The FDA has approved an expanded label for pembrolizumab for use as a monotherapy in the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma and pediatric patients with refractory classical Hodgkin lymphoma, or classical Hodgkin lymphoma that has relapsed after 2 or more lines of therapy.
The FDA has approved an expanded label for pembrolizumab for use as a monotherapy in the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma.1
The FDA also approved an updated pediatric indication for pembrolizumab for use in pediatric patients with refractory classical Hodgkin lymphoma, or classical Hodgkin lymphoma that has relapsed after 2 or more lines of therapy.
The regulatory decision is based on data from the phase 3 KEYNOTE-204 trial (NCT02684292) where pembrolizumab resulted in a 35% reduction in the risk of disease progression or death versus brentuximab vedotin (Adcetris; HR, 0.65; 95% CI, 0.48-0.88; P <0.0027). Moreover, the median progression-free survival (PFS) was 13.2 months (95% CI, 10.9-19.4) with pembrolizumab versus 8.3 months (95% CI, 5.7-8.8) with brentuximab vedotin.
“An estimated 8,500 patients in the United States, many of them 40 years of age or younger, will be diagnosed with classical Hodgkin lymphoma this year. Now patients with classical Hodgkin lymphoma who progress after frontline therapy have a new option in pembrolizumab, which has demonstrated a clinically meaningful improvement in PFS compared with brentuximab vedotin,” said Vicki Goodman, MD, vice president, clinical research, Merck Research Laboratories.1 “At Merck, we are committed to improving outcomes for patients with cancer. Today’s FDA approval builds upon our growing range of options for people with blood cancers.”
KEYNOTE-204 enrolled patients with relapsed or refractory classical Hodgkin lymphoma who relapsed following autologous stem cell transplant or were ineligible for the procedure and progressed on 1 previous line of treatment. Patients had to have measurable disease per International Working Group (IWG) 2007 criteria and an ECOG performance status of 0 or 1. Previous exposure to brentuximab vedotin was permitted.
Participants were stratified based on whether they received a prior autologous stem cell transplant and their status after first-line treatment (primary refractory vs relapsed less than 12 months vs relapsed 12 months or more following end of frontline treatment).
Patients were randomized in a 1:1 fashion to receive either pembrolizumab at 200 mg intravenously (IV) once every 3 weeks for up to 35 cycles or brentuximab vedotin at 1.8 mg/kg IV once every 3 weeks for up to 35 cycles.
Investigators examined response once every 12 weeks in accordance with IWG 2007 Revised Response criteria for Malignant Lymphoma and toxicities were assessed once every 3 weeks throughout the course of the trial period and once every 12 weeks during the follow-up period.
The primary end points of the trial were PFS per blinded independent central review (BICR) via IWG 2007 criteria which was comprised of clinical and imaging data after autologous stem cell transplant or allogeneic stem cell transplant and overall survival. Key secondary end points of the trial included PFS per BICR by IWG 2007 criteria without clinical and imaging data post transplant, objective response rate (ORR) per BICR via IWG 2007, PFS per investigator assessment, duration of response (DOR), and safety.
A total of 304 patients were included in the trial; 151 of these patients were assigned to the pembrolizumab arm and 153 were assigned to the brentuximab vedotin arm. However, 148 patients received pembrolizumab and 152 patients received brentuximab vedotin. The median time from randomization to database cutoff was 25.7 months.
Additionally, 37.1% of patients on the investigative arm versus 36.6% of patients on the control arm had previously undergone an autologous stem cell transplant. A comparable percentage of patients on both arms were primary refractory following frontline treatment (40.4%, pembrolizumab arm; 40.5%, brentuximab vedotin arm). The same was true for those who relapsed less than 12 months following first-line therapy (27.8%, pembrolizumab; 27.5%, brentuximab vedotin) and those who relapsed 12 months or longer after up-front treatment (31.8% vs 32.0%, respectively). Double the patients on the brentuximab vedotin arm had previously received the agent versus those on the pembrolizumab arm (6.5% vs 3.3%, respectively). The median number of previous treatments in the investigative arm was 2 versus 3 in the control arm.
Results presented during the 2020 ASCO Virtual Scientific Program showed that PFS favored pembrolizumab across all of the patient subgroups analyzed, irrespective of whether they previously underwent transplant, what their disease status was following first-line therapy, and if they previously received brentuximab vedotin.2
The PFS rates per independent central review were 50.4% with pembrolizumab versus 33.3% with brentuximab vedotin. The median PFS was 12.6 months (95% CI, 8.7-19.2) versus 8.2 months (95% CI, 5.6-8.6), respectively. Per investigator review, the PFS rate was even higher with pembrolizumab, at 62.2% versus 33.0% with brentuximab vedotin. The median PFS in the investigative versus control arms was 19.2 months (95% CI, 13.8-28.1) versus 8.2 months (95% CI, 5.7-8.6), respectively.
The ORR was also higher with pembrolizumab versus brentuximab vedotin, at 65.6% (95% CI, 57.4-73.1) versus 54.2% (95% CI, 46.0-62.3), respectively (P = .0225). The median DOR per BICR was 20.7 months with pembrolizumab versus 13.8 months with brentuximab vedotin.
With regard to safety, 98.0% of patients on the pembrolizumab arm reported adverse effects (AEs) versus 94.1% of those on the brentuximab vedotin arm; 43.9% vs 43.4%, respectively, experienced toxicities that were grade 3 to 5 in severity. Moreover, 29.7% of patients who received pembrolizumab had serious AEs versus 21.1% of those given brentuximab vedotin. Three patients on the investigative arm died versus 2 on the control arm. Less patients who received the immunotherapy discontinued treatment because of toxicities versus brentuximab vedotin, at 13.5% versus 17.8%, respectively.
Treatment-related toxicities were experienced by 74.3% of those on the investigative arm versus 77.0% of those on the control arm. Less patients on the pembrolizumab arm experienced grade 3-5 treatment-related AEs (TRAEs; 19.6% vs 25.0%, respectively). One patient on the pembrolizumab arm died because of treatment-related grade 5 pneumonia; no patients died on the brentuximab vedotin arm. Treatment discontinuation because of TRAEs was reported in 12.8% versus 16.4% of those on the investigative and control arms, respectively.
TRAEs experienced in more than 10% of patients in either the pembrolizumab or brentuximab vedotin treatment arms included hypothyroidism (15.5% vs 1.3%, respectively), pyrexia (12.8% vs 5.9%), pruritus (10.8% vs 5.3%), fatigue (8.8% vs 10.5%), nausea (4.1% vs 13.2%), peripheral neuropathy (2.0% vs 18.4%), and peripheral sensory neuropathy (2.0% vs 13.2%).
"The patients with classical Hodgkin lymphoma who do not achieve remission following initial treatment or who relapse after transplantation face a poor prognosis, reflecting the unmet need for improved therapies in the relapsed/refractory setting," said John Kuruvilla, MD, a hematologist and associate professor of medicine at Princess Margaret Cancer Centre and the University of Toronto.1 "With this approval, [pembrolizumab] has the potential to change the current standard of care and help these patients achieve better outcomes."
Previously, pembrolizumab was approved by the FDA for use in adult and pediatric patients with refractory classical Hodgkin lymphoma who have relapsed following 3 or more previous lines of treatment based on data from the KEYNOTE-087 trial. The decision was contingent on verification of clinical benefit; those requirements have been met with data from KEYNOTE-204.