FDA Expands Indication for Keytruda for Metastatic Melanoma


The FDA has approved the expanded indication for single-agent pembrolizumab (Keytruda) to include the frontline treatment of patients with unresectable metastatic melanoma regardless of BRAF status.

“Roger M. Perlmutter, MD, PhD”

“Roger M. Perlmutter, MD, PhD”

Roger M. Perlmutter, MD, PhD

The FDA has approved the expanded indication for the anti-PD-1 monoclonal antibody pembrolizumab (Keytruda) to include the frontline treatment of patients with unresectable metastatic melanoma regardless of BRAF status.

The approval was based on a significant improvement in progression-free and overall survival compared with ipilimumab (Yervoy) in the phase III KEYNOTE-006 trial.1

In the study, which compared 2 pembrolizumab regimens with ipilimumab, the PD-L1 inhibitor reduced the risk of disease progression by >40% and the risk of death by >30%.

“As recently as five years ago, there were few treatment options for patients suffering from advanced melanoma,” Roger M. Perlmutter, MD, PhD, president, Merck Research Laboratories, the developer of the PD-1 inhibitor, said in a statement. “Today’s news is another exciting milestone for Keytruda and for patients with this disease."

In addition to the frontline approval, the FDA also updated the label for pembrolizumab to include the treatment of patients with ipilimumab-refractory melanoma, based on a greater than 43% reduction in the risk of death versus chemotherapy in the phase II KEYNOTE-002 trial.2

“This growing body of evidence in patients with advanced melanoma supports the expanded indication for Keytruda,” Omid Hamid, MD, director of the Melanoma Center at The Angeles Clinic and Research Institute, said in a statement. “This approval highlights the importance of Keytruda for advanced melanoma, where we are in need of additional treatment options.”

KEYNOTE-006 included 834 patients with unresectable stage III or IV advanced melanoma who had received no more than 1 prior systemic therapy. Among the overall patient population, 65.8% had not previously received systemic treatment for advanced melanoma and 68.7% had an ECOG performance status of 0.

Patients were randomized in a 1:1:1 ratio to receive 4 cycles of ipilimumab at 3 mg/kg every 3 weeks (n = 278), 10 mg/kg of pembrolizumab every 3 weeks (n = 277), or 10 mg/kg of pembrolizumab every 2 weeks (n = 279). Both doses of pembrolizumab were higher than the previously approved FDA regimen of 2 mg/kg every 3 weeks. However, the frontline approval for pembrolizumab is also for 2 mg/kg every 3 weeks.

Patient response in KEYNOTE-006 was assessed at week 12 and every 6 weeks thereafter by RECIST 1.1. The median follow-up was 7.9 months (range, 6.1-11.5).

At a 6-month assessment, the progression-free survival (PFS) rate with pembrolizumab was 47.3% and 46.4% in the 2- and 3-week arms respectively, compared with 26.5% for the ipilimumab arm (HR, 0.58; P <.001). Median PFS was 5.5, 4.1, and 2.8 months, respectively. The PFS benefit with pembrolizumab over ipilimumab was observed regardless of patients’ PD-L1 status.

The 9-month PFS rates were 40% and 42% compared with 16%, in the 2-week, 3-week, and ipilimumab arms, respectively, according to Merck, which develops pembrolizumab.

The 1-year overall survival (OS) rate was 74.1% for the 2-week pembrolizumab arm versus 58.2% for those receiving ipilimumab (HR, 0.63; 95% CI, 0.47-0.83; P<.0005). In the 3-week pembrolizumab group, the 1-year OS rate was 68.4% (HR vs ipilimumab, 0.69; 95% CI, 0.52-0.90; P = .0036).

The objective response rates (ORR) were 33.7% and 32.9%, in the 2- and 3-week arms. In the ipilimumab arm, the ORR was 11.9%. Complete response rates were 5.0%, 6.1%, and 1.4%, respectively.

The toxicity profiles of the agents were consistent with other reported studies of the two checkpoint agents. Although pembrolizumab was administered for a longer duration, rates of grade 3-5 adverse events (AEs) were lower with both the 2- and 3-week doses versus ipilimumab at 13.3% and 10.1% versus 19.9%, respectively. Discontinuation rates were also lower with pembrolizumab, at 4.0%, 6.9%, and 9.4%, respectively.

