In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.
On December 18, 2015, approval of the programmed cell death protein 1 (PD-1) inhibitor pembrolizumab (Keytruda) was expanded to include initial treatment of patients with unresectable or metastatic melanoma.1,2 The expanded approval was based on clinical benefit of pembrolizumab in a phase III trial in ipilimumab (Yervoy)-naive patients, with additional evidence of benefit in ipilimumab-refractory disease being provided by a randomized phase II trial.3,4 Prior approval had been limited to patients with disease progression following treatment with ipilimumab and, in BRAF V600 mutation–positive patients, treatment with a BRAF inhibitor, and was based on response rate and duration.
Supporting Efficacy Data
In a phase III trial (study 1),2,3 834 ipilimumab-naive patients with unresectable or metastatic melanoma who had received no more than one line of prior systemic therapy were randomized 1:1:1 to receive pembrolizumab at 10 mg/kg every 2 weeks (n = 278) or 10 mg/kg every 3 weeks (n = 277) until disease progression or unacceptable toxicity or ipilimumab at 3 mg/kg every 3 weeks for four doses unless discontinued earlier for disease progression or unacceptable toxicity (n = 256). Patients had a median age of 62 years, 60% were male, 66% had no prior systemic therapy for metastatic disease, 80% had PD-1 ligand (PD-L1)–positive melanoma, 65% had stage M1c disease, 68% had normal lactate dehydrogenase (LDH), 36% had BRAF mutation–positive disease, and 9% had a history of brain metastases. Prior systemic therapy included a BRAF inhibitor in 15%, chemotherapy in 13%, and immunotherapy in 6%.
Overall survival was significantly improved in both the every-2-week (hazard ratio [HR] = 0.63, P < .001) and every-3-week (HR = 0.69, P = .004) pembrolizumab groups vs the ipilimumab group; median overall survival was not reached in the pembrolizumab groups. Median progression-free survival was 5.5 months (HR = 0.58, P < .001) and 4.1 months (HR = 0.58, P < .001) vs 2.8 months. Overall response rates were 34% and 33 % vs 12%. Median response durations were not reached in any group.
In a randomized phase II study (study 2),2,4 528 patients with disease refractory to ipilimumab and a BRAF inhibitor if BRAF V6000 mutation–positive were randomized 1:1:1 to receive pembrolizumab at 2 mg/kg (n = 178) or 10 mg/kg (n = 179) every 3 weeks or investigator’s choice of chemotherapy (n = 171). Chemotherapy consisted of dacarbazine in 26%, temozolomide in 25%, paclitaxel and carboplatin in 25%, paclitaxel in 16%, and carboplatin in 8%. Patients had a median age of 62 years, 61% were male, 98% were white, 41% had elevated LDH, 83% had stage M1c stage disease, 73% had received at least two prior therapies for advanced/metastatic disease (ipilimumab in 100%, BRAF inhibitor in 25%), and 15% had a history of brain metastasis.
Median progression-free survival was 2.9 months (95% confidence interval [CI] = 2.8–3.8 months) in the pembrolizumab 2-mg/kg group (HR = 0.57, P < .001) and 2.9 months (95% CI = 2.8–4.7 months) in the 10-mg/kg group (HR = 0.50, P < .001) vs 2.7 months (95% CI = 2.5–2.8 months) in the control group. Overall, 55% of the control group received pembrolizumab after disease progression. No significant differences in overall survival were observed among either pembrolizumab group and the control group at interim analysis. Objective response rates were 21% and 25% vs 4%.
How It Works
Binding of PD-L1 and PD-L2 to the PD-1 receptor found on T cells inhibits T-cell proliferation and cytokine production. Pembrolizumab is an anti–PD-1 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, thereby releasing PD-1 pathway–mediated inhibition of the immune response, including antitumor immune response. Upregulation of PD-1 ligands is observed in some tumors, and signaling through this pathway can contribute to inhibition of active T-cell tumor immune surveillance. In syngeneic mouse models, inhibition of PD-1 activity resulted in decreased tumor growth.
How It Is Used
The recommended dose of pembrolizumab is 2 mg/kg via intravenous (IV) infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity.
