Combination Therapy With Pembrolizumab in Metastatic Nonsquamous NSCLC


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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 May 10, 2017, pembrolizumab (Keytruda) was granted accelerated approval for use in combination with pemetrexed (Alimta) and carboplatin for treatment of patients with previously untreated metastatic nonsquamous non–small cell lung cancer (NSCLC).1,2

Supporting Efficacy Data

Approval was based on findings in a cohort of the multicohort phase II KEYNOTE-021 study,3 in which 123 patents with locally advanced or metastatic disease were randomized to receive open-label pembrolizumab at 200 mg every 3 weeks combined with pemetrexed and carboplatin for 4 cycles followed by pembrolizumab for a maximum of 24 months (n = 60) or pemetrexed/carboplatin alone (n = 63). At investigator’s discretion, patients in both groups could receive maintenance pemetrexed.

Combination Therapy for Nonsquamous Lung Cancer

  • Pembrolizumab (Keytruda) was granted accelerated approval for use in combination with pemetrexed (Alimta) and carboplatin for treatment of patients with previously untreated metastatic nonsquamous non–small cell lung cancer (NSCLC).
  • The recommended dose of pembrolizumab in this setting is 200 mg via intravenous infusion over 30 minutes every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Randomization was stratified by programmed cell death ligand 1 (PD-L1) tumor expression (tumor proportion score < 1% vs ≥ 1%). Patients with autoimmune disease requiring systemic therapy within the past 2 years, those with a medical condition requiring immunosuppression, or those who had received more than 30 Gy of thoracic radiation within 26 weeks were ineligible for the study.

Patients had a median age of 64 years, 61% were female, 87% were white and 8% were Asian, an Eastern Cooperative Oncology Group performance status was 0 or 1 in 97%, 97% had metastatic disease, 12% had brain metastases, 36% had tumor PD-L1 expression tumor proportion score < 1%, and no patients had sensitizing epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic aberrations.

The overall response rate was 55% in the pembrolizumab group vs 29% in the control group (all partial responses; P = .0032). The proportion of responders with response ≥ 6 months was 93% vs 81%. Median progression-free survival was 13.0 months vs 8.9 months (hazard ratio = 0.53, P = .0205). 

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 ligands, 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 this setting is 200 mg via intravenous infusion over 30 minutes every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. When administered in combination with chemotherapy, pembrolizumab should be given prior to chemotherapy when given on the same day.

OF NOTE

Pembrolizumab carries warnings/precautions for immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, other immune-mediated adverse reactions.

Pembrolizumab treatment should be withheld for grade 2 pneumonitis, grade 2 or 3 colitis, grade 3 or 4 endocrinopathies, grade 4 hematologic toxicity in patients with classical Hodgkin lymphoma, 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 (ULN), 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 grade 3 or 4 infusion-related reactions, any life-threatening adverse reaction (excluding endocrinopathies controlled with hormone replacement therapy or hematologic toxicity in patients with classical Hodgkin lymphoma), 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 ULN, 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

The most common adverse events of any grade in the pembrolizumab group were fatigue (71% vs 50% in control group), nausea (68% vs 56%), constipation (51% vs 37%), rash (42% vs 21%), and dyspnea (39% vs 21%). The most common grade 3 or 4 adverse events were fatigue (3.4% vs 0%) and dyspnea (3.4% vs 0%). The most common grade 3 or 4 laboratory abnormalities were increased lymphocytes (23% vs 28%), decreased hemoglobin (17% vs 19%), decreased neutrophils (14% vs 8%), decreased platelets (9% vs 10%), and hyperglycemia 9% vs 5%).

Serious adverse events occurred in 41% vs 28% of patients. Adverse events led to interruption of pembrolizumab treatment in 39%, most commonly due to fatigue (8%), decreased neutrophil count (8%), anemia (5%), dyspnea (3.4%), and pneumonitis (3.4%). Pembrolizumab was discontinued due to adverse events in 10%, most commonly due to acute kidney injury (3.4%).

Pembrolizumab carries warnings/precautions for immune-mediated pneumonitis, immune-mediated colitis, immune-mediated hepatitis, immune-mediated endocrinopathies (including hypophysitis, thyroid disorders, and type I diabetes), immune-mediated nephritis, other immune-mediated adverse reactions (in donor organ recipients, the benefit of treatment should be considered vs the risk of possible organ rejection), infusion-related reactions, complications of allogeneic hematopoietic stem cell transplantation, and embryofetal toxicity. Patients should be monitored for hepatic, renal, and thyroid function and for hyperglycemia. Breastfeeding women should discontinue treatment or breastfeeding while receiving pembrolizumab. ■

REFERENCES

1. U.S. Food and Drug Administration: Pembrolizumab (Keytruda) 5-10-2017. Available at https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm558048.htm. Accessed May 24, 2017.

2. Keytruda (pembrolizumab) injection for intravenous use prescribing information, Merck Sharp & Dohme Corp, May 2016. Available at https://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pd. Accessed May 24, 2017.

3. Langer CJ, et al: Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer. Lancet Oncol 17:1497-1508, 2016.



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