The phase 3 S1826 trial is the largest Hodgkin lymphoma study in NCTN history.
PET-adapted chemotherapy has traditionally been the standard for advanced stage classic Hodgkin lymphoma (HL), explained Alex Francisco Herrera, MD, hematologist-oncologist and associate professor, Division of Lymphoma, Department of Hematology & Hematopoietic Cell Transplantation at City of Hope National Medical Center in Duarte, California, during a press conference at the American Society of Clinical Oncology 2023 Annual Meeting.
However, global, adult, and pediatric approaches to treatment continue to differ, with radiation therapy still delivered to 55%-60% of pediatric patients with the disease. For this young patient population, the late toxic effects from this treatment are significant.
“[HL] affects a little over 8000 people in the United States each year, and many more globally,” Herrera said. “It also disproportionately affects young patients, so this is folks in their teens, twenties, and thirties.”
Additionally, there’s a long history of treating this cancer, according to Herrera. Over the years, treatment has included using increasing doses of radiation and increasing doses of chemotherapy to try to maximize cure rates.
“Now, that was [the standard] decades ago. Slowly, steadily over time, we’ve been trying to walk that therapy back and de-escalate the therapy,” Herrera said. “[Additionally,] treatment regimens have evolved and differ around the globe. We’ve used [doxorubicin (Lipodox; Sun Pharmaceutical Industries), vinblastine (Velban; Cipla), and dacarbazine (AVD; DTIC-Dome, Hikma Pharmaceuticals)] in North America for years, but even within North America, adult and pediatric approaches differ.”
Herrera explained further that pediatric patients have traditionally received the regimen doxorubicin, bleomycin (Bleo 15K; Cipla), vincristine (Marqibo; CASI Pharmaceuticals), etoposide (Vepesid; Xediton Pharmaceuticals), prednisone (Deltasone; Jubilant Cadista Pharmaceuticals), and cyclophosphamide (Cytoxan; Roxane Laboratories), with a majority of the youngest patients receiving consolidative radiotherapy, even with advanced stage disease. Notably, these young patients are also the most vulnerable to the late toxic effects of the chemotherapy and radiation used.
Brentuximab vedotin (BV; Adcetris, Seagen), an antibody drug conjugate directed against the CD30 on the surface of HL tumor cells, is the first novel therapy developed specifically for treating HL.
“Many studies showed that incorporating [BV] into the first-line therapy for [HL] improved overall survival in adults and event-free survival in pediatric patients, and that led to the approval of the drug for both of those indications,” Herrera said. “Now, despite these improved outcomes with brentuximab vedotin, many patients still are not cured by their initial therapy.”
Although the addition of BV to initial chemotherapy improves overall survival (OS) in adults and PFS in pediatric patients with advanced stage HL, adding BV is actually more toxic than AVD alone, according to Herrera. Even with this added toxicity, most pediatric patients still receive radiation therapy, with 7%-20% of patients developing relapsed/refractory HL.
“So we added [BV] and improved outcomes, but we actually made the therapy more toxic,” Herrera said. “Adult and pediatric approaches also still differ—we still use different regimens, and we still use consolidative radiotherapy for the youngest and most vulnerable patients.”
However, HL is a poster child for the use of PD-1 blockade because the PD-1 pathway is central to the pathogenesis of HL, according to Herrera. Specifically, there are genetic changes in the HL tumor cells that lead to the expression of the PD-1 ligands on the surface of the tumor cells.
“When we use drugs like nivolumab [N, Opdivo; Bristol-Myers Squibb], we see that even patients with the most treatment-resistant [HL] have response rates as high as 70%,” Herrera said. “We incorporated [N] into early studies in the front-line treatment of HL, and we’d seen promising results.”
Based on that rationale, the adult and pediatric National Cancer Institute National Clinical Trials Network (NCTN) cooperative groups collaborated to design the randomized, phase 3 SWOG S1826 trial (NCT03907488). This is the first time these groups have come together and collaborated in a NCTN study, according to Herrera.
“This was really a monumental effort to bring everyone into the room to agree and all treat our patients with the same AVD chemotherapy backbone, and then randomize them in a 1-to-1 fashion to receive either N or [BV] combined with that AVD chemotherapy backbone,” Herrera said.
Herrera explained that patients were eligible for enrollment in S1826 if they were aged 12 years or older with stage 3-4 HL. In total, 994 patients were enrolled from July 9, 2019, to October 5, 2022, with 976 found eligible. The patients were then randomized 1:1 to either 6 cycles of N-AVD (n=489) or BV-AVD (n=487).
