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Keytruda for the treatment of advanced melanoma


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. Pembrolizumab 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.

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.

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 Pembrolizumab compared to Ipilimumab ( Yervoy ) 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 Pembrolizumab 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 overall survival ( 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.

Pembrolizumab 10 mg/kg every two or three weeks showed superior overall survival compared to Ipilimumab ( hazard ratio, HR=0.63 [ 95% CI: 0.47, 0.83; p less than 0.001 ] and HR=0.69 [ 95% CI: 0.52, 0.90; p=0.004 ], respectively ).

Median progression-free survival 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 Pembrolizumab 10 mg/kg every two weeks, Pembrolizumab 10 mg/kg every three weeks and Ipilimumab, respectively.
For progression-free survival, both schedules for Pembrolizumab 10 mg/kg every two or three weeks resulted in superior outcomes compared to Ipilimumab ( HR=0.58 [ 95% CI: 0.46, 0.72; p less than 0.001 ] and hazard ratio: 0.58 [ 95% CI: 0.47, 0.72; p less than 0.001 ], respectively ).
Pembrolizumab every two or three weeks demonstrated a 42% reduction in the risk of disease progression or death as compared to Ipilimumab.

The ORR was 34% ( 95% CI: 28, 40 ) with Pembrolizumab 10 mg/kg every two weeks and 33% ( 95% CI: 27, 39 ) with Pembrolizumab 10 mg/kg every three weeks, as compared with 12% ( 95% CI: 8, 16 ) with Ipilimumab.
10 Pembrolizumab 10 mg/kg every two weeks and three weeks achieved partial response rates of 29% and 27%, respectively, and complete response rates of 5% and 6%, respectively; there was a 10% partial response rate and 1% complete response rate for Ipilimumab.
Among the 94 patients randomized to Pembrolizumab 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 Pembrolizumab 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% had PD-L1 negative melanoma, and 2% had unknown PD-L1 status ( positive: greater than or equal to 1% of tumor cells using an Investigational Use Only assay ).

BRAF mutations were reported in 36% of patients, of which 46% 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 Pembrolizumab versus 28% with Ipilimumab ), diarrhea ( 26% with Pembrolizumab ), rash ( 24% with Pembrolizumab vs 23% with Ipilimumab ), and nausea ( 21% with Pembrolizumab ).
Corresponding incidence rates are listed for Ipilimumab only for those adverse reactions that occurred at the same or lower rate than with Pembrolizumab.

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 Pembrolizumab.

Based on its mechanism of action, Pembrolizumab 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 Pembrolizumab.

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 has demonstrated Keytruda was superior to investigator’s choice chemotherapy.

KEYNOTE-002 is a multicenter, randomized controlled study of 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 Pembrolizumab.

Median progression-free survial 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 Pembrolizumab 2 mg/kg every three weeks ( n=180 ), Pembrolizumab 10 mg/kg every three weeks ( n=181 ) and chemotherapy ( n=179 ), respectively.
Doses of Pembrolizumab 2 mg/kg or 10 mg/kg every three weeks were superior compared to chemotherapy for the PFS primary endpoint ( HR=0.57 [ 95% CI: 0.45, 0.73; p less than 0.001 ] and HR=0.50 [ 95% CI: 0.39, 0.64; p less than 0.001 ], respectively ).
Pembrolizumab 2 mg/kg every three weeks demonstrated a 43% reduction in the risk of disease progression or death compared to chemotherapy.

There was no statistically significant difference between Pembrolizumab and chemotherapy in the interim overall survival analysis.

The ORR was 21% ( 95% CI: 15, 28 ) with Pembrolizumab 2 mg/kg every three weeks and 25% ( 95% CI: 19, 32 ) with Pembrolizumab 10 mg/kg every three weeks, as compared with 4% ( 95% CI: 2, 9 ) with chemotherapy.
2 Pembrolizumab 2 mg/kg and 10 mg/kg every three weeks achieved partial response rates of 19% and 23%, respectively, and complete response rates of 2% and 3%, respectively; there was a 4% partial response rate and no complete responses for chemotherapy.
Among the 38 patients randomized to Pembrolizumab 2 mg/kg with an objective response, response durations ranged from 1.3+ to 11.5+ months.
Among the 46 patients randomized to Pembrolizumab 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 Pembrolizumab ), pruritus ( 28% with Pembrolizumab vs. 8% with chemotherapy ), rash ( 24% with Pembrolizumab vs. 8% with chemotherapy ), constipation ( 22% with Pembrolizumab vs. 20% with chemotherapy ), nausea ( 22% with Pembrolizumab ), diarrhea ( 20% with Pembrolizumab vs. 20% with chemotherapy ), and decreased appetite ( 20% with Pembrolizumab ).
Corresponding incidence rates are listed for chemotherapy only for those adverse reactions that occurred at the same or lower rate than with Pembrolizumab. ( Xagena )

Source: Merck & Co, 2015

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