The quadruple combination of brentuximab vedotin (BV), nivolumab, doxorubicin, and dacarbazine showed a high and durable complete response rate (CRR) in patients with early-stage classical Hodgkin lymphoma (cHL). These updated results from part C of the phase II SGN35-027 study, now with a median follow-up of 27.9 months, were presented at the 66th American Society of Hematology Annual Meeting and Exposition in San Diego.1
Of 154 cHL patients with Ann Arbor stage I/II and no bulky disease, 92% had a complete response (CR) with a 24-month CR duration of 96%. The 24-month progression-free survival (PFS) rate was 97%.
“We see a very high CRR and favorable PFS with the vast majority of patients remaining in remission at last follow-up, suggesting that most patients are cured with this approach,” study author Jeremy S. Abramson, MD, of Massachusetts General Hospital Cancer Center in Boston, told ASH Clinical News.
Early-stage cHL is highly curable, but the current standard treatment approach of doxorubicin, bleomycin, vinblastine, and dacarbazine, with or without consolidative radiation, results in short- and long-term toxicities for these patients. BV, an antibody-drug conjugate, is routinely combined with doxorubicin, vinblastine, and dacarbazine (AVD) for advanced-stage cHL, but this targeted combination significantly increases toxicity, especially myelosuppression and peripheral neuropathy resulting from overlapping toxicities of BV and vinblastine. Nivolumab, a checkpoint inhibitor approved in relapsed or refractory cHL, is an additional highly active targeted drug available in combination for newly diagnosed advanced-stage cHL, but neither targeted therapy is approved or guideline-recommended for limited-stage disease.
The regimen of BV, nivolumab, doxorubicin, and dacarbazine tested by Dr. Abramson and his colleagues in the current study omits bleomycin and vinblastine to decrease the risk of hematologic toxicities and peripheral neuropathy, as well as radiation to reduce the risk of late effects. “We believe this combination is likely to optimize efficacy by incorporating the best drugs for cHL while improving the safety profile with the omission of two older chemotherapy drugs and radiation,” Dr. Abramson said.
In part C of the SGN35-027 non-randomized, open-label phase II trial, patients with previously untreated early-stage cHL received BV, nivolumab, doxorubicin, and dacarbazine on days 1 and 15 for four 28-day cycles. BV was given at a dose of 1.2 mg/kg, nivolumab at a dose of 240 mg, doxorubicin at a dose of 25 mg/m2, and dacarbazine at a dose of 375 mg/m2, all intravenously. The primary endpoint of CRR was measured at the end of the treatment. The initial results, after a 16.5-month median follow-up, were originally presented at the 65th ASH Annual Meeting in 2023.2
The median age of the patients on the study was 31 years (range = 18-77), 55% were female, and 84% identified as white. Seventeen (11%) of the patients had extranodal disease present, and 97 patients (63%) had unfavorable disease per the German Hodgkin Study Group risk criteria. Of the 154 patients who received at least one dose of the quadruple therapy, 147 patients (94%) completed the full course of treatment, four discontinued due to an adverse event (AE), one due to an investigator decision, and two due to a patient, non-AE decision.
Of the 154 patients, seven patients had a partial response (4%), and 141 patients (92%) had a CR. The CRR was 95% in the favorable risk subgroup and 91% in the unfavorable risk subgroup.
At 24 months, the estimated PFS rate was 100% among the 56 patients with favorable risk disease and 95% among the 97 patients in the unfavorable risk disease subgroup. Five patients had progressive disease, all of whom had unfavorable disease at diagnosis; no progressive disease was reported among the favorable disease group.
The estimated overall survival rate was 100% at 24 months after a median 30.9 months of follow-up. One patient, a 62-year-old female with stage II unfavorable disease, died due to secondary malignancy (mantle cell lymphoma), 215 days from any study treatment.
Six patients (4%) received a subsequent therapy, including two who received consolidative radiotherapy while in CR and two who received systemic therapy for progressive disease.
The quadruple regimen had an acceptable side effect profile. Any grade treatment-emergent adverse events (TEAEs) occurred in 99% of patients, and 44% experienced grade 3 or greater TEAEs. The most common TEAEs were nausea, peripheral sensory neuropathy, fatigue, constipation, alopecia, increase in alanine aminotransferase (ALT), and diarrhea. Serious TEAEs occurred in 19% of patients, and 12% of patients experienced treatment-related serious TEAEs, the most common of which was pyrexia in 3% of patients.
Any-grade treatment-emergent immune-mediated adverse events (IMAEs) with a potential immunologic cause occurred in 22% of patients, and 8% had grade 3 or greater IMAEs. Five patients (3%) discontinued nivolumab due to an IMAE, which included pneumonitis (1%), ALT increase (1%), hepatitis (1%), and thyroiditis (1%).
“This was an extremely well-tolerated regimen,” Dr. Abramson said. “The omission of vinblastine and bleomycin resulted in low rates of grade 4 neutropenia, no neutropenic fever, and even decreased alopecia, which patients certainly appreciate. The rate of immune-related side effects related to nivolumab was quite low.”
Any conflicts of interest declared by the authors can be found in the original abstract.
References
- Abramson JS, Straus DJ, Bartlett NL, et al. Updated analysis of brentuximab vedotin, nivolumab, doxorubicin, and dacarbazine for nonbulky, early-stage classical Hodgkin lymphoma. Abstract 460. Presented at the 66th American Society of Hematology Annual Meeting and Exposition; December 8, 2024; San Diego, California.
- Abramson JS, Straus DJ, Bartlett NL, et al. Brentuximab vedotin, nivolumab, doxorubicin, and dacarbazine (AN+AD) for early-stage classical Hodgkin lymphoma (SGN35-027 Part C). Abstract 611. Presented at the 65th ASH Annual Meeting and Exposition; December 10, 2023; San Diego, California.
