Nivolumab(n)‐avd improves progression‐free survival compared to brentuximab vedotin(bv)‐avd in advanced stage (as) classic hodgkin lymphoma (hl): results of swog s1826

Background: The addition of BV to initial chemotherapy improves outcomes in adult and pediatric patients (pts) with AS HL. However, frontline BV adds toxicity, most pediatric pts receive radiation therapy (RT), and 7%–20% of pts still develop relapsed/refractory (RR) HL. The PD-1 pathway is central to the pathogenesis of HL and PD-1 blockade is effective in RR HL. The adult and pediatric cooperative groups of the National Clinical Trials Network (NCTN) conducted the randomized, phase 3 S1826 trial to evaluate N-AVD versus BV-AVD in pts with newly diagnosed AS HL. Methods: Eligible pts were ≥12 years (y) with stage 3–4 HL. Pts were randomized 1:1 to either 6 cycles of N-AVD or BV-AVD. G-CSF neutropenia prophylaxis was required with BV-AVD versus optional with N-AVD. Pre-specified pts could receive RT to residually metabolically active lesions on end of treatment PET. Pts were stratified by age, international prognostic score (IPS), and intent to use RT. Response and disease progression were assessed by investigators using 2014 Lugano Classification. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), event-free survival, patient-reported outcomes (PROs), and safety. Results: 994 pts were enrolled from 7/9/19 to 10/5/22; 976 were eligible and randomized to N-AVD (n = 489) or BV-AVD (n = 487). Median age was 27y (range 12–83y), 56% of pts were male, 76% were white, 12% were black, and 13% were Hispanic. 24% of pts were <18y, 10% were > 60y, and 32% had IPS 4–7. To date, <1% of pts received RT. At the planned 2nd 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. 30 PFS events occurred after N-AVD versus 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); 1y PFS: N-AVD, 94%, BV-AVD, 86% (Figure). 11 deaths (7 due to adverse events, AE) were observed after BV-AVD compared to 4 after N-AVD (3 due to AE). The rate of grade (gr) ≥3 hematologic AE was 48.4% (45.1% gr ≥3 neutropenia) after N-AVD compared to 30.5% (23.9% gr ≥3 neutropenia) after BV-AVD. Rates (any gr) 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. Hypo/hyperthyroidism was more frequent after N-AVD (7%/3% N vs. <1% BV) while peripheral neuropathy was more common after BV-AVD (sensory: 28.1%, 1.2% gr ≥ 3 N vs. 54.2%,7.8% gr ≥ 3 BV; motor: 4% N vs. 6.8% BV). Encore Abstract—previously submitted to ASCO 2023 The research was funded by: Funding provided by the National Cancer Institute of the National Institutes of Health U10CA180888, U10CA180819, U10CA180821, U10CA180820, U10CA180863, UG1CA189955 and funding and drug provided by Bristol-Myers Squibb, drug provided by SeaGen for patients enrolled in Canada. Keywords: Hodgkin lymphoma, immunotherapy, targeting the tumor microenvironment Conflicts of interests pertinent to the abstract A. F. Herrera Consultant or advisory role: Bristol-Myers Squib, Genentech, Merck, SeaGen, AstraZeneca, Karyopharm, ADC Therapeutics, Takeda, Tubulis, Regeneron, Genmab, Pfizer, Caribou Biosciences, Adicet Bio, Abbvie, Allogene Therapeutics, Roche Diagnostics Research funding: Bristol-Myers Squib, Genentech, Merck, SeaGen, KITE Pharma/Gilead Sciences, AstraZeneca, ADC Therapeutics S. M. Castellino Consultant or advisory role: SeaGen Inc. scientific advisory board; no honorarium taken S. C. Rutherford Consultant or advisory role: ADC Therapeutics, Genmab, Karyopharm, Kite, SeaGen Research funding: Genentech, Karyopharm A. M. Evens Consultant or advisory role: Seattle Genetics, Hutchmed, Incyte, Daiichi Sankyo, Epizyme, Novartis, Abbvie, and Pharmacyclics K. Davison Consultant or advisory role: BMS, SeaGen S. K. Parsons Consultant or advisory role: SeaGen S. Ahmed Consultant or advisory role: ADC therapeutics, KITE/Gilead, Myeloid Therapeutics, Tessa Therapeutics, Chimagen Research funding: Seattle Genetics, Merck, Xencor, Chimagen and Tessa Therapeutics C. Casulo Research funding: BMS, Gilead, Genetnech and SecuraBio N. L. Bartlett Consultant or advisory role: ADC Therapeutics, Foresight Diagnostics, Kite, Roche/Genentech, Seattle Genetics Research funding: ADC Therapeutics, Autolus, BMS/Celgene, Forty Seven, Gilead/Kite Pharma, Janssen, Merck, Millennium, Pharmacyclics, Roche/Genentech, Seattle Genetics M. G. Mei Consultant or advisory role: Novartis, SeaGen, CTI, Janssen, EUSA Research funding: BMS, Beigene, Morphosys, Incyte Other remuneration: Speakers' Bureau: Morphosys, SeaGen B. T. Hess Consultant or advisory role: BMS, ADC Therapeutics H. Saeed Consultant or advisory role: SeaGen, BMS Research funding: BMS P. Torka Consultant or advisory role: Genentech, Genmab, Lilly Oncology, Seagen, TG therapeutics, ADC therapeutics B. Hu Consultant or advisory role: Novartis, Bristol Meyers Squibb, Eli Lilly, GenMab Honoraria: MJH Life Sciences, Binaytara Foundation, Patient Power Health, Beigene, Artiva Biotherapeutics, Guidepoint Research funding: Genentech, Celgene, CRISPR Therapeutics, Morphosys AG, Caribou Biosciences, Repare Therapeutics, Artiva Biotherapeutics C. Moskowitz Research funding: Seattle genetics S. Kaur Other remuneration: Speaker—Eli Lily G. Goyal Consultant or advisory role: 2nd. MD, Opna Bio LLC Other remuneration: UpToDate K. Blum Research funding: Seattle Genetics and BMS L. Kostakoglu Shields Consultant or advisory role: Genentech/Roche A. Prica Honoraria: AstraZeneca, Kite/Gilead, Abbvie M. A. Shipp Consultant or advisory role: AstraZeneca Research funding: BMS, AstraZeneca, Abbvie, Bayer M. Crump Consultant or advisory role: Kite, Novartis, Epizyme B. Kahl Consultant or advisory role: SeaGen J. P Leonard Consultant or advisory role: Abbvie, Astellas, AstraZeneca, Bayer, Beigene, BMS, Calithera, Constellation, Caribou Biosciences, Eisai, Lilly, Epizyme, Genmab, Grail, Incyte, Jansssen, MEI Pharma, Merck, Mustang Bio, Novartis, Pfizer, Roche/Genentech, Seagen, Second Genome, Sutro K. M. Kelly Consultant or advisory role: Seagen (non-paid)