Frontline PET-Directed Therapy with Brentuximab Vedotin Plus AVD Followed By Nivolumab Consolidation in Patients with Limited Stage Hodgkin Lymphoma

Introduction Treatment of Hodgkin lymphoma (HL) often requires a careful balance between providing effective therapy to cure the disease while minimizing long-term treatment-related complications, which may occur decades after the patient is cured of HL, especially in young adult patients. Therefore, novel treatment strategies for limited stage HL aim to reduce the exposure to conventional cytotoxic chemotherapy and radiation therapy while retaining a high probability of cure. This is especially relevant to limited stage HL, in which frontline therapy is curative in most patients, but treatment strategies may involve radiation or chemotherapy escalation. Based on the established efficacy of brentuximab vedotin (BV) and nivolumab (NVB) in HL, we hypothesized that an abbreviated course of A+AVD (BV, doxorubicin, vinblastine, dacarbazine) induction followed by NVB consolidation would lead to high response rates and sustained remissions without excess short- or long-term toxicity in patients with limited stage non-bulky HL.

Methods In this phase 2 single-arm multicenter study, patients with previously untreated limited stage non-bulky (mass < 10 cm) classical HL received 3 cycles of A+AVD followed by NVB consolidation up to 8 cycles (ACCRU-LY1601; NCT03233347). Growth-factor support with G-CSF was required in all patients treated with A+AVD. Patients who were PET-negative (Deauville score 1-3) after A+AVD induction proceeded to receive consolidation therapy with NVB (3 mg/kg every 2 weeks). Subjects who were PET-positive after A+AVD induction received 4 cycles of BV+NVB followed by NVB consolidation. End-of-Treatment (EOT) PET scan was obtained 8 weeks after the last dose of NVB. Responses were scored based on Lugano 2014.

Results A total of 83 patients enrolled on ACCRU-LY1601 between July 2018 and July 2022. The study enrollment was completed after meeting the target accrual. In 75 evaluable patients with available clinical data, the median age was 33 years (range, 19-60), 49% patients were female, 88% had Stage II HL, and 33% reported B symptoms. Of 65 patients who completed A+AVD induction with evaluable PET scan results, 97% patients achieved negative interim PET scan. The most common grade ≥ 3 Adverse Events (AEs) associated with A+AVD induction included neutropenia (31%) and nausea (6.5%), comparable to the ECHELON1 data in patients with advanced stage HL. Twenty seven (35%) patients developed peripheral sensory neuropathy (PN) while on A+AVD with the majority (17 patients) having grade 1 PN. One patient (1.3%) had grade 3 PN. NVB-related grade ≥ 3 AEs included elevated lipase (6%) and neutropenia (3%). One patient developed a grade 4 endocrine disorder with diabetic ketoacidosis while on NVB consolidation. Patients who achieved negative interim PET scan after A+AVD induction received a median of 8 cycles of NVB consolidation with a complete response (CR) rate of 100% based on negative PET at EOT. Out of two patients who had positive PET after A+AVD induction, one patient received 4 cycles of BV+NVB followed by 8 cycles of NVB consolidation per the study protocol and achieved a CR at EOT. The other patient with Deauville score 4 on interim PET came off the study treatment secondary to grade 3 PN and is in complete remission following radiation therapy. A total of 2 patients received radiation as part of non-protocol therapy after coming off the study treatment. With a median follow-up duration of 22 months, there has been no event of disease progression or death in all eligible patients who received any therapy per the study protocol.

Conclusion ACCRU-LY1601 represents the largest study reported to date to incorporate two novel agents (BV and NVB) in patients with previously untreated limited stage HL. ACCRU-LY1601 demonstrates encouraging safety and clinical outcomes of A+AVD induction followed by NVB consolidation in limited stage non-bulky HL. The majority (97%) of patients achieved negative interim PET after an abbreviated course of A+AVD, and 100% of patients remain progression-free after NVB consolidation with a median follow up of 22 months on the current study. Given the high curability of limited stage HL, longer follow-up and cost-benefit analyses are being conducted to define further evaluation of this novel regimen.

Park:Rafael Pharma: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees; Gilead: Speakers Bureau; Teva: Consultancy; Morphosys: Membership on an entity's Board of Directors or advisory committees; G1 Therapeutics: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; Seattle Genetics: Research Funding, Speakers Bureau. Ansell:SeaGen: Research Funding; Takeda: Research Funding; Bristol Myers Squibb: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; Pfizer: Research Funding; ADC Therapeutics: Research Funding. Svoboda:TG: Research Funding; SEAGEN: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Merck: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genmab: Consultancy; BMS: Consultancy, Research Funding; Atara: Consultancy; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; ADCT: Consultancy. Smith:Portola Pharmaceuticals: Research Funding; Numab Therapeutics AG: Consultancy; Nanjing Pharmaceuticals Co., Ltd: Research Funding; MorphoSys: Research Funding; Merck Sharp/Dohme Corp: Research Funding; Kymera Therapeutics: Research Funding; KITE pharma: Consultancy; Karyopharm: Consultancy; Incyte Corporation: Consultancy, Research Funding; Genentech: Research Funding; Epizyme: Consultancy; Enterome: Research Funding; De Novo Biopharma: Research Funding; Beigene: Consultancy, Research Funding; Bayer: Research Funding; AstraZeneca: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; Abbvie: Consultancy; Viracta Therapeutics: Research Funding. Budde:Genentech: Other: Advisory Board; ADC Therapeutics: Other: Advisory Board; Merck: Research Funding; AstraZeneca: Research Funding; Amgen Inc: Research Funding; Ziopharm Oncology Inc: Other: DMSC member for a phase 1 clinical trial. Lee:Janssen: Honoraria; Cancer Experts: Honoraria; Aptitude Health: Honoraria; Curio Science: Honoraria; Century Therapeutics: Membership on an entity's Board of Directors or advisory committees; Korean Society of Cardiology: Honoraria; Olson Research: Honoraria; Celgene: Research Funding; Octernal Therapeutics: Research Funding; Seagen: Research Funding; Takeda: Research Funding; Guidepoint Global: Honoraria; Deloitte: Honoraria; Pharmcyclics: Research Funding; Briston-Myers Squibb: Research Funding.

Brentuximab vedotin and nivolumab in previously untreated limited stage non-bulky Hodgkin lymphoma