The FDA has granted priority review to a new supplemental biologics license application for pembrolizumab monotherapy as a treatment for adult patients with relapsed/refractory classical Hodgkin lymphoma.
The FDA has granted priority review to a new supplemental biologics license application (sBLA) for pembrolizumab (Keytruda) monotherapy as a treatment for adult patients with relapsed/refractory classical Hodgkin lymphoma.1
“Classical Hodgkin lymphoma accounts for more than 9 in 10 cases of Hodgkin lymphoma, which impacts approximately 7400 patients a year in the United States. For patients with classical Hodgkin lymphoma who do not achieve remission after first-line treatment, there is particularly poor prognosis due to the limited options available,” Jonathan Cheng, MD, vice president of oncology clinical research of Merck Research Laboratories, stated in a press release. “We look forward to working with the FDA to bring Keytruda to more patients with classical Hodgkin lymphoma after initial treatment.”
The regulatory decision was based on data findings the pivotal phase 3 KEYNOTE-204 trial, in which the agent significantly improved progression-free survival (PFS) over the current standard of care, brentuximab vedotin (Adcetris), in this patient population. Under the Prescription Drug User Fee Act, the FDA will make a decision on the sBLA on October 30, 2020.
Results presented at the 2020 ASCO Virtual Scientific Program showed that that treatment with single-agent pembrolizumab led to a statistically significant and clinically meaningful improvement in PFS compared with brentuximab vedotin in patients with relapsed/refractory classical Hodgkin lymphoma who either have relapsed post autologous stem cell transplant or are not candidates for transplant.2 The median PFS was 13.2 months with pembrolizumab versus 8.3 months with the control (HR, 0.65; 95% CI, 0.48-0.88; P = .00271).
Notably, the PFS benefit observed with the PD-1 inhibitor was upheld in key patient subgroups, including those who were ineligible for transplant (HR, 0.61), those with primary refractory disease (HR, 0.52) and those who never received brentuximab vedotin (HR, 0.67).
Additionally, the objective response rate with pembrolizumab was 65.6% (95% CI, 57.4-73.1) versus 54.2% (95% CI, 46.0-62.3) with brentuximab vedotin (P = .0225). Complete response (CR) was the best overall response achieved in 24.5% of patients on the pembrolizumab arm. Approximately 41% of patients who received the PD-1 inhibitor achieved a partial response (PR) and 13.9% achieved stable disease. Twenty-six patients experienced disease progression on the pembrolizumab arm versus 28 patients on the control arm. The median time to response with pembrolizumab and brentuximab vedotin was 2.8 months on both arms.
The duration of response (DOR) by blinded independent central review (BICR) with pembrolizumab was 20.7 months (range, 0.0+ to 33.2+) versus 13.8 months with brentuximab vedotin (range, 0.0+ to 33.9+). The DOR rates with pembrolizumab and brentuximab vedotin were 62.4% and 50.0%, respectively.
In the open-label, phase 3 KEYNOTE-204 trial, a total of 304 patients with relapsed/refractory classical Hodgkin lymphoma underwent randomization to either single-agent pembrolizumab (n = 151) or brentuximab vedotin (n = 153). Pembrolizumab was administered intravenously at 200 mg on day 1 of each 3-week treatment cycle for up to 35 cycles. Brentuximab vedotin was also given intravenously at 1.8 mg/kg, for a maximum of 180 mg per dose, on day 1 of each 3-week cycle for up to 35 cycles.
In order to be eligible for participation on the trial, patients had to have relapsed/refractory disease, have responded to brentuximab vedotin alone or in combination if received as prior treatment, have measurable disease, an ECOG performance status ranging from 0 to 1, and acceptable organ function. Patients who had hypersensitivity to the active substance in brentuximab vedotin or pembrolizumab, were immunosuppressed or had received steroid treatment, or who had previously received chemotherapy, or a monoclonal antibody, were not eligible for participation.
The primary end points of the trial were PFS per BICR by International Working Group (IWG) 2007 criteria including clinical and imaging data following autologous stem cell transplant or allogeneic stem cell transplant and overall survival. Secondary end points of the trial included PFS per BICR by IWG 2007 criteria excluding clinical and imaging data following autologous transplant or allogeneic transplant, ORR by BICR per IWG 2007, PFS per investigator review, DOR, and safety.
Safety data with the agent were found to be consistent with the known toxicity profiles of each agent. Adverse events (AEs) occurred in 98% of those on the pembrolizumab arm versus 94.1% of those on the brentuximab vedotin arm. Grade 3 to 5 AEs were observed in 43.9% versus 43.4% of those who received single-agent pembrolizumab and brentuximab vedotin, respectively. Serious AEs were reported in 29.7% of patients on the pembrolizumab arm and 21.1% of those on the comparator arm. Three deaths were reported on the investigational arm and 2 deaths were reported on the control arm.
Moreover, 13.5% of patients on the pembrolizumab arm discontinued treatment because of AEs compared with 17.8% of those on the brentuximab vedotin arm. AEs deemed to be related to treatment were reported in 74.3% and 77.0% of those receiving pembrolizumab or brentuximab vedotin, respectively. Treatment-related AEs that led to therapy discontinuation were reported in 12.8% of those on the pembrolizumab arm and 16.4% of those on the control arm.
KEYNOTE-204 is the confirmatory trial for the PD-1 inhibitor’s 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. The agent was initially granted an approval for use in this setting in March 2017, based on data from the phase 2 KEYNOTE-087 trial.
The nonrandomized, open-label KEYNOTE-087 trial enrolled 210 adult patients with relapsed/refractory classical Hodgkin lymphoma and examined pembrolizumab administered at 200 mg every 3 weeks until progressive disease, intolerable toxicity, or for up to 2 years in those who did not experience progression.
Results demonstrated that at a median follow-up of 9.4 months, the ORR with pembrolizumab was 69% (95% CI, 62-72), which was comprised of a 22% CR rate and a 47% PR rate.3 The median DOR with the agent was 11.1 months (range, 0+ to 11.1) among 145 responsive patients.3
Pembrolizumab is currently under investigation in several hematologic malignancies through a broad clinical program, which includes 3 registrational trials in classical Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. The program also comprises over 60 investigator-initiated studies spanning 15 tumors.