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 October 24, 2016, pembrolizumab (Keytruda) was approved for use in patients with metastatic non–small cell lung cancer (NSCLC) whose tumors have high programmed cell death ligand 1 (PD-L1) expression (tumor proportion score ≥ 50%) as determined by a U.S. Food and Drug Administration (FDA)-approved test, with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations and no prior systemic chemotherapy for metastatic NSCLC.1,2 This is the first FDA approval of a checkpoint inhibitor for the first-line treatment of lung cancer.
The approval also expands the indication in second-line treatment to patients with metastatic NSCLC whose tumors express PD-L1 (tumor proportion score ≥ 1%) as determined by an FDA-approved test with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving pembrolizumab. This approval converts the prior accelerated approval in the second-line treatment of metastatic NSCLC patients to regular approval.
Supporting Efficacy Data
Approval was based on the results of two randomized trials showing significant improvements in progression-free survival and overall survival among patients receiving pembrolizumab vs chemotherapy.
In the phase III KEYNOTE-024 trial,2,3 305 patients who had received no prior treatment for metastatic NSCLC, with a tumor proportion score ≥ 50% and no sensitizing EGFR mutations or ALK translocations, were randomly assigned to receive pembrolizumab at 200 mg every 3 weeks (n = 154) or investigator’s choice of therapy from among 5 platinum-based regimens for 4 to 6 cycles (n = 151). Median progression-free survival was 10.3 months with pembrolizumab vs 6.0 months with chemotherapy (hazard ratio [HR] = 0.50, P < .001). A prespecified interim analysis showed significant improvement in overall survival with pembrolizumab (median not reached in either group, HR = 0.60, P < .005).
In the phase II/III KEYNOTE-010 trial,2,4 1,033 previously treated patients with a tumor proportion score ≥ 1% were randomized 1:1:1 to receive pembrolizumab at 2 mg/kg (n = 344), pembrolizumab at 10 mg/kg (n = 346), or docetaxel at 75 mg/m² (n = 343) every 3 weeks. Median overall survival was 10.4 months in the 2-mg/kg pembrolizumab group (HR = 0.71, P < .001) and 12.7 months in the 10-mg/kg pembrolizumab group (HR = 0.61, P < .001) vs 8.5 months in the docetaxel group.
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
The recommended dose of pembrolizumab in NSCLC is 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.
Pembrolizumab 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 infusion should be stopped and treatment permanently discontinued for grade 3 or 4 infusion-related reactions. 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% persisting for ≥ 1 week in patients with liver metastasis who began treatment with grade 2 increased AST or ALT, 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.
Adverse event data in labeling for the NSCLC indications are from the trial in previously treated patients. The adverse event profile was similar for the 2-mg/kg and 10-mg/kg dose, with the summary safety results therefore being provided in a pooled analysis among the 682 pembrolizumab patients.
The most common adverse events of any grade in pembrolizumab recipients were fatigue (25%), decreased appetite (25% vs 23% in docetaxel group), dyspnea (23% vs 20%), and nausea (20% vs 18%). The most common grade 3 or 4 adverse events included dyspnea (3.7% vs 2.6%). The most common grade 3 or 4 laboratory abnormalities were increased alkaline phosphatase (3.0% vs 0.7%) and increased ALT (2.7% vs 0.4%). Rare but serious adverse events in pembrolizumab patients included immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis.
Adverse events led to treatment interruption in 23% of pembrolizumab patients (due to diarrhea, fatigue, pneumonia, liver enzyme elevation, decreased appetite, and pneumonitis in 1.0% to 1.3% each) and to treatment discontinuation in 8%, with the most common cause being pneumonitis (1.8%).
Pembrolizumab carries warnings/precautions for immune-mediated adverse reactions, including immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies (including hypophysitis, thyroid disorders, and type 1 diabetes), and nephritis; infusion-related reactions; and embryofetal toxicity. Hepatic, renal, and thyroid function should be routinely monitored. Women who are breastfeeding should discontinue breastfeeding during pembrolizumab treatment. ■
2. Keytruda (pembrolizumab) injection for intravenous use prescribing information, Merck Sharp & Dohme Corp, October 2016. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2016/125514s012lbl.pdf. Accessed November 8, 2016.
4. Herbst RS, Baas P, Kim DW, et al: Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): A randomised controlled trial. Lancet 387:1540-1550, 2016.