Nivolumab-Chemotherapy Combo Boosts PFS in cHL, Poised for Standard Use

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The N-AVD regimen consisting of nivolumab (Opdivo) with doxorubicin, vinblastine, and dacarbazine, demonstrated superior progression-free survival (PFS) vs BV-AVD (brentuximab vedotin [Adcetris] with doxorubicin, vinblastine, and dacarbazine) in advanced classical Hodgkin lymphoma (cHL). N-AVD boasts a favorable toxicity profile with minimal immune-related adverse events (AEs) and is especially beneficial for patients aged 60 and older, according to data from the SWOG S1826 trial (NCT03907488), presented by Iris Isufi, MD, at the NCCN 2024 Annual Congress.¹

“The [SWOG S1826] study has not yet been published, and follow-up is ongoing to confirm the durability of PFS, long-term safety, overall survival [OS], patient-reported outcomes, and formal cost analysis. However, the study did make significant progress in recruiting diverse populations and toward harmonizing pediatric and adult therapy for cHL and is indeed well positioned to become a standard therapy for advanced-stage HL,” Isufi said during the presentation of the data.

Isufi is associate professor of medicine, codirector of the Adult CAR T-Cell Therapy Program (Hematology), coleader of the Cellular Therapy Clinical Research Team, and cochair of the Cellular Therapy-SAFE Committee at Yale Cancer Center/Smilow Cancer Hospital, New Haven, Connecticut.

SWOG S1826 Trial Results

In the SWOG S1826 trial, newly diagnosed patients with stage III or IV HL were randomly assigned 1:1 to receive either the N-AVD regimen (n=489) or the BV-AVD regimen (n=487).²

The 1-year PFS rates were 94% (95% CI, 91%-96%) in the N-AVD arm and 86% (95% CI, 82%-90%) in the BV-AVD arm, with an HR of 0.48 (99% CI, 0.27–0.87; P = .0005). The 1-year event-free survival (EFS) rate was 91% (95% CI, 88%-94%) vs 84% (95% CI, 80%-88%), respectively, with an HR of 0.56 (99% CI, 0.33-0.95). The 1-year OS rates were 95% (range, 83%-99%) in the N-AVD arm vs 83% (range, 67%-92%) in the BV-AVD arm, with an HR of 0.35 (95% CI, 0.07-1.75; P = .091). In addition, the median follow-up was 12.1 months, and the nonrelapse mortality rate was 4% vs 14%, respectively.

The 1-year PFS rate for patients 60 years or older was 93% in the N-AVD arm vs 64% in the BV-AVD arm with an HR of 0.35 (95% CI, 0.12-1.02; P = .022).

Investigators reported that 428 patients in the N-AVD arm and 400 patients in the BV-AVD arm completed treatment, with 22 and 30 patients, respectively, still undergoing treatment. In the N-AVD arm, 39 patients discontinued all treatment vs 57 patients in the BV-AVD arm: 22 vs 18 patients due to AEs, 10 vs 14 patients due to refusal unrelated to AEs, 0 vs 7 because of progression or relapse, 2 vs 8 patients due to death, and 5 vs 10 patients discontinued treatment for other reasons or protocols not specified. In total, 11% of patients discontinued nivolumab and 109 (22%) discontinued brentuximab vedotin,and 0.4% vs 0.8% received radiotherapy, respectively.

Methods

In the N-AVD arm of the trial, patients received 240 mg of nivolumab, and patients in the BV-AVD arm received 1.2 mg/kg of brentuximab vedotin. In both arms, treatment was administered on days 1 and 15 of each cycle for a duration of 6 cycles. In addition, granulocyte colony-stimulating factor was required for the BV-AVD arm and optional for the N-AVD arm. For patients 17 years or younger, nivolumab was administered at a dose of 3 mg/kg, with a maximum dose of 240 mg.

Patients were stratified by age (12-17 years, 18-60 years, and > 60 years), International Prognostic Score (IPS; 0-3 and 4-7), and whether radiotherapy was planned at the end of the treatment phase.

The primary end point was PFS, and secondary end points were EFS, OS, end of treatment complete metabolic response, and patient-reported outcomes.