“The study actually accrued patients almost a year ahead of schedule. That’s how exciting this was—the fact that everyone got in the room and all the cooperative groups were doing this together just showed how we can advance research more quickly by all working together across the age spectrum,” Herrera said.
Specifically, 56% of patients were male, 76% were White, 12% were Black, and 13% were Hispanic, with 32% of patients with international prognostic score (IPS) 4-7. Additionally, Herrera noted that the median age of participants was 27 years (range, 12-83 years).
“Overall, S1826 was a representative trial, with a quarter of patients under 18 [years] and 10% of patients over the age of 60 [years]. Also, a quarter of patients were Hispanic or Black, with quite good representation from higher risk subgroups—so this was a real real-world trial, which is the strength of cooperative groups working together,” Herrera said.
Patients were also required to have BV-AVD G-CSF neutropenia prophylaxis vs optional with N-AVD. However, pre-specified patients could receive radiation therapy to residually metabolically active lesions at the end of PET treatment. Additionally, patients were stratified by age, IPS, and intent to use radiation therapy, with response and disease progression assessed by investigators using 2014 Lugano Classification. The primary endpoint of the trial was PFS, with secondary endpoints including OS, event-free survival, patient-reported outcomes (PROs), and safety.
So far in the trial, less than 1% of patients received radiation therapy, according to Herrera. At the planned second interim analysis (50% of total PFS events), the SWOG Data and Safety Monitoring Committee recommended to report the primary results because the primary PFS endpoint crossed the protocol-specified conservative statistical boundary.
“This signified that the trial had met its primary endpoint. N-AVD had reduced the risk of disease progression or death by half when compared to BV-AVD,” Herrera said. “This benefit from N-AVD was also consistent across the different age groups and other subgroups enrolled in the trial.”
There were also 30 PFS events that occurred after N-AVD vs 58 events after BV-AVD. With a median follow up of 12.1 months, PFS was superior in the N-AVD arm [HR 0.48, 99% CI 0.27-0.87, one-sided p=0.0005), with 1-year PFS at 94% for N-AVD and 86% for BV-AVD. Further, 11 deaths (7 due to adverse events [AEs]) occurred after BV-AVD compared to 4 after N-AVD (3 due to AEs).
“The benefit for N-AVD was actually most marked in patients with stage 4 disease—the most aggressive, the most spread [HL],” Herrera said. “So not only did we improve outcomes with this drug, but we also reduced toxicity as well, and, in a way, de-escalated therapy.”
The rate of grade 3 or higher hematologic AEs were 48.4% (45.1% grade 3 or more neutropenia) after N-AVD compared to 30.5% (23.9% grade 3 or more neutropenia) after BV-AVD. Rates (any grade) of febrile neutropenia (5.6% N vs 6.4% BV), pneumonitis (2.0% N vs 3.2% BV), ALT elevation (30.7% N vs 39.8% BV), and colitis (1% N vs 1.3% BV) were similar. Additionally, hypo/hyperthyroidism was more frequent after N-AVD (7%/3% N vs less than 1% BV) whereas peripheral neuropathy (any grade) was more common after BV-AVD (sensory: 28.1% N vs 54.2% BV; motor: 4% N vs 6.8% BV).
“Most importantly though, there was no increase in infectious toxicity with N-AVD, even though there was more neutropenia in the N-AVD arm,” Herrera said. “There was also more peripheral neuropathy in the BV-AVD arm—I can’t emphasize how important neuropathy is as an AE in these young patients who have the rest of their lives ahead of them. It’s fantastic to be cured of your cancer, but tough to spend the rest of your life not being able to feel your fingers and toes.”
Based on these results, investigators observed that N-AVD improved PFS vs BV-AVD in patients with advanced stage HL. Importantly, few immune AEs were observed and less than 1% of patients received radiation therapy; however, longer follow-up is needed to assess OS and PROs.
“S1826, the largest [HL] study in NCTN history, is a really key step towards harmonizing the pediatric and adult treatment of advanced stage [HL],” Herrera said. “Based on these data, N-AVD is poised to be a new standard therapy for this disease.”
Herrera AF. SWOG S1826, a randomized study of nivolumab(N)-AVD versus brentuximab vedotin(BV)-AVD in advanced stage (AS) classic Hodgkin lymphoma (HL). Presented at: 2023 ASCO Annual Meeting in Chicago, IL at press conference on June 3, 2023. Accessed June 3, 2023. https://meetings.asco.org/2023-asco-annual-meeting/15047