The U.S. Food and Drug Administration (FDA) has approved an expanded label for pembrolizumab (Keytruda®, Merck & Co/MSD). The expanded label includes pembrolizumab, an anti-PD-1 therapy, as monotherapy for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL).

The expanded label also includes an approval for pediatric patients with refractory cHL, or cHL that has relapsed after two or more lines of therapy.

The approval is based on results from the Phase III KEYNOTE-204 trial in which pembrolizumab significantly reduced the risk of disease progression or death by 35% (HR=0.65 [95% CI, 0.48-0.88; p<0.0027]) compared to brentuximab vedotin (Adcetris®; Seagen).[1]

Additionally, median progression-free survival (PFS) was 13.2 months (95% CI, 10.9-19.4) for patients treated with pembrolizumab and 8.3 months (95% CI, 5.7-8.8) for patients treated with BV. The FDA also approved an updated pediatric indication for pembrolizumab for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after two or more lines of therapy.

Hodgkin Lymphoma
Hodgkin lymphoma is a type of lymphoma that develops in the white blood cells called lymphocytes, which are part of the immune system. The disease can start almost anywhere – most often in lymph nodes in the upper part of the body, with the most common sites being in the chest, neck or under the arms.

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The latest available data shows that worldwide there were approximately 80,000 new cases of Hodgkin lymphoma, and more than 26,000 people died from the disease in 2018.

Pembrolizumab (Keytruda®, Merck & Co/MSD) is a prescription medicine used to treat a kind of skin cancer called melanoma. Keytruda®, 100mg/4mL Vial and Carton

“An estimated 8,500 patients in the United States, many of them 40 years of age or younger, will be diagnosed with cHL this year (2020). Now patients with cHL who progress after frontline therapy have a new option in pembrolizumab, which has demonstrated a clinically meaningful improvement in progression-free survival compared to brentuximab vedotin,” said Vicki Goodman, M.D., vice president, clinical research, Merck Research Laboratories.

“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,” Goodman added.

Classical Hodgkin lymphoma accounts for more than nine in 10 cases of Hodgkin lymphoma in developed countries.

Pembrolizumab, a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells, works by increasing the ability of the body’s immune system to help detect and fight tumor cells.

Clinical trial program
Merck has the industry’s largest immuno-oncology clinical research program. There are currently more than 1,200 trials studying pembrolizumab across a wide variety of cancers and treatment settings. The pembrolizumab clinical program seeks to understand the role of pembrolizumab across cancers and the factors that may predict a patient’s likelihood of benefitting from treatment with pembrolizumab, including exploring several different biomarkers.

Immune-mediated adverse reactions, which may be severe or fatal, can occur with pembrolizumab, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, severe skin reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplantation (HSCT). Based on the severity of the adverse reaction, pembrolizumab should be withheld or discontinued and corticosteroids administered if appropriate.

“The patients with cHL 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, M.D., hematologist and associate professor of medicine, Princess Margaret Cancer Centre and University of Toronto.

“With this approval, pembrolizumab has the potential to change the current standard of care and help these patients achieve better outcomes,” Kuruvilla added.

Pediatric patients
Pembrolizumab was previously approved under the FDA’s accelerated approval process for the treatment of adult and pediatric patients with refractory cHL, or who have relapsed after three or more prior lines of therapy based on data from the KEYNOTE-087 trial.

In accordance with accelerated approval regulations, continued approval was contingent upon verification and description of clinical benefit; these accelerated approval requirements have been fulfilled with the data from KEYNOTE-204.

Project Orbis
This approval was reviewed under the FDA’s Project Orbis, an initiative of the FDA Oncology Center of Excellence that provides a framework for concurrent submission and review of oncology drugs among its international partners. For this application, a modified Project Orbis was undertaken, and the FDA is collaborating with the Australian Therapeutic Goods Administration and Health Canada on their ongoing review of the application.

This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.

