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FDA has approved Keytruda in metastatic non-small cell lung cancer for first-line treatment of patients whose tumors have high PD-L1 expression with no EGFR or ALK genomic tumor aberrations


The Food and Drug Administration ( FDA ) has approved Keytruda ( Pembrolizumab), an anti-PD-1 ( programmed death receptor-1 ) therapy, for the first-line treatment of patients with metastatic non-small cell lung cancer ( NSCLC ) whose tumors have high PD-L1 expression ( tumor proportion score [ TPS ] of 50% or more ) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.
With this new indication, Keytruda is now the only anti-PD-1 therapy to be approved in the first-line treatment setting for these patients.
In addition, the FDA approved a labeling update to include data from KEYNOTE-010 in the second-line or greater treatment setting for patients with metastatic NSCLC whose tumors express PD-L1 ( TPS of 1% or more ) 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 Keyruda.
In metastatic NSCLC, Keytruda is approved for use at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Pembrolizumab is a humanized monoclonal antibody that works by increasing the ability of the body’s immune system to help detect and fight tumor cells.
Pembrolizumab blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Immune-mediated adverse reactions occurred with Keytruda including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis. Based on the severity of the adverse reaction, Keytruda should be withheld or discontinued and corticosteroids administered when appropriate.
Keytruda can also cause severe or life-threatening infusion-related reactions. Monitor patients for signs and symptoms of infusion-related reactions and for grade 3 or 4 reactions, stop infusion and permanently discontinue Keytruda.
Based on its mechanism of action, Keytruda can cause fetal harm when administered to a pregnant woman. Female patients of reproductive potential should be advised of the potential hazard to a fetus.

Data supporting first-line approval

The approval was based on data from KEYNOTE-024, a randomized, open-label, phase 3 study evaluating Pembrolizumab monotherapy compared to standard-of-care ( SOC ) Platinum-containing chemotherapy for the treatment of patients with both squamous ( 18% ) and non-squamous ( 82% ) metastatic NSCLC.

The study enrolled patients who had not received prior systemic chemotherapy treatment for their metastatic disease and whose tumors had high PD-L1 expression ( TPS of 50% or more ) and with no EGFR or ALK aberrations.
The study randomized 305 patients to receive Pembrolizumab ( 200 mg every three weeks ) or investigator-choice standard-of- care Platinum-based chemotherapy ( Pemetrexed + Carboplatin, Pemetrexed + Cisplatin, Gemcitabine + Cisplatin, Gemcitabine + Carboplatin, or Paclitaxel + Carboplatin ).
Pemetrexed maintenance therapy was permitted for patients with non-squamous histologies.

The primary endpoint was progression-free survival ( PFS ); additional efficacy outcome measures were overall survival ( OS ) and overall response rate ( ORR ).

Based on an interim analysis demonstrating Pembrolizumab was superior compared to chemotherapy for both the primary endpoint of progression-free survival and the secondary endpoint of overall survival, the trial was stopped early in June 2016 to give patients still on chemotherapy the opportunity to receive Pembrolizumab.
Findings demonstrated that Pembrolizumab has reduced the risk of progression or death by 50% compared to chemotherapy ( hazard ratio, HR=0.50 [ 95% CI, 0.37, 0.68 ]; p less than 0.001 ).
Additionally, Pembrolizumab resulted in a 40% reduction in the risk of death compared to chemotherapy ( HR=0.60 [ 95% CI, 0.41, 0.89 ]; p=0.005 ).

Data supporting second-line labeling update

KEYNOTE-010 is a randomized, open-label, phase 2/3 trial evaluating ( 2 mg/kg [ n=344 ] or 10 mg/kg [ n=346 ] every three weeks ) compared to standard-of-care chemotherapy ( Docetaxel, 75 mg/m2 every three weeks [ n=343 ] ) in 1,033 patients with squamous ( 21% ) and non-squamous ( 70% ) metastatic NSCLC with all levels of PD-L1 expression ( TPS of 1% or more ) who had progressed following Platinum-containing chemotherapy and, if appropriate, targeted therapy for EGFR or ALK genomic tumor aberrations.
Additionally, results were reported in a subset of patients who had high PD-L1 expression ( TPS of 50% or more ) in the Pembrolizumab 2 mg/kg ( n=139 ), Pembrolizumab 10 mg/kg ( n=151 ), and chemotherapy cohorts ( n=152 ).
The primary endpoints were overall survival and progression-free survival. Additional efficacy measures included ORR and response duration.

Pembrolizumab has demonstrated superior overall survival versus Docetaxel in patients with all levels of PD-L1 expression. Based on exploratory analyses, higher overall survival was associated with higher PD-L1 expression level.

In KEYNOTE-010, treatment was discontinued for adverse reactions in 8% of the 682 patients receiving Pembrolizumab across both doses. The most common adverse event resulting in permanent discontinuation of Pembrolizumab was pneumonitis ( 1.8% ).
Adverse reactions leading to interruption of Pembrolizumab occurred in 23% of patients; the most common ( greater than or equal to 1% ) were diarrhea ( 1% ), fatigue ( 1.3% ), pneumonia ( 1% ), liver enzyme elevation ( 1.2% ), decreased appetite ( 1.3% ), and pneumonitis ( 1% ).
The most frequent adverse reactions ( reported in at least 10% of Pembrolizumab patients and occurring at the same or higher incidence than in the Docetaxel arm ) were decreased appetite ( 25% for Pembrolizumab vs. 23% for Docetaxel ), dyspnea ( 23% vs. 20% ), nausea ( 20% vs. 18% ), cough ( 19% vs. 14% ), rash ( 17% vs. 8% ), constipation ( 15% vs. 12% ), vomiting ( 13% vs. 10% ), arthralgia ( 11% vs. 9% ), back pain ( 11% vs. 8% ), and pruritus ( 11% vs. 3% ). Other clinically important adverse reactions occurring in patients receiving Pembrolizumab were fatigue ( 25% ), diarrhea ( 14% ), asthenia ( 11% ), and pyrexia ( 11% ).

PD-L1 Companion diagnostic for patients with metastatic NSCLC

The PD-L1 IHC 22C3 PharmDx kit was approved in 2015 by the FDA for use in detecting PD-L1, an immune-related biomarker expressed on some tumor cells. The diagnostic is intended to aid in identifying appropriate patients for treatment with Keytruda, including previously treated patients whose tumors have any level of PD-L1 expression ( TPS of 1% or more ) and previously untreated patients whose tumors have high levels of PD-L1 expression ( TPS of 50% or more ).
Tumors with a TPS of less than 1% are considered to have no PD-L1 expression. ( Xagena )

Source: Merck, 2016

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