The current standard of care for early-stage classic Hodgkin lymphoma (cHL) is combination chemotherapy — adriamycin, bleomycin, vinblastine, dacarbazine (ABVD) — with or without radiation therapy, while brentuximab vedotin plus chemotherapy (BV-AVD) or combination chemotherapy is the standard treatment for advanced-stage cHL. Although BV-AVD is associated with an overall survival (OS) benefit in advanced-stage cHL, it is also associated with more toxicity, including more peripheral neuropathy, febrile neutropenia, and need for growth factor support.1 PD-1 blockade is an effective treatment for relapsed/refractory cHL,2,3,4 and promising early results have been observed with the introduction of PD-1 blockade as part of initial therapy for cHL.5,6,7
In this single-center phase II study, Lynch and colleagues evaluated the safety and efficacy of concurrent pembrolizumab with AVD (APVD) in frontline cHL and examined the utility of circulating tumor DNA (ctDNA) measurements to dynamically assess the depth of response. Thirty patients were enrolled (six with early-stage unfavorable cHL, six with early-stage favorable cHL, and 18 with advanced-stage cHL). Patients received between two and six cycles depending on their stage and risk factors. The safety of concurrent APVD as initial therapy for cHL was consistent with the expected toxicity profiles of PD-1 blockade and combination chemotherapy, including a febrile neutropenia rate of 17% without an apparent increase in the expected rate of infectious complications (unlike BV-AVD). Immune-related toxicities were observed: Nearly half of patients experienced rash, and five experienced transaminitis requiring pembrolizumab modification and corticosteroids, including 10% who discontinued pembrolizumab. However, these toxicities were reversible.
Remarkably, only one patient experienced biopsy-proven relapse after APVD. Over a median followup of 2.1 years, the two-year rates of progression-free survival (PFS) and OS were 97% and 100%, respectively. Despite this impressive efficacy, the rates of negative positron emission tomography (PET) scans at interim and end-of-treatment (EOT) were lower than what is typically observed with other regimens (57% and 82%, respectively). Five patients had positive EOT PET scans, but only one patient ultimately had biopsy-proven progressive disease; the remaining four had no evidence of relapse, even 36 months after completion of study treatment. Although PET results correlated poorly with outcomes, ctDNA analysis by PhaseED-Seq performed better, with 81% and 92% of patients, respectively, having undetectable ctDNA after two cycles and at EOT. Baseline quantitative ctDNA level correlated with baseline stage and metabolic tumor volume, and early-stage patients had lower ctDNA levels than advanced-stage patients, as expected. Clearance of ctDNA after two cycles (p=0.025) and at EOT (p=0.0012) was associated with improved PFS after APVD.
In Brief
The study by Lynch and colleagues8 adds to the growing body of evidence that incorporating PD-1 blockade into frontline therapy for cHL is a promising approach. The study also highlighted an upcoming challenge posed by a potential shift to anti-PD-1–based frontline therapy in cHL: The current standard for response assessment (PET scans) appears to underperform in this setting. The study authors present a potential solution in the form of ctDNA assessment for cHL, though further validation is needed. Limitations of the study include the heterogenous patient population and small sample size, thus limiting the immediate clinical impact of the findings. Several ongoing studies, including the recently completed randomized SWOG S1826 study evaluating nivolumab-AVD versus BV-AVD as initial treatment for advanced-stage cHL,9 should help shed further light on the performance of frontline therapy involving PD-1 blockade in comparison to that of the current standard treatments.
The treatment landscape of cHL has been rapidly evolving with the increasing use of novel agents such as BV and PD-1 blockade in earlier lines of therapy. This study supports the concept that combining PD-1 blockade with anthracycline-containing chemotherapy in the initial treatment of cHL is a promising approach, with excellent efficacy and a favorable safety profile. Exciting correlative analyses demonstrate the potential of ctDNA as a more sensitive method to assess response and tumor burden than the current standard PET scans in patients with cHL, particularly in patients receiving anti-PD-1–based therapy.
The ongoing randomized phase III SWOG S1826 study (NCT03907488) will build on this and other single-arm studies evaluating PD-1 blockade combined with chemotherapy for the treatment of cHL. The results have the potential to establish a new treatment paradigm in advanced-stage cHL. Future studies will be necessary to evaluate this approach in early-stage cHL and study the integration of ctDNA as a dynamic tool to refine treatment approaches in cHL.
Competing Interests
Dr. Kambhampati indicated no relevant conflicts of interest. Dr. Herrera provides consulting and receives research funding from Merck, Bristol Myers Squibb, and Seattle Genetics.
