On April 19, 2019, pembrolizumab was approved for use in combination with the small-molecule tyrosine kinase inhibitor axitinib for the first-line treatment of patients with advanced renal cell carcinoma.1,2
Supporting Efficacy Data
Approval was based on findings in the open-label phase III KEYNOTE-426 trial,2,3 in which 861 patients who had not received systemic therapy for advanced disease were randomly assigned to receive pembrolizumab at 200 mg every 3 weeks in combination with axitinib at 5 mg orally twice daily (n = 432) or sunitinib at 50 mg orally once daily for 4 weeks and then off treatment for 2 weeks (n = 429) with treatment continued until disease progression or unacceptable toxicity. Pembrolizumab was received for a maximum of 24 months.
Patients were enrolled irrespective of programmed cell death ligand 1 (PD-L1) tumor expression status. Patients with active autoimmune disease requiring systemic immunosuppression within the past 2 years were ineligible.
Pembrolizumab carries warnings/precautions for immune-mediated adverse reactions, infusion-related reactions, complications of allogeneic hematopoietic stem cell transplantation, and embryofetal toxicity.
Patients had a median age of 62 years (range = 26–90 years; 38% ≥ 65 years), 73% were male, 79% were white and 16% Asian, 19% and 80% of patients had a baseline Karnofsky performance score of 70 to 80 and 90 to 100, and patient distribution by International Metastatic Renal Cell Carcinoma Database Consortium risk categories was 31% favorable, 56% intermediate, and 13% poor.
In a prespecified interim analysis, overall survival was improved in the pembrolizumab/axitinib group vs the sunitinib group (hazard ratio [HR] = 0.53, P < .0001). Median overall survival was not reached in either group. Overall survival at 12 months was 90% in the pembrolizumab/axitinib group vs 78% in the sunitinib group. As assessed by blinded independent central review using Response Evaluation Criteria in Solid Tumors, version 1.1, median progression-free survival was 15.1 months vs 11.1 months (HR = 0.69, P = .0001). Overall confirmed response rates were 59% vs 36% (P < .0001).
How It Works
Binding of PD-L1 and PD-L2 to the programmed cell death protein 1 (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
In renal cell carcinoma, the recommended dose of pembrolizumab is 200 mg via intravenous infusion over 30 minutes every 3 weeks in combination with 5 mg of oral axitinib twice daily until disease progression, unacceptable toxicity, or for pembrolizumab, up to 24 months in patients without disease progression. When axitinib is used in combination with pembrolizumab, dose escalation of axitinib above the initial 5-mg dose may be considered at intervals of 6 weeks or longer.
No dose reductions of pembrolizumab are recommended. Treatment should be withheld or discontinued to manage adverse reactions. Pembrolizumab infusion should be interrupted or slowed for grade 1 or 2 infusion-related reactions and permanently discontinued for grade 3 or 4 reactions. Specific management guidelines for immune-mediated adverse events are provided in the warnings/precautions section of product labeling.
Pembrolizumab treatment should be withheld for the following, primarily immune-mediated, adverse reactions: grade 2 pneumonitis; grade 2 or 3 colitis; immune-mediated hepatitis in patients with hepatocellular carcinoma and aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 5 times upper limit of normal (ULN) if baseline < 2 times ULN, AST or ALT > 3 times baseline if baseline ≥ 2 times ULN, total bilirubin > 2.0 mg/dL if baseline less than 1.5 mg/dL, or total bilirubin > 3.0 mg/dL regardless of baseline level; immune-mediated hepatitis in patients without hepatocellular carcinoma with AST or ALT greater than 3 but no more than 5 times ULN or total bilirubin greater than 1.5 but no more than 3 times ULN; grade 3 or 4 endocrinopathies; grade 4 hematologic toxicity in patients with classical Hodgkin lymphoma or primary mediastinal large B-cell lymphoma; grade 2 nephritis; grade 3 skin reactions or suspected Stevens-Johnson syndrome or toxic epidermal necrolysis; and any other grade 2 or 3 immune-mediated adverse reaction, based on severity and type. Treatment can be resumed when adverse reactions recover to grade 0 or 1.
