This approval marks the second FDA-approved indication in advanced melanoma for KEYTRUDA, which is now the first anti-PD-1 therapy approved for previously untreated advanced melanoma patients regardless of BRAF status.
The FDA-approved dose of KEYTRUDA is 2 mg/kg every three weeks.
In a Phase 3 trial, KEYNOTE-006, patients with unresectable or metastatic melanoma who were treated with KEYTRUDA experienced superior overall survival (OS) compared to those treated with ipilimumab. In this study supporting the first-line approval, patients given KEYTRUDA 10 mg/kg every two weeks demonstrated a 37 percent reduction in the risk of death and those given KEYTRUDA 10 mg/kg every three weeks demonstrated a 31 percent reduction in the risk of death, both compared to ipilimumab (hazard ratio: 0.63 [95% CI: 0.47, 0.83; p<0.001] and hazard ratio: 0.69 [95% CI: 0.52, 0.90; p=0.004], respectively).
Immune-mediated adverse reactions occurred with KEYTRUDA including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis.
Based on the severity of the adverse reaction, KEYTRUDA should be withheld or discontinued and corticosteroids administered. For more information regarding immune-mediated adverse reactions, see "Selected Important Safety Information" below.
Merck Research Laboratories president Roger Perlmutter said: "As recently as five years ago, there were few treatment options for patients suffering from advanced melanoma.
"Today’s news is another exciting milestone for KEYTRUDA and for patients with this disease. Data supporting the approval emerged from a large and diverse patient population, including patients with very advanced disease and patients whose tumors carried BRAF mutations, thus demonstrating both the breadth of our clinical development program for KEYTRUDA, and the potential of KEYTRUDA to extend the lives of those afflicted with this grievous malignancy."
KEYTRUDA (pembrolizumab) is a humanized monoclonal antibody that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA 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.
"This growing body of evidence in patients with advanced melanoma supports the expanded indication for KEYTRUDA," said Dr. Omid Hamid, Director of the Melanoma Center at The Angeles Clinic and Research Institute, and a principal investigator for the KEYTRUDA melanoma clinical program. "This approval highlights the importance of KEYTRUDA for advanced melanoma, where we are in need of additional treatment options."
Data Supporting First-Line Indication in Advanced Melanoma and KEYTRUDA Full Approval
The approval was based on data from a multicenter, controlled, Phase 3 study, KEYNOTE-006, which evaluated KEYTRUDA compared to ipilimumab in 834 patients with unresectable or metastatic melanoma with progression of disease; no prior therapy with ipilimumab; and prior therapy with at most one other systemic treatment.
Patients were randomized (1:1:1) to receive KEYTRUDA at a dose of 10 mg/kg every two (n=279) or three weeks (n=277) until disease progression or unacceptable toxicity, or ipilimumab, the standard of care at the time of the study, at a dose of 3 mg/kg every three weeks for four doses unless discontinued earlier for disease progression or unacceptable toxicity (n=278). The primary efficacy outcome measures were OS and progression-free survival (PFS) (as assessed by Blinded Independent Central Review (BICR) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1).
Secondary efficacy outcome measures were overall response rate (ORR) and response duration. KEYTRUDA 10 mg/kg every two or three weeks showed superior OS compared to ipilimumab (hazard ratio: 0.63 [95% CI: 0.47, 0.83; p<0.001] and hazard ratio: 0.69 [95% CI: 0.52, 0.90; p=0.004], respectively). Median PFS was 5.5 months (95% CI: 3.4, 6.9), 4.1 months (95% CI: 2.9, 6.9), and 2.8 months (95% CI: 2.8, 2.9) with KEYTRUDA 10 mg/kg every two weeks, KEYTRUDA 10 mg/kg every three weeks and ipilimumab, respectively.
For PFS, both schedules for KEYTRUDA 10 mg/kg every two or three weeks resulted in superior outcomes compared to ipilimumab (hazard ratio: 0.58 [95% CI: 0.46, 0.72; p<0.001] and hazard ratio: 0.58 [95% CI: 0.47, 0.72; p<0.001], respectively).
KEYTRUDA every two or three weeks demonstrated a 42 percent reduction in the risk of disease progression or death as compared to ipilimumab. The ORR was 34 percent (95% CI: 28, 40) with KEYTRUDA 10 mg/kg every two weeks and 33 percent (95% CI: 27, 39) with KEYTRUDA (pembrolizumab) 10 mg/kg every three weeks, as compared with 12 percent (95% CI: 8, 16) with ipilimumab. KEYTRUDA 10 mg/kg every two weeks and three weeks achieved partial response rates of 29 percent and 27 percent, respectively, and complete response rates of 5 percent and 6 percent, respectively; there was a 10 percent partial response rate and 1 percent complete response rate for ipilimumab.
Among the 94 patients randomized to KEYTRUDA 10 mg/kg every two weeks with an objective response, response durations ranged from 1.4+ to 8.2 months. Among the 91 patients randomized to KEYTRUDA 10 mg/kg every three weeks with an objective response, response durations ranged from 1.4+ to 8.1+ months.