Supporting Data
The approval was based on data from KEYNOTE-204 (NCT02684292), a randomized, open-label, active-controlled trial conducted in 304 patients with relapsed or refractory cHL. The trial enrolled adults with relapsed or refractory disease after at least one multi-agent chemotherapy regimen. Patients were randomized 1:1 to receive either KEYTRUDA 200 mg intravenously every three weeks or BV 1.8 mg/kg intravenously every three weeks.

Treatment was continued until unacceptable toxicity, documented disease progression or a maximum of 35 cycles (up to approximately two years). Disease assessment was performed every 12 weeks.

Randomization was stratified by prior autologous HSCT (yes vs. no) and disease status after frontline therapy (primary refractory vs. relapse less than 12 months after completion vs. relapse 12 months or more after completion). The main efficacy measure was PFS as assessed by blinded independent central review (BICR) using 2007 revised International Working Group (IWG) criteria.

Patients were enrolled and randomized to pembrolizumab (n=151) or BV (n=153). The study population characteristics were median age of 35 years (range, 18 to 84); 57% male; 77% white, 9% Asian and 3.9% Black.

The median number of prior therapies was two (range, 1 to 10) in the pembrolizumab arm and three (range, 1 to 11) in the BV arm, with 18% in both arms having one prior line. Forty-two percent of patients were refractory to the last prior therapy, 29% had primary refractory disease, 37% had prior autologous HSCT, 5% had received prior BV, and 39% had prior radiation therapy.

In KEYNOTE-204, pembrolizumab reduced the risk of disease progression or death by 35% (HR=0.65 [95% CI, 0.48-0.88; p=0.0027]) and showed a median PFS of 13.2 months (95% CI, 10.9-19.4). Median PFS was 8.3 months (95% CI, 5.7-8.8) for patients treated with BV.

For PFS, in the pembrolizumab arm, there were 81 patients (54%) with an event versus 88 patients (58%) in the BV arm. For patients treated with pembrolizumab, the objective response rate (ORR) was 66% (95% CI, 57-73), with a complete response rate of 25% and a partial response rate of 41%. For patients treated with BV, the ORR was 54% (95% CI, 46-62), with a complete response rate of 24% and a partial response rate of 30%. The difference in ORRs is not statistically significant. Among the responding patients, median duration of response (DOR) was 20.7 months (range, 0.0+ to 33.2+) with pembrolizumab and 13.8 months (range, 0.0+ to 33.9+) with BV.

In KEYNOTE-204, the median duration of exposure to pembrolizumab was 10 months (range, 1 day to 2.2 years), with 68% receiving at least six months of treatment and 48% receiving at least one year of treatment. Serious adverse reactions occurred in 30% of patients who received pembrolizumab.

Serious adverse reactions in those greater than or equal to 1% of patients included pneumonitis, pneumonia, pyrexia, myocarditis, acute kidney injury, febrile neutropenia and sepsis. Three patients (2%) died from causes other than disease progression: two from complications after allogeneic HSCT and one from an unknown cause.

Clinical trials
Study of Pembrolizumab (MK-3475) vs. Brentuximab Vedotin in Participants With Relapsed or Refractory Classical Hodgkin Lymphoma (MK-3475-204/KEYNOTE-204) – NCT02684292

Highlights of Prescribing Information
Pembrolizumab (Keytruda®, Merck & Co/MSD) [Prescribing Information]
Brentuximab vedotin (Adcetris®; Seagen) [Prescribing Information]

[1] Pembrolizumab Improves Progression-Free Survival in Relapsed/Refractory Hodgkin Lymphoma. Oncologist. 2020 Jul;25 Suppl 1(Suppl 1):S18-S19. doi: 10.1634/theoncologist.2020-0561. Epub 2020 Jun 26. PMID: 32588926; PMCID: PMC7330920.

Featured Image: Merck | MSD Exhibition booth at the 2019 annual meeting of the American Society of Medical Oncology (ASCO).

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