Sequential Pembrolizumab and Chemotherapy Results in Excellent Responses in Newly Diagnosed Classical Hodgkin Lymphoma

A brief course of pembrolizumab monotherapy followed by AVD chemotherapy (doxorubicin, vinblastine, and dacarbazine) was associated with reductions in metabolic tumor volume and prolonged survival in patients with newly diagnosed classical Hodgkin lymphoma (cHL), according to a study published in Blood.

These results are promising, said corresponding author Jane Winter, MD, of Northwestern University in Evanston, Illinois, and are a welcome advance as the current standard of care – ABVD chemotherapy (doxorubicin, bleomycin, vinblastine, and dacarbazine) – is does not cure all patients. Bleomycin-free strategies without radiotherapy also are needed to reduce the risk of complications.

“Previously, checkpoint inhibitors have been used in patients with relapsed or refractory Hodgkin lymphoma and have been shown to be of benefit, but the complete response rates are relatively low,” Dr. Winter told ASH Clinical News when asked about the rationale for the pembrolizumab and chemotherapy approach. “We felt that it was highly likely that these agents would be more effective in previously untreated patients.”

The multicenter, single-arm, phase II study enrolled 30 adults with early unfavorable or advanced-stage cHL, per National Comprehensive Cancer Network criteria. Participants underwent a baseline diagnostic CT and PET-CT scan within 4 weeks of study start (PET1).

Per study protocol, patients received pembrolizumab 200 mg as a single agent via 30-minute intravenous infusions every 3 weeks, for a total of three doses, followed by interim PET-CT scan (PET2) to assess complete metabolic response (CMR; the study’s primary endpoint). They then received 4 to 6 cycles of intravenous AVD chemotherapy every 14 days of a 28-day cycle. The AVD treatment regimen consisted of:

  • doxorubicin 25 mg/m2
  • vinblastine 6 mg/m2
  • dacarbazine 375 mg/m2

According to Dr. Winter, bleomycin was omitted because of concerns of its possible interaction with pembrolizumab, as well as its potential to increase the risk of pulmonary toxicity.

Patients with advanced-stage disease received 6 cycles of AVD, while those with unfavorable stage disease received 4 cycles. Repeat PET-CT scans were performed after 2 cycles of AVD (PET3).

The patient population included 12 patients with early stage unfavorable disease (40%) and 18 with advanced-stage disease (60%). In addition, 12 patients had either large mediastinal masses or bulky disease (40%), and another 3 patients with early unfavorable disease had disease measuring between 7 and 10 cm. Most of the study population (n=22) met criteria for receiving 6 cycles of AVD.

The authors reported that all patients completed the prescribed pembrolizumab and AVD regimen and had entered follow-up. After 3 doses of pembrolizumab monotherapy, the CMR rate on PET2 was 37%, with 11 patients achieving a Deauville 5-point scale score of 1 (n=2), 2 (n=2), or 3 (n=7). One-quarter of patients with quantifiable PET-CT achieved a >90% reduction in metabolic tumor volume (n=7/28). (TABLE)

When the authors analyzed PET3 results, they found that the CMR rate increased to 100% after 2 cycles of AVD; these responses were maintained through the end of treatment.

There were no deaths, disease progressions, or changes in therapy observed over a median follow-up period of 22.5 months (range = 14.2-30.6). The median progression-free survival and overall survival had not been reached at the time of the study’s publication.

The study protocol recommended but did not require that patients with positive PET3 transition to escalated chemotherapy, and select older patients (age >60 years) were eligible for consolidation with pembrolizumab in the case of a positive PET3 or inability to tolerate the full prescribed course of chemotherapy. However, “given the excellent tolerability and safety of the sequential therapy, no patients received pembrolizumab maintenance or transitioned to escalated [chemotherapy],” the researchers wrote.

Most of the 126 pembrolizumab-related adverse events (AEs) being grades 1 or 2 (93.7%). One patient had reversible grade 4 transaminitis and a second patient developed reversible Bell’s palsy. Immune-related AEs included grade 1 rash (n=6) and grade 2 infusion reactions (n=4).

These results demonstrate that sequencing a short course of single-agent pembrolizumab and AVD chemotherapy is safe and effective in this setting, and the effect did not appear to be related to disease stage or disease bulk, the investigators concluded.

Limitations of the study were the small number of patients as well as the relatively short follow-up duration. Dr. Winter added that the studied strategy also may be helpful for patients with bulky mediastinal masses, but further investigation is needed, particularly in head-to-head trials.

Study authors report relationships with Merck, which sponsored this trial.

Reference

Allen PB, Savas H, Evens AM, et al. Pembrolizumab followed by AVD in untreated early unfavorable and advanced stage classical Hodgkin lymphoma. Blood. 2020 September 29. [Epub ahead of print]