Pembrolizumab infusion should be stopped and treatment permanently discontinued for grade 3 or 4 infusion-related reactions. Treatment should be withheld for grade 2 pneumonitis, grade 2 or 3 colitis, grade 3 or 4 endocrinopathies, grade 2 nephritis, aspartate transaminase (AST) or alanine transaminase (ALT) > 3 to 5 times or total bilirubin > 1.5 to 3 times the upper limit of normal, and any other severe or grade 3 treatment-related adverse reaction. Treatment can be resumed when adverse reactions recover to grade 0 or 1.
Pembrolizumab should be permanently discontinued for any life-threatening adverse reaction (excluding endocrinopathies controlled with hormone replacement therapy), grade 3 or 4 pneumonitis or recurrent grade 2 pneumonitis, grade 3 or 4 nephritis, AST or ALT > 5 times or total bilirubin > 3 times the upper limit of normal, AST or ALT increases of ≥ 50% in patients with liver metastasis who began treatment with grade 2 increased AST or ALT, grade 3 or 4 infusion-related reactions, inability to reduce corticosteroid dose to ≥ 10 mg/d of prednisone or its equivalent within 12 weeks, persistent grade 2 or 3 adverse reactions (excluding endocrinopathies controlled with hormone replacement therapy) that do not recover to grade 0 or 1 within 12 weeks of the last dose, and any recurrent severe or grade 3 treatment-related adverse reaction.
No dose adjustment is needed for patients with renal impairment. No dose adjustment is needed for patients with mild hepatic impairment; the drug has not been studied in patients with moderate or severe hepatic impairment.
Among 1,567 patients with unresectable or metastatic melanoma who received pembrolizumab at 2 mg/kg every 3 weeks or 10 mg/kg every 2 or 3 weeks in three clinical trials, the most serious risks were immune-mediated adverse reactions, including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis. Other clinically significant immune-mediated adverse reactions included arthritis, exfoliative dermatitis, bullous pemphigoid, uveitis, myositis, Guillain-Barré syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, and inflammatory foci in brain parenchyma resulting in partial seizures.
In study 1, adverse events were similar in the 10 mg/kg-every-2-week and 10 mg/kg-every-3-week groups. The most common adverse events of any grade in pembrolizumab patients were fatigue (28% vs 28% in the ipilimumab group), rash (24% vs 23%), and arthralgia (18% vs 10%); grade 3 or 4 adverse events included fatigue (0.9% vs 3.1%), back pain (0.9% vs 0.8%), and dyspnea (0.9% vs 0.8%). The most common grade 3 or 4 lab abnormalities were hyponatremia (4.6% vs 7.0%) and hyperglycemia (4.2% vs 3.8%). Adverse events led to interruption of pembrolizumab in 21% of patients, with the most common cause being diarrhea (2.5%), and to treatment discontinuation in 9%, with the most common causes being colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%).
In study 2, adverse events were similar in the pembrolizumab 2-mg/kg and 10-mg/kg groups. The most common adverse events of any grade in pembrolizumab patients were pruritus (28% vs 8% in the control group), rash (24% vs 8%), and constipation (22% vs 20%). Grade 3 or 4 adverse events included asthenia (2.0% vs 1.8%) and abdominal pain (1.7% vs 1.2%). The most common grade 3 or 4 lab abnormalities were increased alkaline phosphatase (3.1% vs 1.9%) and increased AST (2.2% vs 0.6%). Adverse events led to interruption of pembrolizumab in 14% of patients, with the most common causes being dyspnea (1%), diarrhea (1%), and maculopapular rash (1%), and to treatment discontinuation in 12%, with the most common causes being general physical health deterioration (1%), asthenia (1%), dyspnea (1%), pneumonitis (1%), and generalized edema (1%).
Pembrolizumab carries warnings/precautions for immune-mediated adverse reactions, including immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies (including hypophysitis, thyroid disorders, and type 1 diabetes), nephritis, infusion-related reactions, and embryofetal toxicity. Hepatic, renal, and thyroid function should be routinely monitored. Breastfeeding women should discontinue breastfeeding while receiving pembrolizumab. ■
Report Adverse Events
Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).