February 1, 2020 - The European Medicines Agency’s Committee of Medicinal Products for Human Use has recommended a label expansion for pembrolizumab for use as a single agent in adult and pediatric patients aged 3 years and older with relapsed/refractory classical Hodgkin lymphoma for whom autologous stem cell transplant has failed or following at least 2 previous therapies when ASCT is not an option.
The European Medicines Agency’s Committee of Medicinal Products for Human Use has recommended a label expansion for pembrolizumab (Keytruda) for use as a single agent in adult and pediatric patients aged 3 years and older with relapsed/refractory classical Hodgkin lymphoma for whom autologous stem cell transplant (ASCT) has failed or following at least 2 previous therapies when ASCT is not an option.1
The positive opinion is based on data from the phase 3 KEYNOTE-204 trial (NCT02684292), where treatment with the PD-1 inhibitor resulted in a 4.9-month progression-free survival (PFS) benefit over brentuximab vedotin (Adcetris) in patients with relapsed/refractory classical Hodgkin lymphoma, according to data presented during the 2020 ASCO Virtual Scientific Program.2
The median PFS with pembrolizumab was 13.2 months versus 8.3 months with brentuximab vedotin (HR, 0.65; 95% CI, 0.48-0.88; P = .00271). Patients who were not candidates for ASCT also experienced a PFS benefit with the PD-1 inhibitor over brentuximab vedotin (HR, 0.61; 95% CI, 0.42-1.23), as did those with primary refractory disease (HR, 0.52; 95% CI, 0.33-0.83), and those who never received brentuximab vedotin (HR, 0.67; 95% CI, 0.49-0.92).
The recommendation is also based on supportive data from an updated analysis of the phase 3 KEYNOTE-087 trial (NCT02453594), which supported the European approval of the PD-1 inhibitor for the treatment of patients with relapsed/refractory classical Hodgkin lymphoma for whom ASCT and brentuximab have failed and who are not candidates for transplant and have relapsed on brentuximab vedotin.
The final decision for the marketing authorization is anticipated in the first quarter of 2021. If approved, this will be the first pediatric indication for pembrolizumab in the European Union, according to Merck.
“This positive opinion reinforces the importance of [pembrolizumab] for certain adult and pediatric patients with relapsed or refractory classical Hodgkin lymphoma in the European Union,” Vicki Goodman, MD, vice president of clinical research at Merck Research Laboratories, stated in a press release. “We look forward to the decision by the European Commission and will continue to expand our clinical development program in blood cancers with [pembrolizumab] and our recently acquired investigational therapies to help address the unmet needs of patients.”
A total of 304 patients were enrolled to the open-label, phase 3 KEYNOTE-204 trial. To be eligible for enrollment, patients had to have relapsed/refractory classical Hodgkin lymphoma and have relapsed following transplant or were ineligible for transplant and have progressed on 1 previous line of treatment. Patients also needed to have measurable disease per International Working Group (IWG) criteria and an ECOG performance status of 0-1.
In the trial, a total of 151 patients were randomized to receive intravenous (IV) pembrolizumab at a dose of 200 mg every 3 weeks for up to 25 cycles, while 153 patients were given IV brentuximab vedotin at a dose of 1.8 mg/kg every 3 weeks for up to 25 cycles. Patients were stratified based on prior transplant (yes vs no) and status after first-line treatment (primary refractory vs relapsed less than 12 months vs relapsed more than 12 months following end of frontline treatment).
The primary end points of the trial were PFS per blinded independent central review (BICR) and IWG 2007 criteria including clinical and imaging information after autologous or allogeneic transplantation and overall survival. Key secondary end points included PFS per BICR and IWG 2007 criteria excluding clinical and imaging data following transplant, objective response rate (ORR) per BICR and IWG 2007 criteria, PFS per investigator assessment, duration of response, and safety.
The median age of study participants was 35.5 years, with 16.15% of patients aged 65 years or older. Moreover, 36.9% of patients previously received ASCT, while the remaining participants did not. Approximately 40% had primary refractory disease, 27.6% had relapsed less than 12 months following first-line treatment, and 31.9% had relapsed 12 months or longer after frontline therapy.
Additional data showed that the PFS excluding clinical and imaging data following transplant was 12.6 months in the investigative arm versus 8.2 months in the control arm (HR, 0.62; 95% CI, 0.46-0.85); the 12-month PFS rates were 50.4% and 33.3%, respectively. Per investigator assessment, the median PFS was 19.2 months with pembrolizumab versus 8.2 months with brentuximab vedotin (HR, 0.49; 95% CI, 0.36-0.67).
Moreover, pembrolizumab elicited an ORR of 65.6% (95% CI, 57.4%-73.1%) versus 54.2% (95% CI, 46.0%-62.3%) with brentuximab vedotin (P = .0225). In the pembrolizumab arm, the ORR was comprised of a 24.5% complete response rate, a 41.1% partial response rate, and a 13.9% stable disease rate. Twenty-six patients (17.2%) experienced progressive disease on the investigative arm. The median time to response to treatment with pembrolizumab was 2.8 months. Additionally, the median DOR in the investigative and control arms was 20.7 months and 13.8 months, respectively.
Regarding safety, 98.0% of those who received the PD-1 inhibitor experienced toxicities versus 94.1% of those who received brentuximab vedotin; 43.9% versus 43.4% of these effects were grade 3-5 in severity. Moreover, 29.7% of those who received pembrolizumab experienced a serious adverse effect (AE) versus 21.1% of those who were given brentuximab vedotin. Twenty patients (13.5%) who received the immunotherapy discontinued treatment because of toxicities versus 27 patients who were given brentuximab vedotin (17.8%).
Treatment-related toxicities were reported in 74.3% versus 77.0% of patients on the investigative and control arms, respectively, and 19.6% versus 25.0%, respectively, were grade 3-5 in severity. One patient on the investigative arm died from a treatment-related toxicity, which was grade 5 pneumonia, while no treatment-related deaths were reported on the control arm. Nineteen patients (12.8%) on the pembrolizumab arm discontinued due to treatment-related AEs versus 25 patients (16.4%) on the brentuximab arm.
The most frequently reported treatment-related AEs on the pembrolizumab arm included hypothyroidism (15.5%), pyrexia (12.8%), pruritus (10.8%), fatigue (8.8%), nausea (4.1%), peripheral neuropathy (2.0%), and peripheral sensory neuropathy (2.0%). The most common treatment-related toxicities on the control arm included peripheral neuropathy (18.4%), nausea (13.2%), and peripheral sensory neuropathy (13.2%), among others. The most commonly experienced immune-mediated AEs on the pembrolizumab arm included hypothyroidism (18.9%), pneumonitis (10.8%), and hyperthyroidism (5.4%).
In March 2017, the FDA granted an accelerated approval to pembrolizumab for use in adult and pediatric patients with classical Hodgkin lymphoma who are refractory or have relapsed following 3 or more lines of treatment. In October 2020, the FDA gave the green light to an expanded label for pembrolizumab for use as a single agent in adult patients with relapsed or refractory classical Hodgkin lymphoma; the regulatory agency also approved an updated pediatric indication for the agent’s use in pediatric patients with refractory classical Hodgkin lymphoma or classical Hodgkin lymphoma that has relapsed after 2 or more lines of therapy.