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.

Safety Profile

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. ■

References

1. U.S. Food and Drug Administration: Pembrolizumab (Keytruda) Checkpoint Inhibitor. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm526430.htm. Accessed November 8, 2016.

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.

3. Reck M, Rodriguez-Abreu D, Robinson AG, et al: Pembrolizumab versus chemotherapy for PD-L1–positive non–small-cell lung cancer. N Engl J Med. October 8, 2016 (early release online).

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.