Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced that the U.S. Food and Drug Administration (FDA) has approved an expanded label for KEYTRUDA, Merck’s anti-PD-1 therapy, as monotherapy for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL). The approval is based on results from the Phase 3 KEYNOTE-204 trial in which KEYTRUDA 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 (BV). Additionally, median progression-free survival (PFS) was 13.2 months (95% CI, 10.9-19.4) for patients treated with KEYTRUDA and 8.3 months (95% CI, 5.7-8.8) for patients treated with BV. The FDA also approved an updated pediatric indication for KEYTRUDA for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after two or more lines of therapy.

“An estimated 8,500 patients in the U.S., many of them 40 years of age or younger, will be diagnosed with cHL this year. Now patients with cHL who progress after frontline therapy have a new option in KEYTRUDA, which has demonstrated a clinically meaningful improvement in progression-free survival compared to brentuximab vedotin,” said Dr. Vicki Goodman, 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.”

Immune-mediated adverse reactions, which may be severe or fatal, can occur with KEYTRUDA, 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, KEYTRUDA should be withheld or discontinued and corticosteroids administered if appropriate. KEYTRUDA can also cause severe or life-threatening infusion-related reactions. Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. For more information, see “Selected Important Safety Information” below.

“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 Dr. John Kuruvilla, hematologist and associate professor of medicine, Princess Margaret Cancer Centre and University of Toronto. “With this approval, KEYTRUDA has the potential to change the current standard of care and help these patients achieve better outcomes.”

KEYTRUDA 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.

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.

Data Supporting the Approval
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 KEYTRUDA (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 KEYTRUDA 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, KEYTRUDA 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 KEYTRUDA arm, there were 81 patients (54%) with an event versus 88 patients (58%) in the BV arm. For patients treated with KEYTRUDA, 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 KEYTRUDA and 13.8 months (range, 0.0+ to 33.9+) with BV.

In KEYNOTE-204, the median duration of exposure to KEYTRUDA 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 KEYTRUDA. 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.

Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 14% of patients; 7% of patients discontinued treatment due to pneumonitis. Dosage interruption of KEYTRUDA due to an adverse reaction occurred in 30% of patients. Adverse reactions that required dosage interruption in greater than or equal to 3% of patients were upper respiratory tract infection, pneumonitis, transaminase increase and pneumonia. Thirty-eight percent of patients had an adverse reaction requiring systemic corticosteroid therapy. The most common adverse reactions (greater than or equal to 20%) were upper respiratory tract infection (41%), musculoskeletal pain (32%), diarrhea (22%), and pyrexia, fatigue, rash and cough (20% each).