Response-Adapted Therapy with Nivolumab and Brentuximab Vedotin (BV), Followed By BV and Bendamustine for Suboptimal Response, in Children, Adolescents, and Young Adults with Standard-Risk Relapsed/Refractory Classical Hodgkin Lymphoma

Introduction: Classical Hodgkin lymphoma (cHL) is among the most common malignancies in adolescents and young adults. High-dose chemotherapy (HDCT) and autologous hematopoietic stem cell transplantation (ASCT) are standard for most patients with relapsed/refractory (R/R) disease. Current salvage therapies are associated with excessive toxicity and variable complete remission rates (Harker-Murray et al, Pediatr Blood Cancer 2014). Novel regimens that increase remission rates and reduce late effects of therapy are needed, particularly for young patients. Nivolumab (nivo) is a fully human IgG4 anti-programmed death-1 monoclonal antibody. Brentuximab vedotin (BV) is a CD30-directed antibody-drug conjugate. In a phase 1/2 study of adults with R/R cHL, the combination of nivo + BV was well tolerated, with a high response rate as first salvage regimen (Herrera et al, Blood 2018). CheckMate 744 (AHOD1721; NCT02927769) is the first risk-stratified, response-adapted, phase 2 study of nivo + BV, followed by BV + bendamustine for suboptimal response, in children, adolescents, and young adults with R/R cHL with low or standard risk of relapse. Here we report preliminary, investigator (INV)-assessed results from the standard-risk (R2) cohort.

Methods: This open-label study enrolled patients aged 5-30 years with pathologically confirmed cHL, excluding nodular lymphocyte-predominant HL, after failure/non-response to first-line therapy and without prior ASCT. Stratification to R2 was based on refractory disease or early relapse; B symptoms, extranodal disease, or extensive disease with radiation therapy (RT) contraindicated at relapse; relapse in a prior RT field; or stage IIIB or IV at initial diagnosis. Patients in R2 received induction (IND) with 4 cycles of nivo + BV. Patients without complete metabolic response (CMR; Deauville score 1-3) received intensification (INT) with 2-4 cycles of BV + bendamustine. Patients with CMR after IND or INT discontinued study treatment, proceeded to HDCT/ASCT, and entered follow-up. Tumors were assessed by INV and blinded independent central review (BICR) per Lugano 2014 criteria (Cheson et al, J Clin Oncol 2014) every 2 treatment cycles. Treatment decisions were based on BICR assessment. The primary endpoint was CMR rate by BICR prior to HDCT/ASCT. Secondary endpoints included INV-assessed response and safety.

Results: At database lock (DBL), 32 patients in R2 had entered IND. Median age was 16 y (range 9-30), 78% were aged <18 y, and 72% were male. Fifteen patients (47%) had relapsed disease and 17 (53%) refractory; 14 (44%) had B symptoms or extranodal disease at relapse. At DBL, 25 patients (78%) had completed IND (4 cycles of nivo + BV); 7 ongoing. At the end of IND, INV-assessed responses were 16 (64%) CMR, 4 (16%) partial metabolic response, and 1 (4%) progressive metabolic disease; 4 (16%) were pending tumor assessment. Based on BICR assessment, 6 patients entered and completed INT; all achieved CMR after 2 cycles of BV + bendamustine. Overall, all evaluable patients achieved CMR by INV after completing IND or INT. At DBL, 18 patients had proceeded to HDCT/ASCT. During IND, 29 patients (91%) had ≥1 adverse event (AE) due to any cause; 7 (22%) grade 3-4. The most common AEs were nausea (53%), diarrhea (31%), and pyrexia (28%). Six patients (19%) had infusion-related reactions (IRRs); 1 (3%) grade 3-4. Four patients (13%) had drug-related serious AEs; 2 (6%) grade 3-4 (1 IRR and 1 activated partial thromboplastin time prolonged). Two patients (6%) had immune-mediated AEs, including 1 grade 3-4 IRR noted above; none had immune-related serious AEs. During INT, 3/6 patients (50%) had AEs; none grade 3-4; most common were nausea (33%) and vomiting (33%); 1 patient (3%) had grade 1 IRR. Overall, no AEs led to discontinuation and there were no deaths.

Conclusion: For children, adolescents, and young adults with standard-risk R/R cHL prior to ASCT, this risk-stratified, response-adapted approach using nivo, BV, and bendamustine resulted in high CMR rates and was well tolerated, making it a promising novel salvage therapy. Most evaluated patients achieved CMR with IND (nivo + BV); all 6 who went to INT (BV + bendamustine) achieved CMR. Updated results based on a planned interim analysis including more patients and BICR-assessed response data will be presented.

Study support: Sponsored by Bristol-Myers Squibb in collaboration with Children's Oncology Group (COG) and EuroNet group.