Patient Demographics

Patient demographics were well balanced between treatment arms, with women comprising 45% of the N-AVD arm and 44% of the BV-AVD arm. The median age was 27 years (range, 12-83) vs 26 years (range, 12-81), respectively, and the races represented in the trial were White (77% vs 75%), Black (12% vs 11%), Asian (2% vs 3%), or other/unknown (9% vs 10%). In addition, there were 14% patients in the N-AVD arm and 12% of patients in the BV-AVD arm who were Hispanic.

In terms of staging, 38% of patients in the N-AVD arm and 34% in the BV-AVD arm had stage III disease, and 62% and 65%, respectively, had stage IV disease. For 0.2% of patients in the N-AVD arm and 1% in the BV-AVD arm, the disease stage was not reported. There were 68% of patients with an IPS of 0 to 3 in the N-AVD arm vs 68% in the BV-AVD arm and 32% of patients in each arm had an IPS of 4 to 7. Bulky disease of 10 cm or more was present in 32% vs 27% of patients, respectively, and 2% vs 1% were HIV positive.

Eligibility

To be eligible, patients must have been 12 years or older, have controlled HIV positivity, and a Zubrod performance status of 0 to 2 (the Lansky Play-Performance Scale was used for pediatrics). They also had a left ventricular ejection fraction of 50% or higher (or a shortening fraction of 27% or greater) and a creatinine clearance of at least 30 mL/min/1.73 m² (or a creatinine clearance or glomerular filtration rate of 70 or more with serum creatinine no more than 1.5 times the upper limit of normal for pediatrics). Total bilirubin levels must have been at or below 2 times the upper limit of normal, and aspartate aminotransferase and alanine aminotransferase levels had been at or below 3 times the upper limit of normal.

Key exclusions included interstitial lung disease or pneumonitis, peripheral neuropathy of grade 2 or higher, and active autoimmune disease.

Safety

Hematologic AEs of any grade in the N-AVD (n = 483) vs BV-AVD (n = 473) arms included neutropenia (55% vs 32%, respectively), anemia (38% vs 44%), and thrombocytopenia (10% vs 17%). For grade 3 AEs, neutropenia occurred in 47% vs 25%, anemia in 6% vs 9%, and thrombocytopenia in 2% vs 3%. Infectious AEs in the N-AVD and BV-AVD arms included febrile neutropenia (5% vs 7%), sepsis (2% vs 3%), and infections/infestations (5% vs 8%), indicating no increase in infectious toxicity in the N-AVD arm.

“Most importantly, regarding immune AEs of interest, what we observed is that patients did develop some transaminitis, which was not dissimilar between the N-AVD vs BV-AVD arms and rates of grade 3 or higher transaminitis were [also] not dissimilar,” Isufi explained. “Hypothyroidism was more common in the N-AVD arm in 7% of patients but was low grade. Only one patient [in the N-AVD arm] developed grade 3 or higher hypothyroidism , and 3% of patients had low grade hyperthyroidism,” she noted.

Background

“HL affects over 8000 people with 900 deaths per year in the US, and the current 5-year survival rate for advanced stage is 83% with the standard of care,” Isufi said. The ABVD regimen, which is made up of doxorubicin, bleomycin, vinblastine, and dacarbazine, has been the long-standing preferred treatment for advanced HL, according to NCCN guidelines, yielding cure rates of 70% to 80% with an acceptable AE profile.³ However, it carries a risk of bleomycin-induced pulmonary toxicity in about 6% of patients. This risk is heightened in older patients and those with reduced renal function, and when used with granulocyte colony-stimulating factor or thoracic radiation therapy, Isufi explained.

Other Trial Regimen Data

Isufi also addressed data from the ECHELON-1 (NCT01712490) and HD21 (NCT02661503) trial regimens.^4,5

In the randomized, phase 3 ECHELON-1 trial, BV-AVD vs ABVD were compared in 1334 patients with newly diagnosed HL.4 BV-AVD lowered the risk of progression or death by 32% vs ABVD. BV-AVD significantly enhanced OS, showing a 41% reduction in the risk of death vs ABVD.