Eighty percent of patients had PD-L1 positive melanoma, 18 percent had PD-L1 negative melanoma, and 2 percent had unknown PD-L1 status (positive: greater than or equal to 1 percent of tumor cells using an Investigational Use Only assay). BRAF mutations were reported in 36 percent of patients, of which 46 percent were previously treated with a BRAF-inhibitor. Patients with BRAF V600E mutated melanoma were not required to have received prior BRAF inhibitor therapy.
The most commonly reported adverse reactions were fatigue (28% with KEYTRUDA vs. 28% with ipilimumab), diarrhea (26% with KEYTRUDA), rash (24% with KEYTRUDA vs. 23% with ipilimumab), and nausea (21% with KEYTRUDA). Corresponding incidence rates are listed for ipilimumab only for those adverse reactions that occurred at the same or lower rate than with KEYTRUDA.
Severe and life-threatening infusion-related reactions have been reported in 3 (0.1%) of 2,117 patients. Monitor patients for signs and symptoms of infusion related reactions including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA.
Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. If used during pregnancy, or if the patient becomes pregnant during treatment, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during treatment and for four months after the last dose of KEYTRUDA.
FDA Approves Labeling Update in Advanced Melanoma: Supporting Data from KEYNOTE-002
Additionally, the FDA approved an update to the product labeling for KEYTRUDA for the treatment of patients with ipilimumab-refractory advanced melanoma. This update is based on results from the randomized Phase 2 trial, KEYNOTE-002, which demonstrated KEYTRUDA was superior to investigator’s choice chemotherapy.
KEYNOTE-002 is a multicenter, randomized controlled study of KEYTRUDA (pembrolizumab) 2 mg/kg every three weeks or 10 mg/kg every three weeks compared to investigator’s choice chemotherapy (dacarbazine, temozolomide, carboplatin plus paclitaxel, paclitaxel, or carboplatin) in 540 patients with unresectable or metastatic melanoma with progression of disease; refractory to two or more doses of ipilimumab and, if BRAF V600 mutation positive, a BRAF or MEK inhibitor; and disease progression within 24 weeks following the last dose of ipilimumab.
Patients on chemotherapy who experienced progression of disease were offered KEYTRUDA. Median PFS was 2.9 months (95% CI: 2.8, 3.8), 2.9 months (95% CI: 2.8, 4.7), and 2.7 months (95% CI: 2.5, 2.8) with KEYTRUDA 2 mg/kg every three weeks (n=180), KEYTRUDA 10 mg/kg every three weeks (n=181) and chemotherapy (n=179), respectively.
Doses of KEYTRUDA 2 mg/kg or 10 mg/kg every three weeks were superior compared to chemotherapy for the PFS primary endpoint (hazard ratio: 0.57 [95% CI: 0.45, 0.73; p<0.001] and hazard ratio: 0.50 [95% CI: 0.39, 0.64; p<0.001], respectively). KEYTRUDA 2 mg/kg every three weeks demonstrated a 43 percent reduction in the risk of disease progression or death compared to chemotherapy. There was no statistically significant difference between KEYTRUDA and chemotherapy in the interim OS analysis.
The ORR was 21 percent (95% CI: 15, 28) with KEYTRUDA 2 mg/kg every three weeks and 25 percent (95% CI: 19, 32) with KEYTRUDA 10 mg/kg every three weeks, as compared with 4 percent (95% CI: 2, 9) with chemotherapy. KEYTRUDA 2 mg/kg and 10 mg/kg every three weeks achieved partial response rates of 19 percent and 23 percent, respectively, and complete response rates of 2 percent and 3 percent, respectively; there was a 4 percent partial response rate and no complete responses for chemotherapy. Among the 38 patients randomized to KEYTRUDA 2 mg/kg with an objective response, response durations ranged from 1.3+ to 11.5+ months. Among the 46 patients randomized to KEYTRUDA 10 mg/kg with an objective response, response durations ranged from 1.1+ to 11.1+ months.
The most commonly reported adverse reactions were fatigue (43% with KEYTRUDA), pruritus (28% with KEYTRUDA vs. 8% with chemotherapy), rash (24% with KEYTRUDA vs. 8% with chemotherapy), constipation (22% with KEYTRUDA vs. 20% with chemotherapy), nausea (22% with KEYTRUDA), diarrhea (20% with KEYTRUDA vs. 20% with chemotherapy), and decreased appetite (20% with KEYTRUDA). Corresponding incidence rates are listed for chemotherapy only for those adverse reactions that occurred at the same or lower rate than with KEYTRUDA.
KEYTRUDA was initially approved in 2014 under the FDA’s accelerated approval process for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. At the time of the initial approval, an improvement in survival or disease-related symptoms was not established. In accordance with the accelerated approval process, full approval was contingent upon verification and description of clinical benefit, which has now been demonstrated in KEYNOTE-002 and KEYNOTE-006.