Pembrolizumab followed by AVD in untreated early unfavorable and advanced-stage classical Hodgkin lymphoma

Abstract

Pembrolizumab, a humanized IgG4 monoclonal antibody targeting programmed death-1 protein, has demonstrated efficacy in relapsed/refractory classical Hodgkin lymphoma (cHL). To assess the complete metabolic response (CMR) rate and safety of pembrolizumab monotherapy in newly diagnosed cHL, we conducted a multicenter, single-arm, phase 2 investigator-initiated trial of sequential pembrolizumab and doxorubicin, vinblastine, and dacarbazine (AVD) chemotherapy. Patients ≥18 years of age with untreated, early, unfavorable, or advanced-stage disease were eligible for treatment. Thirty patients (early unfavorable stage, n = 12; advanced stage, n = 18) were treated with 3 cycles of pembrolizumab monotherapy followed by AVD for 4 to 6 cycles, depending on stage and bulk. Twelve had either large mediastinal masses or bulky disease (>10 cm). After pembrolizumab monotherapy, 11 patients (37%) demonstrated CMRs, and an additional 7 of 28 (25%) patients with quantifiable positron emission tomography computed tomography scans had >90% reduction in metabolic tumor volume. All patients achieved CMR after 2 cycles of AVD and maintained their responses at the end of treatment. With a median follow-up of 22.5 months (range, 14.2-30.6) there were no changes in therapy, progressions, or deaths. No patients received consolidation radiotherapy, including those with bulky disease. Therapy was well tolerated. The most common immune-related adverse events were grade 1 rash (n = 6) and grade 2 infusion reactions (n = 4). One patient had reversible grade 4 transaminitis and a second had reversible Bell's palsy. Brief pembrolizumab monotherapy followed by AVD was both highly effective and safe in patients with newly diagnosed cHL, including those with bulky disease. This trial was registered at www.clinicaltrials.gov as #NCT03226249.

Conflict of interest statement

Conflict-of-interest disclosure: P.B.A. has received honoraria from the advisory boards of Imbrium and Bayer and fees from the speakers bureaus of Curio Science and Purdue Pharma LP, outside the submitted work. A.M.E. has received grants from ORIEN and Tesaro and other support from Seattle Genetics, MorphoSys, Mylteni, Epizyme, Novartis, Pharmacyclics, Research to Practice, Physician Education Resource, Cota, and OncLive, outside the submitted work. R.H.A. reports consulting or advisory roles with Genentech/Roche, Portola Pharmaceuticals, Sanofi, Seattle Genetics, Takeda; grants from Celgene, Forty Seven, Inc, Genentech/Roche, Janssen Pharmaceutical, Kura, Merck, Millennium Pharmacyclics, Regeneron, and Seattle Genetics, outside the submitted work. B.P. has received grants and personal fees from Takeda and grants and personal fees from Seattle Genetics, outside the submitted work. R.K. has received rants and personal fees from Gilead and Kite; grants and personal fees from BMS, Celgene, and Juno; grants from Takeda; and personal fees from BeiGene, AstraZeneca, and Karyopharm, outside the submitted work; J.N.W. reports an honorarium for serving on an advisory board for Merck and for Karyopharm, and that her spouse serves on data and safety monitoring boards for Novartis, Ariad/Takeda, and Epizyme and as a consultant to Novartis, CVS/Caremark, Fly Pharma, Astra Zeneca, and Amgen. The remaining authors declare no competing financial interests.

© 2021 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Complete metabolic response rates by Lugano 2014 criteria. Response rates to pembrolizumab monotherapy, after 2 cycles of AVD and at EOT are shown (n = 30). *In 2 patients with early unfavorable stage cHL who received 4 cycles of AVD chemotherapy, diagnostic CT-scans substituted for PET4, as permitted by protocol at EOT.

Figure 2.

Kaplan-Meier estimate of PFS. Median follow-up 22.5 months (range, 14.2-30.6). OS is identical and not shown.

Figure 3.

Decline in MTV. Percentage decline in MTV after pembrolizumab monotherapy in the 28 patients with quantifiable disease was calculated with an automatic software tool applying a local SUV maximum threshold of 41% (SyngoVia software, multifoci segmentation tool; Siemens). Each bar corresponds to an individual patient. The decline in MTV could not be measured in 2 of 30 cases; 1 patient had uptake that could not be distinguished from PET-avid myocardium, because of the close approximation, and another had a computer-generated decline in MTV of 100% that was inconsistent with clinical and qualitative assessment demonstrating a small focus of residual disease and a Deauville score of 4.

Figure 4.

PET-CT’s before and after single agent pembrolizumab. (A) A coronal fused PET-CT image of a 23-year-old woman with cHL shows intensely hypermetabolic bulky lymphadenopathy involving the entire anterior mediastinum, left axillary, bilateral supraclavicular, and subpectoral nodal stations before therapy with pembrolizumab. (B) After 3 cycles of pembrolizumab monotherapy, there was marked anatomic and metabolic improvement of the disease. The residual mass has fluorodeoxyglucose (FDG) activity similar to liver background uptake, with the exception of mild FDG hypermetabolism in the anterior mediastinum (arrow), Deauville 4. (C) A coronal fused PET-CT image of another 23-year-old woman with cHL shows intensely hypermetabolic bulky lymphadenopathy involving the anterior mediastinum and the left axillary and left subpectoral nodal stations with a small right subpectoral lymph node before therapy. (D) After 3 cycles of pembrolizumab monotherapy with CMR, Deauville 3.