cycles.
Radiotherapy was administered to patients who had slow-responding lesions, as identified on centrally reviewed PET-CT after two cycles. A similar percentage of patients in the brentuximab and standard care groups received radiotherapy (53.4% and 56.8%), the researchers commented.
At a median follow-up of 42.1 months, the primary endpoint of 3-year event-free survival was 92.1% with brentuximab vedotin versus 82.5% in the standard care group (hazard ratio for event or death, 0.41).
Overall survival at 3 years was similar in the two groups (99.3% and 98.5%, respectively).
Toxic effects were also similar in the two groups, the researchers commented.
Of note, patients with slow-responding lesions appeared to particularly benefit from the addition of brentuximab vedotin, the authors point out. Three-year event-free survival with standard chemotherapy was 68.3% versus 85.7% among those with slow- versus rapid-responding lesions, respectively, whereas the corresponding rates in the brentuximab vedotin group were 90.7% and 92.3%.
“The superior event-free survival that we found with brentuximab vedotin plus dose-intensive chemotherapy…provides support for its use as first-line therapy in children and adolescents with high-risk Hodgkin lymphoma. Long-term follow-up will be important to more thoroughly assess the occurrence of late events and overall survival,” the team concluded.
Commenting to Medscape Medical News, Feraco said this was “a rigorously designed randomized phase 3 study” in which “more than 90% of these children and young adults were alive and free of lymphoma at 3 years.” She also highlighted the benefits in those with slow-responding lesions.
“Additionally, rates of clinically meaningful peripheral neuropathy — a major consideration for older adults treated with brentuximab vedotin — were low and did not differ between treatment groups,” she said.
However, Feraco again stressed the need to also focus on reducing long-term treatment effects.
“As we seek the optimal regimen for Hodgkin lymphoma in the young, we hope to maximize cure rates while reducing the burden of chronic conditions that may result from our treatments,” she added.
The study authors agree with these future goals, but they also point out that “increasing survival and reducing the incidence of long-term treatment-associated organ dysfunction among children with high-risk Hodgkin lymphoma starts with enhanced disease control at initial treatment” as lower risk of relapse could reduce the need for retreatment with additional toxic therapies.
Castellino, Kelly, and colleagues in COG now seek to build on the current findings in a new phase 3 trial planned for 2023 with an aim of enrolling nearly 2000 children and adults with medium- and low-risk disease to assess whether brentuximab vedotin plus immunotherapy with nivolumab can prolong progression-free survival and further reduce exposure to standard chemotherapy and radiation.
The study was supported by the National Cancer Institute, Seagen (manufacturer of brentuximab vedotin), and St. Baldrick’s Foundation. Feraco is an investigator within the Pediatric Hodgkin Consortium, which is currently investigating a regimen that includes multi-agent chemotherapy and brentuximab vedotin for young people with high-risk pediatric Hodgkin lymphoma. Feraco, as well as Castellino and Roschewski, have reported no relevant financial relationships. Kelly has reported relationships with Merck and Seagen. Bollard has reported relationships with numerous pharmaceutical companies.
Sharon Worcester, MA, is an award-winning medical journalist based in Birmingham, Alabama, writing for Medscape, MDedge, and other affiliate sites. She currently covers oncology, but she has also written on a variety of other medical specialties and healthcare topics. She can be reached at firstname.lastname@example.org or on Twitter: @SW_MedReporter.