Pembrolizumab demonstrated a statistically significant and clinically meaningful improvement in progression-free survival compared with brentuximab vedotin in adult patients with relapsed/refractory classic Hodgkin lymphoma, meeting one of the dual primary endpoints of the phase III KEYNOTE-204 trial.
Jonathan Cheng, MD
Pembrolizumab (Keytruda) demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared with brentuximab vedotin (Adcetris) in adult patients with relapsed/refractory classical Hodgkin lymphoma, meeting 1 of the dual primary endpoints of the phase III KEYNOTE-204 trial (NCT02684292).1
The topline findings were part of the interim analysis that was conducted by an Independent Data Monitoring Committee. Per a prespecified analysis plan, overall survival (OS), the study's other dual primary endpoint, was not formally tested at this analysis. The study will continue to evaluate for OS, stated Merck (MSD), the developer of pembrolizumab, in a press release.
Moreover, the safety profile with pembrolizumab was found to be consistent with prior studies of the PD-1 inhibitor, and no new safety signals were identified.
Full findings will be presented at an upcoming medical meeting and will also be submitted to regulatory authorities.
"Patients with classical Hodgkin lymphoma are generally young and when they do not achieve remission following standard treatment, their cancer is challenging to treat," Jonathan Cheng, MD, vice president, oncology clinical research, Merck Research Laboratories, stated in the press release. "These pivotal phase III data indicate a statistically significant and clinically meaningful improvement in progression-free survival with Keytruda compared, in head to head fashion, with the currently approved therapy of brentuximab vedotin. These data are strongly supportive of Keytruda's current indication in [classical Hodgkin lymphoma] and we plan to file these data with regulatory authorities as quickly as is possible."
KEYNOTE-204 is the confirmatory trial for pembrolizumab's current indication in Hodgkin lymphoma, which is for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma, or who have relapsed following ≥3 lines of therapy. Pembrolizumab was initially granted approval in this setting in March 2017, based on findings from the phase II KEYNOTE-087 trial.
In the open-label, phase III KEYNOTE-204 trial, 304 patients with relapsed/refractory classical Hodgkin lymphoma were randomized to receive single-agent pembrolizumab or brentuximab vedotin. Pembrolizumab was given at 200 mg intravenously on day 1 of each 3-week cycle for up to 35 cycles; brentuximab vedotin was administered intravenously at 1.8 mg/kg, for a maximum 180 mg per dose, on day 1 of each 3-week cycle for up to 35 cycles.
To be eligible for enrollment, patients must have had relapsed/refractory classical Hodgkin lymphoma, responded to brentuximab vedotin alone or in combination if received as prior treatment, had measurable disease, ECOG performance status of 0 or 1, and adequate organ function. Those with hypersensitivity to the active substance in brentuximab vedotin or pembrolizumab, had immunosuppression or had received steroid treatment, or who had prior chemotherapy or a prior monoclonal antibody, among other criteria, could not enroll on the study.
The primary endpoints are PFS and OS; secondary endpoints include objective response rate (ORR), complete response (CR) rate, and safety.
In the nonrandomized, open-label KEYNOTE-087 trial, 210 adult patients with relapsed/refractory classical Hodgkin lymphoma were enrolled. The median age was 35 years (range, 18-76) and 9% of patients were ≥65 years. Fifty-four percent of patients were male and 88% were white. The ECOG performance status was 0 for 49% of patients and 1 for 51% of patients.
The median number of prior therapies was 4 (range, 1-12) and 58% of patients were refractory to their last prior therapy, including 35% with primary refractory disease and 14% with classical Hodgkin lymphoma that was chemorefractory to all prior regimens. Prior treatment included autologous hematopoietic stem cell transplantation (61%), brentuximab vedotin (83%), and radiation (36%).
Pembrolizumab was administered at 200 mg every 3 weeks until disease progression, unacceptable toxicity, or up to 2 years in patients who did not progress. Patients were assessed every 12 weeks to determine the status of their disease.
Findings showed that, at a median follow-up of 9.4 months, the ORR with pembrolizumab was 69% (95% CI, 62-75), which included a 22% CR rate and a 47% partial response rate.2 The median duration of response was 11.1 months (range, 0+ to 11.1) among the 145 responding patients.
Regarding safety, the most common adverse events (AEs) were fatigue (26%), pyrexia (24%), cough (24%), musculoskeletal pain (21%), diarrhea (20%), and rash (20%). Adverse events occurring in at least 10% of patients included dyspnea, arthralgia, vomiting, nausea, pruritus, hypothyroidism, upper respiratory tract infections, headache, peripheral neuropathy, hyperbilirubinemia and increased creatinine.
Serious AEs occurred in 16% of patients. The most frequent serious AEs included pneumonia, pneumonitis, pyrexia, dyspnea, GVHD, and herpes zoster. AEs requiring corticosteroid therapy occurred in 15% of patients.
AEs led to discontinuations and treatment interruptions in 5% and 26% of patients, respectively. There were 2 patient deaths that were both unrelated to disease: 1 patient died of septic shock and 1 patient died of GVHD after subsequent allogeneic hematopoietic stem cell transplantation.
For safety data, the FDA assessed a study of 40 pediatric patients with advanced melanoma, PD-L1—positive advanced, relapsed, or refractory solid tumors, or lymphoma. The safety profile in the pediatric patients was consistent to that observed in adults. Some AEs occurred at a higher rate (≥15% difference) in children than in adults, including fatigue, vomiting, abdominal pain, hypertransaminasemia, and hyponatremia. Pembrolizumab exposure at a dose of 2 mg/kg every 3 weeks in these pediatric patients was comparable to that observed in adults.
Pembrolizumab is being evaluated across hematologic malignancies through a broad clinical program, including 3 registrational trials in classical Hodgkin lymphoma and primary mediastinal large B-cell lymphoma, as well as ≥60 investigator-initiated trials across 15 cancers, Merck stated in the press release.