Nivolumab and brentuximab vedotin with or without bendamustine for R/R Hodgkin lymphoma in children, adolescents, and young adults

Abstract

Children, adolescents, and young adults (CAYA) with relapsed/refractory (R/R) classic Hodgkin lymphoma (cHL) without complete metabolic response (CMR) before autologous hematopoietic cell transplantation (auto-HCT) have poor survival outcomes. CheckMate 744, a phase 2 study for CAYA (aged 5-30 years) with R/R cHL, evaluated a risk-stratified, response-adapted approach with nivolumab plus brentuximab vedotin (BV) followed by BV plus bendamustine for patients with suboptimal response. Risk stratification was primarily based on time to relapse, prior treatment, and presence of B symptoms. We present the primary analysis of the standard-risk cohort. Data from the low-risk cohort are reported separately. Patients received 4 induction cycles with nivolumab plus BV; those without CMR (Deauville score >3, Lugano 2014) received BV plus bendamustine intensification. Patients with CMR after induction or intensification proceeded to consolidation (high-dose chemotherapy/auto-HCT per protocol). Primary end point was CMR any time before consolidation. Forty-four patients were treated. Median age was 16 years. At a minimum follow-up of 15.6 months, 43 patients received 4 induction cycles (1 discontinued), 11 of whom received intensification; 32 proceeded to consolidation. CMR rate was 59% after induction with nivolumab plus BV and 94% any time before consolidation (nivolumab plus BV ± BV plus bendamustine). One-year progression-free survival rate was 91%. During induction, 18% of patients experienced grade 3/4 treatment-related adverse events. This risk-stratified, response-adapted salvage strategy had high CMR rates with limited toxicities in CAYA with R/R cHL. Most patients did not require additional chemotherapy (bendamustine intensification). Additional follow-up is needed to confirm durability of disease control. This trial was registered at www.clinicaltrials.gov as #NCT02927769.

Graphical abstract

Figure 1.

CheckMate 744 R2 cohort study design and patient disposition. Response rates are reported before consolidation. Patients who achieved partial metabolic response (PMR)/no metabolic response (NMR) per blinded independent central review (BICR) after 4 cycles of nivolumab plus BV induction received intensification with BV plus bendamustine. Patients who achieved CMR per BICR after 4 cycles of nivolumab plus BV induction or after 2 or 4 cycles of BV plus bendamustine intensification proceeded to consolidation with high-dose chemotherapy (HDCT) and auto-HCT. Patients who had progressive metabolic disease (PMD) after induction, or PMR, NMR, or PMD after intensification, could proceed to follow-up. Shaded area indicates study treatment phases. ^aPET–computed tomography/magnetic resonance imaging (real-time BICR) was performed after 4 cycles of nivolumab plus BV and after every 2 cycles of BV plus bendamustine before consolidation. ^bIf approved by study medical monitor. ^cOne patient received ifosfamide, carboplatin, and etoposide for progression. ^dPatients who withdrew consent during the study or who proceeded to follow-up after induction were included for response assessment.

Figure 2.

Best reduction in tumor volume per BICR in patients who proceeded to consolidation on protocol. On the basis of sum of products of diameters (SPD) for target lesions. Includes patients with baseline and ≥1 on-study value (before consolidation or subsequent therapy). Negative values indicate reduction from baseline in SPD. Square symbol represents percentage change truncated to 100%. PMR, partial metabolic response.

Figure 3.

PFS per BICR. Symbols represent censored observations. Patients who did not progress or die, or who started subsequent therapy (including auto-HCT off protocol) without prior reported progression or death, were censored at the last tumor assessment. NR, not reached.