Merck, known as MSD outside the United States and Canada, announced the FDA has approved Keytruda, Merck’s anti-PD-1 therapy, in combination with carboplatin and either paclitaxel or nab-paclitaxel, for the first-line treatment of patients with metastatic squamous non-small cell lung cancer based on results from the KEYNOTE-407 trial.
In the pivotal phase III trial of patients regardless of tumor PD-L1 expression status, KEYTRUDA in combination with chemotherapy (carboplatin and either paclitaxel or nab-paclitaxel) significantly improved overall survival, reducing the risk of death by 36 percent compared to chemotherapy alone (HR=0.64 [95% CI, 0.49, 0.85]; p=0.0017).
This approval marks the first time an anti-PD-1 regimen has been approved for the first-line treatment of squamous NSCLC regardless of tumor PD-L1 expression status.
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.
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 is the first anti-PD-1 approved in the first-line setting as both combination and monotherapy in certain patients with metastatic NSCLC. With this approval, all appropriate patients with metastatic squamous NSCLC and all appropriate patients with metastatic nonsquamous NSCLC and no EGFR or ALK genomic tumor aberrations are now eligible for a KEYTRUDA-based regimen as their first-line treatment option.
The approval was based on data from KEYNOTE-407, a randomized, double-blind, multicenter, placebo-controlled study. The key eligibility criteria for this study were metastatic squamous NSCLC, regardless of tumor PD-L1 expression status, and no prior systemic treatment for metastatic disease.
Patients with autoimmune disease that required systemic therapy within two years of treatment; a medical condition that required immunosuppression; or 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 and carboplatin every three weeks for four cycles, plus paclitaxel every three weeks for four cycles or nab-paclitaxel on Days 1, 8 and 15 of every three-week cycle for four cycles, followed by Keytruda 200 mg every three weeks; or placebo and carboplatin every three weeks for four cycles, plus paclitaxel every three weeks for four cycles or nab-paclitaxel on Days 1, 8 and 15 of every three-week cycle for four cycles, followed by placebo every three weeks.
Treatment with Keytruda or placebo continued until progression of disease, unacceptable toxicity, or a maximum of 24 months. Patients in the placebo arm were offered Keytruda as a single agent at the time of disease progression.
Primary efficacy outcome measures were OS as well as progression-free survival and objective response rate as assessed by blinded independent central review using RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of five target lesions per organ. An additional efficacy outcome measure was duration of response.
In KEYNOTE-407, there was a statistically significant improvement in OS, PFS and ORR in patients randomized to KEYTRUDA in combination with carboplatin and either paclitaxel or nab-paclitaxel compared with patients randomized to placebo with carboplatin and either paclitaxel or nab-paclitaxel.
In KEYNOTE-407, safety data are available for the first 203 patients who received KEYTRUDA and chemotherapy (n=101) or placebo and chemotherapy (n=102). The safety of KEYTRUDA in combination with carboplatin and either paclitaxel or nab-paclitaxel was investigated in 101 patients at the first interim analysis of KEYNOTE-407.
Keytruda was discontinued for adverse reactions in 15 percent of patients with no single type of adverse reaction accounting for the majority. Adverse reactions leading to interruption of Keytruda occurred in 43 percent of patients.
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. Keytruda 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.