BV-AVD eliminated exposure to bleomycin and does not require PET2 (PET scan after 2 cycles of chemotherapy) interim staging. It offered OS benefits, resulting in fewer disease-related deaths and second malignancies vs ABVD, making it a preferred first-line treatment for previously untreated stage III or IV cHL, Isufi explained. However, BV-AVD presents increased toxicity in older patients. The ECHELON-1 trial did not include baseline or prospective geriatric assessments, thus in older patients with high Cumulative Illness Rating Scale for Geriatrics co-morbidity scores, alternative treatment strategies—such as sequential administration of BV-AVD, BV combinations, or checkpoint inhibitor combinations—should be considered.

In the randomized, multicenter, parallel, open-label, phase 3 HD21 trial, investigators sought to compare the following regimens in 1500 patients, 60 years or younger, with untreated advanced-stage cHL.⁵

BrECADD (full dose level 4)

• Brentuximab vedotin 1.8 mg/kg intravenous (IV)

• Etoposide 150 mg/m² IV

• Cyclophosphamide 1250 mg/m² IV

• Doxorubicin 40 mg/m² IV

• Dacarbazine 250 mg/m² IV

• Dexamethasone 40 mg/m²

BEACOPP (full dose level 4)

• Etoposide 200 mg/m² IV

• Doxorubicin 35 mg/m² IV

• Cyclophosphamide 1250 mg/m² IV

• Bleomycin 10 mg/m² IV

• Vincristine 1.4 mg/m² IV

• Procarbazine 100 mg/m²

• Prednisone 40 mg/m²

Isufi explained that the PET2-guided BrECADD demonstrated high response rates, allowing most patients to be effectively treated with just 4 cycles. This regimen was better tolerated and showed superior PFS vs escalated (e)BEACOPP, with PFS rates among the highest reported in randomized controlled trials for newly diagnosed, advanced-stage cHL. However, the study, designed as a noninferiority trial to eBEACOPP, highlights the need for randomized controlled data on brentuximab vedotin combined with AVD.1

“Data from studies like ECHELON-1, HD21, and SWOG S1826 will inform future studies regarding de-escalation of therapy and giving less chemotherapy. What do I do with the currently available data when deciding what treatment to choose? I pay particular attention to the patient’s fitness level, comorbidities, their ability to perform activities of daily living [ADLs], including instrumental ADLs, and I tailor treatment as best as I can to the individual patient, but it is great to have all these available options,” Isufi concluded.

REFERENCES:

1. Isufi I. What is optimal first-line management of advanced classic Hodgkin lymphoma? Presented at: NCCN 2024 Annual Congress; September 20-21, 2024; New York, New York.

2. Herrera AF, LeBlanc ML, Castellino SM, et al. SWOG S1826, a randomized study of nivolumab(N)-AVD versus brentuximab vedotin (BV)-AVD in advanced stage (AS) classic Hodgkin lymphoma (HL). J Clin Oncol. 2023;41(suppl 17):LBA4. doi:10.1200/jco.2023.41.17_suppl.lba4

3. Hodgkin lymphoma. NCCN Guidelines Version 3.2024. https://tinyurl.com/3rtcrc92

4. Ansell SM, Radford J, Connors JM, et al; ECHELON-1 Study Group. Overall survival with brentuximab vedotin in stage III or IV Hodgkin’s lymphoma. N Engl J Med. 2022;387(4):310-320. doi:10.1056/nejmoa2206125

5. Borchmann P, Ferdinandus J, Schneider G, et al; German Hodgkin Study Group; Swiss Group for Clinical Cancer Research; Arbeitsgemeinschaft Medikamentöse Tumortherapie; Nordic Lymphoma Group; Australasian Leukaemia and Lymphoma Group. Assessing the efficacy and tolerability of PET-guided BrECADD versus eBEACOPP in advanced-stage, classical Hodgkin lymphoma (HD21): a randomised, multicentre, parallel, open-label, phase 3 trial. Lancet. 2024;404(10450):341-352. doi:10.1016/s0140-6736(24)01315-1