Adverse reactions for which pembrolizumab should be permanently discontinued include grade 3 or 4 or recurrent grade 2 pneumonitis or grade 4 colitis. Among patients with immune-related hepatitis and hepatocellular carcinoma, pembrolizumab should be discontinued for ALT or AST > 10 times ULN, Child-Pugh score ≥ 9, gastrointestinal bleeding suggestive of portal hypertension, new onset of clinically detectable ascites, or encephalopathy. Among those with immune-mediated hepatitis without hepatocellular carcinoma, the drug should be discontinued in cases without liver metastases if AST or ALT is > 5 times ULN or total bilirubin > 3 times ULN. In those with liver metastasis and grade 2 AST or ALT at baseline, the drug should be discontinued for an increase in AST or ALT of 50% or more relative to baseline that persists for ≥ 1 week.
In addition pembrolizumab should be permanently discontinued for grade 3 or 4 nephritis; grade 4 skin reactions or confirmed Stevens-Johnson syndrome or toxic epidermal necrolysis; other immune-mediated reactions of grade 3 based on the severity and type of reaction or grade 4 reactions; recurrent immune-mediated adverse reactions including recurrent grade 2 pneumonitis and other recurrent grade 3 or 4 events; inability to taper corticosteroid treatment; and persistent grade 2 or 3 adverse reactions (excluding endocrinopathy).
Product labeling provides information on dose modification of pembrolizumab and axitinib when used in combination. Axitinib product labeling should be consulted when the drugs are used in combination in this setting.
In KEYNOTE-426, the most common adverse events of any grade in the pembrolizumab/axitinib group (≥ 30%) were diarrhea (56% vs 45% in sunitinib group), fatigue or asthenia (52% vs 51%), hypertension (48% vs 48%), hepatotoxicity (39% vs 25%), hypothyroidism (35% vs 32%), and decreased appetite (30% vs 29%). The most common grade 3 or 4 adverse events included hypertension (24% vs 20%), hepatotoxicity (20% vs 4.9%), and diarrhea (11% vs 5%). An oral prednisone dose equivalent of ≥ 40 mg was given to 27% of patients in the pembrolizumab/axitinib group for immune-mediated adverse events.
Serious adverse events occurred in 40% of the pembrolizumab/axitinib group, with the most common being hepatotoxicity (7%), diarrhea (4.2%), and acute kidney injury (2.3%). Adverse events led to permanent discontinuation of either pembrolizumab or axitinib in 31% of patients (13% pembrolizumab only, 13% axitinib only, and 8% both drugs), with the most common causes being hepatotoxicity (13%), diarrhea/colitis (1.9%), acute kidney injury (1.6%), and cerebrovascular accident (1.2%). Fatal adverse reactions occurred in 3.3% of patients receiving pembrolizumab/axitinib, including three cases of cardiac arrest; two cases of pulmonary embolism; and one case each of cardiac failure, death due to unknown cause, myasthenia gravis, myocarditis, Fournier’s gangrene, plasma cell myeloma, pleural effusion, pneumonitis, and respiratory failure.
Pembrolizumab carries warnings/precautions for immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies (including hypophysitis, thyroid disorders, and type 1 diabetes), nephritis, skin adverse reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis, and other immune-mediated adverse reactions. The drug’s labeling also has warnings/precautions for infusion-related reactions, complications of allogeneic hematopoietic stem cell transplantation, and embryofetal toxicity.
Treatment of patients with multiple myeloma with a PD-1– or PD-L1–blocking antibody in combination with a thalidomide analog plus dexamethasone is not recommended outside of controlled clinical trials. Patients should be monitored for hepatic, renal, and thyroid function, as well as for hyperglycemia. Patients should be advised not to breastfeed during pembrolizumab/axitinib therapy.■
1. U.S. Food and Drug Administration: FDA approves pembrolizumab plus axitinib for advanced renal cell carcinoma. Available at www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-pembrolizumab-plus-axitinib-advanced-renal-cell-carcinoma. Accessed November 26, 2019.
2. Keytruda (pembrolizumab) injection for intravenous use prescribing information, Merck and Co, April 2019. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2019/125514Orig1s054lbl.pdf. Accessed November 26, 2019.
3. Rini BI, Plimack ER, Stus V, et al: Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 380:1116-1127, 2019.