John Kuruvilla, MD of the Princess Margaret Cancer Centre and the University of Toronto discusses KEYTRUDA Is the First Anti-PD-1 Therapy Approved for Adult Patients With Relapsed or Refractory cHL After Frontline Therapy.
KENILWORTH, N.J.—(BUSINESS WIRE)—Outside of the United States and Canada, Merck (NYSE: MRK), known as MSD, today reported that the U.S. The Food and Drug Administration (FDA ) has approved an extended label for the care of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL) with KEYTRUDA, Merck's anti-PD-1 therapy, as monotherapy. The approval is based on findings from the KEYNOTE-204 Phase 3 study in which KEYTRUDA significantly decreased the risk of disease worsening or death by 35% (HR=0.65 [95 % CI, 0.48-0.88; p<0.0027]) as opposed to brentuximab vedotin (BV). In addition, median progression-free survival (PFS) was 13.2 months (95 % CI, 10.9-19.4) for KEYTRUDA treated patients and 8.3 months (95 % CI, 5.7-8.8) for BV treated patients. A revised pediatric label for KEYTRUDA was also approved by the FDA for the treatment of pediatric patients with refractory cHL or relapsed cHL after two or more lines of therapy.
Immune-mediated, serious or fatal adverse reactions, like pneumonitis, colitis, hepatitis, endocrinopathy, nephritis, severe skin reactions, rejection of solid organ transplants, and complications of allogeneic hematopoietic stem cell transplantation (HSCT), can occur with KEYTRUDA. KEYTRUDA should be withheld or withdrawn depending on the nature of the adverse reaction, and corticosteroids should be administered if necessary. KEYTRUDA can also cause serious or life-threatening reactions associated with the infusion. Based on its mechanism of action, when given to a pregnant woman, KEYTRUDA can cause fetal damage.
KEYTRUDA has already been approved as part of 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 therapy lines, based on evidence from the KEYNOTE-087 study. Continued approval depended on verification and explanation of the clinical benefit in compliance with the accelerated approval regulations; these accelerated approval criteria were met with KEYNOTE-204 results.
This approval was reviewed under the Orbis Project of the FDA, an initiative of the FDA Oncology Center of Excellence, which offers a forum for the simultaneous submission and evaluation between its foreign partners of oncology drugs. An updated Project Orbis was conducted for this application, and the FDA is working on its ongoing review of the application with the Australian Therapeutic Products Administration and Health Canada.
Information Supporting the Approval
The approval was based on evidence from a randomized, open-label, active-controlled study, KEYNOTE-204 (NCT02684292), performed in 304 patients with relapsed or refractory cHL. After at least one multi-agent chemotherapy treatment, the study recruited adults with relapsed or refractory illness. In order to receive either KEYTRUDA 200 mg intravenously every three weeks or BV 1.8 mg/kg intravenously every three weeks, patients were randomized to 1:1.
Until unacceptable toxicity, recorded worsening of the disease, or up to a maximum of 35 cycles (up to approximately two years), treatment was continued. The assessment of the disease was conducted every 12 weeks. Previous autologous HSCT (yes vs. no) and disease status after frontline therapy is stratified by randomization (primary refractory vs. relapse less than 12 months after completion vs. relapse 12 months or more after completion). As evaluated by the Blinded Independent Central Review (BICR) using the updated International Working Group (IWG) guidelines of 2007, the key efficacy indicator was PFS.
KEYTRUDA (n=151) or BV (n=153) patients were enrolled and randomized. The median age of 35 years was the study population characteristics (range, 18 to 84); 57 percent male; 77 percent white, 9 percent Asian, and 3.9 percent Black. The median number of prior therapies in the KEYTRUDA arm was two (range, 1 to 10) and three (range, 1 to 11) in the BV arm, with 18 percent having one prior line in both arms. Forty-two percent of patients were refractory to the last prior treatment, 29 percent had primary refractory disease, 37 percent had previous autologous HSCT, 5 percent had previous BV, and 39 percent had previous radiation treatment.
KEYTRUDA decreased the risk of disease development or death by 35% (HR=0.65 [95 % CI, 0.48-0.88; p=0.0027]) in KEYNOTE-204 and demonstrated a median PFS of 13.2 months (95 % CI, 10.9-19.4). For patients treated with BV, the median PFS was 8.3 months (95 % CI, 5.7-8.8). For PFS, 81 patients (54 percent) had an incident in the KEYTRUDA arm, compared to 88 patients (58 percent) in the BV arm. The objective response rate (ORR) was 66 percent (95 percent CI, 57-73) for patients treated with KEYTRUDA, with a 25 percent full response rate and a 41 percent partial response rate. The ORR was 54 percent for patients treated with BV (95 percent CI, 46-62), with a complete response rate of 24 percent and a partial response rate of 30 percent. Not statistically important is the gap in ORRs. The median period of response (DOR) among the responding patients was 20.7 months (range, 0.0 + to 33.2 +) with KEYTRUDA and 13.8 months (range, 0.0 + to 33.9 +) with BV.
The median period of KEYTRUDA exposure was 10 months for KEYNOTE-204 (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. In 30 percent of patients who received KEYTRUDA, severe adverse effects occurred. Pneumonitis, pneumonia, pyrexia, myocarditis, acute kidney injury, febrile neutropenia, and sepsis were severe adverse effects in those greater than or equal to 1 percent of the patients. Three patients (2%) died due to factors other than disease progression: two due to allogeneic HSCT complications and one due to an unknown cause.
In 14 percent of patients, permanent discontinuation of KEYTRUDA due to an adverse reaction occurred; 7 percent of patients discontinued treatment because of pneumonitis. In 30 percent of patients, dose interruption of KEYTRUDA due to an adverse reaction occurred. Upper respiratory tract infection, pneumonitis, transaminase rise, and pneumonia were adverse reactions requiring dosage interruption are greater than or equal to 3 percent of patients. Thirty-eight percent of patients suffered an adverse reaction that involved treatment with systemic corticosteroids. Upper respiratory tract infection (41%), musculoskeletal pain (32%), diarrhea (22%), and pyrexia, weakness, rash, and cough (20 percent each) were the most common adverse reactions (greater than or equivalent to 20 percent).