Sequential pembrolizumab and AVD are highly effective at any PD-L1 expression level in untreated Hodgkin lymphoma

Abstract

In a multicenter, phase II investigator-initiated trial of sequential pembrolizumab and AVD, nearly two-thirds of patients with untreated unfavorable or advanced stage classic Hodgkin Lymphoma (cHL) achieved PET-defined complete or near complete metabolic responses (CMR) following 3 doses of pembrolizumab monotherapy. Furthermore, all achieved CMR following 2 cycles of AVD chemotherapy and 100% of patients were alive without relapse at the time of initial publication. We now report long-term follow-up, including 3-year OS and planned correlative analyses. Thirty patients received single agent pembrolizumab every 3 weeks x 3, followed by AVD chemotherapy for 4-6 cycles depending on stage and bulk. PET/CT scan was performed after pembrolizumab monotherapy, 2 cycles of AVD, and at the end of therapy. Baseline biopsy samples were analyzed for genomic alterations of chromosome 9p24.1 and PD-1 pathway markers by immunohistochemistry. At a median follow up of 33.1 months (range, 26.0-43.0), PFS and OS remain 100%. All patients had genomic alterations in 9p24.1 and were positive for PD-L1 by immunohistochemistry. There was no relationship between response to single agent pembrolizumumab measured by decline in metabolic tumor volume and 9p24.1 alterations or PD-1 pathway H-scores. With additional follow-up, sequential pembrolizumab and AVD remains highly effective. The high response rates observed at all PD-ligand levels suggest that even low levels of PD ligand expression are sufficient for response to PD-1 blockade in untreated cHL. An international phase II trial (NCT05008224) to confirm these findings is ongoing.

Nivolumab and Doxorubicin, Vinblastine, and Dacarbazine in Early-Stage Unfavorable Hodgkin Lymphoma: Final Analysis of the Randomized German Hodgkin Study Group Phase II NIVAHL Trial

“…This sustained outstanding disease control is in line with an interim NIVAHL analysis 6 and a smaller trial investigating sequential pembrolizumab and AVD in 30 patients with earlystage unfavorable and advanced-stage HL. 7 The primary goal of novel first-line HL treatments is achieving highest possible cure rates at minimal treatment-related morbidity. 8,9 All experimental treatments in this setting need to undergo rigorous testing to avoid compromising the unprecedented improvements of HL outcomes over the past few decades.…”

“…This sustained outstanding disease control is in line with an interim NIVAHL analysis 6 and a smaller trial investigating sequential pembrolizumab and AVD in 30 patients with early-stage unfavorable and advanced-stage HL. 7…”

“…Although histologic remissions were observed within days, 15 correlative studies did not reveal any readily available biomarker for early CR in NIVAHL 4,16,17 or other first-line trials. 1,7 A rapidly growing number of clinical trials, including the randomized S1826 intergroup trial (ClinicalTrials.gov identifier: NCT03907488), are investigating anti–PD-1-based first-line HL treatment. More recent approaches to individualize anti–PD-1-based first-line HL treatment by on-treatment risk stratification include the GHSG INDIE (ClinicalTrials.gov identifier: NCT04837859).…”

Advances in positron emission tomography and radiomics

“…A new concept of "near CMR" with >90% reduction in MTV has been suggested as a more sensitive method of response to checkpoint inhibitors than CMR, given either sequentially or in combination with doxorubicin, vinblastine and darcarbazine (AVD) chemotherapy in first-line treatment of patients with HL. 62,63 The combination of emerging blood biomarkers as well as established risk factors with early PET scans, which may provide complementary information to monitor response is appealing. Kurtz et al 36 demonstrated that early molecular response after one or two cycles of treatment with circulating tumor DNA (ctDNA) in 217 patients with DLBCL and interim PET (in the subset of 66 patients who had early PET scans) were independent predictors of PFS and OS.…”

Filling the Gap: The Immune Therapeutic Armamentarium for Relapsed/Refractory Hodgkin Lymphoma

“…A recent phase II trial investigated for the first time pembrolizumab as upfront first-line treatment in a sequential scheme followed by AVD. After three cycles of pembrolizumab 37% of patients were in CR with all patients achieving at least a PR, including in advanced stages, after 2 cycles of AVD [ 113 ]. Long-term results confirmed excellent PFS and OS which remained both at 100% after three years from therapy [ 114 ].…”