The most frequently reported all-grade AEs in the 2- and 3-week pembrolizumab arms were fatigue (20.9%, 19.1%), diarrhea (16.9%, 14.4%), rash (14.7%, 13.4%), and pruritus (14.4%, 14.1%). All grade 3/4 AEs occurred in <1% of the pembrolizumab arms, except diarrhea (2.5% and 1.1%).

In the ipilimumab arm, the most common all-grade AEs were pruritus (25.4%), diarrhea (22.7%), fatigue (15.2%), and rash (14.5%). Grade 3/5 AEs occurred in <1% patients in the ipilimumab arm, except diarrhea (3.1%) and fatigue (1.2%). There was 1 patient death associated with ipilimumab treatment.

"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,” said Perlmutter.

For the second new indication, the KEYNOTE-002 study enrolled 540 patients with ipilimumab-refractory advanced melanoma. A majority of patients enrolled (83%) had M1c disease and 73% had received at least 2 prior systemic therapies.

Patients received pembrolizumab at 2 mg/kg (n = 180), 10 mg/kg (n = 181), or chemotherapy (n = 179). The chemotherapy utilized was investigator's choice and consisted primary of paclitaxel plus carboplatin, paclitaxel, carboplatin, dacarbazine, or temozolomide. Pembrolizumab was administered every 3 weeks.

The coprimary endpoints of the study were PFS and OS. The secondary endpoints of the study focused on ORR, duration of response (DOR), and safety, with responses assessed using RECIST 1.1 criteria.

Overall, following 410 PFS events, the risk of disease progression or death was reduced by 43% with pembrolizumab at 2 mg/kg (HR, 0.57; 95% CI 0.45—0.73; P <.0001) and 50% with pembrolizumab at 10 mg/kg (HR, 0.50; 0.39—0.64; P<.0001), compared with chemotherapy. Six-month PFS rates were 34%, 38%, and 16%, respectfully, with 9-month PFS rates of 24%, 29%, and 8%.

At the 2-mg/kg dose, the ORR with pembrolizumab was 21% with a median DOR not yet reached. At the analysis, 92% of responses were ongoing. In the 10-mg/kg arm, the ORR was 25% (DOR not yet reached) and 87% of patients remained in response. A statistical different in DOR was not seen between pembrolizumab arms (P = .21).

The ORR in the chemotherapy arm was 4%, the median DOR was 37 weeks, and 63% of responses were ongoing at the time of the analysis.

Treatment-related grade 3/4 AEs occurred in 11% of patients treated with the 2-mg/kg dose, 14% with 10-mg/kg, and 26% with chemotherapy.

The most frequently occurring grade 3/4 treatment-related AEs in the 2 mg/kg pembrolizumab group were fatigue, generalized edema, and myalgia (1% each). In the 10-mg/kg arm, the most common grade 3/4 AEs were hypopituitarism, colitis, diarrhea, decreased appetite, hyponatremia, and pneumonitis (1% each).

Among patients receiving chemotherapy, the grade 3/4 AEs most frequently observed were anemia (5%), fatigue (5%), neutropenia (4%), and leucopenia (4%).

The rates of serious adverse events were 8%, 11%, and 11%, respectively. Treatment discontinuation as a result of adverse events occurred in 3% of patients treated with the 2-mg/kg dose, 7% with 10-mg/kg, and 6% in those receiving chemotherapy. One treatment-related death was reported in the 2-mg/kg pembrolizumab arm compared with none with chemotherapy.

Pembrolizumab was previously approved by the FDA for patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor.

In November, the FDA approved the PD-1 inhibitor nivolumab (Opdivo) for the frontline treatment of patients with BRAF wild-type advanced melanoma. A supplemental application was also submitted to the FDA for frontline nivolumab in patients with BRAF V600 mutation—positive advanced melanoma; however, in November, the FDA issued a complete response letter to the manufacturer, Bristol-Myers Squibb, informing the company that additional data were needed for the application.


Robert C, Schachter J, Long GV, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015;372(26):2521-2532.

Ribas A, Puzanov I, Dummer R, et al. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015;16(8):908-918.

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