The U.S. Food and Drug Administration ( FDA ) has approved an expanded label for Keytruda, an anti-PD-1 therapy, in combination with Pemetrexed ( Alimta ) and Platinum chemotherapy for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer ( NSCLC ), with no EGFR or ALK genomic tumor aberrations, based on results of the KEYNOTE-189 trial.
In the pivotal, phase 3 KEYNOTE-189 trial of patients regardless of PD-L1 tumor expression status, Keytruda in combination with Pemetrexed and Platinum chemotherapy demonstrated a statistically significant and clinically meaningful improvement in overall survival ( OS ) ( hazard ratio, HR=0.49 [ 95% CI, 0.38-0.64 ]; p less than 0.00001 ), reducing the risk of death by half compared to chemotherapy alone.
The study also showed a significant improvement in progression-free survival ( PFS ) compared to chemotherapy alone ( HR=0.52 [ 95% CI, 0.43-0.64 ]; p less than 0.00001 ).
Immune-mediated adverse reactions, which may be severe or fatal, can occur with Keytruda, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, severe skin reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplantation ( HSCT ).
Based on the severity of the adverse reaction, Keytruda should be withheld or discontinued and corticosteroids administered if appropriate.
Keytruda can also cause severe or life-threatening infusion-related reactions.
Based on its mechanism of action, Keytruda can cause fetal harm when administered to a pregnant woman.
Keytruda in combination with Pemetrexed and Carboplatin was first approved in 2017 under the FDA’s accelerated approval process for the first-line treatment of patients with metastatic nonsquamous NSCLC, based on tumor response rates and progression-free survival data from the phase 2 study ( KEYNOTE-021, Cohort G1 ).
In accordance with the accelerated approval process, continued approval was contingent upon verification and description of clinical benefit, which has now been demonstrated in KEYNOTE-189 and has resulted in the FDA converting the accelerated approval to full ( regular ) approval.
Keytruda is the first anti-PD-1 approved in the first-line setting as both combination and monotherapy in certain patients with metastatic NSCLC.
The approval was based on data from KEYNOTE-189, a phase 3, randomized, multicenter, double-blind, active-controlled trial in systemic-therapy naïve patients with metastatic NSCLC, regardless of PD-L1 tumor expression status and with no EGFR or ALK genomic tumor aberrations.
Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or patients who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible.
Patients were randomized to receive Keytruda 200 mg, Cisplatin or Carboplatin, and Pemetrexed intravenously Q3W for 4 cycles followed by Keytruda 200 mg for up to 24 months and Pemetrexed Q3W ( n=410 ); or Cisplatin or Carboplatin and Pemetrexed intravenously Q3W for 4 cycles followed by Pemetrexed Q3W ( n=206 ).
Treatment continued until progression of disease or unacceptable toxicity.
Primary efficacy outcome measures were overall survival ( OS ) and progression-free survival ( PFS ) assessed by blinded independent central review ( BICR ) per RECIST v1.1 ( modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ ). Secondary efficacy outcome measures were overall response rate ( ORR ) and duration of response ( DOR ).
Patients receiving chemotherapy and Pemetrexed who experienced disease progression could cross over to receive Keytruda as monotherapy.
In KEYNOTE-189, safety was evaluated in 405 patients who received Keytruda in combination with Pemetrexed and Platinum chemotherapy and 202 patients who received placebo, Pemetrexed, and Platinum chemotherapy.
Keytruda was discontinued for adverse reactions in 20% of patients. The most common adverse reactions resulting in permanent discontinuation of Keytruda were pneumonitis ( 3% ) and acute kidney injury ( 2% ).
Adverse reactions leading to the interruption of Keytruda occurred in 53% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of Keytruda ( greater than or equal to 5% ) were neutropenia ( 13% ), asthenia / fatigue ( 7% ), anemia ( 7% ), and thrombocytopenia ( 5% ).
Adverse reactions of any grade occurring in at least 20% of patients receiving Keytruda in combination with Pemetrexed and Platinum chemotherapy were nausea ( 56% ), fatigue ( 56% ), constipation ( 35% ), diarrhea ( 31% ), decreased appetite ( 28% ), rash ( 25% ), vomiting ( 24% ), cough ( 21% ), dyspnea ( 21% ), and pyrexia ( 20% ).
Pembrolizumab, the active substance in Keytruda, is an anti-PD-1 therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells.
Pembrolizumab is a humanized monoclonal antibody that 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. ( Xagena )
Source: Merck, 2018