The US Food and Drug Administration (FDA) today granted accelerated approval to an immunotherapy drug, Keytruda or Pembrolizumab, for patients with advanced, metastatic non-small cell lung cancer (NSCLC) whose disease has progressed after other treatments (chemotherapy or targeted therapy) and whose tumors express the protein PDL1. Based on the FDA approval, patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving Pembrolizumab.
PDL1 COMPANION DIAGNOSTIC TEST: Pembrolizumab that is manufactured by Merck, has been approved for use with a companion diagnostic, the immunohistochemistry (IHC) test that looks for the presence of the PDL1 protein- the PDL1 IHC 22C3 pharmDx test. This is the first companion diagnostic test that has been approved to check for the expression/presence of the PDL1 protein in NSCLC tumors. This is an important advance, because the use of the companion diagnostic test will potentially help to identify NSCLC patients most likely to respond to this therapy and benefit from it.
Per Merck, this companion diagnostic will be available commercially to laboratories in the U.S. through Dako North America Inc., and testing using the assay will be available at U.S. reference laboratories including Laboratory Corporation of America® Holdings (LabCorp®), Quest Diagnostics, and GE Healthcare Clarient Diagnostic Services.
IMMUNOTHERAPY FOR LUNG CANCER: Pembrolizumab is the second immunotherapeutic to be approved for non-small cell lung cancer in the past few months by the FDA, the first being Opdivo or Nivolumab that was approved by the FDA in March 2015. Both Nivolumab and Pembrolizumab have a similar mechanism of action. One difference, however, is that Nivolumab has been approved only for patients with advanced, metastatic squamous non-small cell lung cancer, while Pembrolizumab has been approved for both subsets of NSCLC- squamous and non-squamous. Another difference is that Pembrolizumab may only be used for patients whose tumors are PDL1 positive based on the results of the FDA approved test, while Nivolumab is PDL1-agnostic.
MECHANISM OF ACTION: Pembrolizumab works by blocking the interaction of the PD1 (Programmed Death receptor 1) protein with its ligand, the PDL1 (Programmed Death Ligand 1) protein. This interaction of PD1 with PDL1 is used by the immune system to prevent attack on the body’s own cells. Cancer cells usurp this mechanism to avoid immune attack and grow unchecked. By blocking the PD1-PDL1 interaction, as is achieved by the new immunotherapeutic drugs such as Nivolumab and Pembrolizumab, the immune system is able to recognize cancer cells and mount an attack against them.
ADMINISTRATION: The FDA has approved the use of Pembrolizumab in the United States at a dose of 2 mg/kg administered as an intravenous infusion over 30 minutes every three weeks for the treatment of patients with metastatic NSCLC patients whose tumors express PD-L1 with disease progression on or after platinum-containing chemotherapy, or, if appropriate, targeted therapy.
CLINICAL TRIAL RESULTS: The accelerated FDA approval was based on a multicenter, open-label multi-cohort, clinical trial, the KEYNOTE-001 study that evaluated Pembrolizumab in a cohort of 280 patients with metastatic NSCLC that had progressed following platinum-containing chemotherapy, and if appropriate, targeted therapy for EGFR (epidermal growth factor receptor) or ALK (anaplastic lymphoma kinase) mutations and any evidence of PD-L1 expression by a clinical trial immunohistochemistry assay.
In the KEYNOTE-001 trial, Pembrolizumab demonstrated an overall response rate of 41 percent (n-25/61) in patients with a PDL1 expression score of 50 percent or more. According to Merck, 84% (n=21/25) of the patients who responded had ongoing responses, including 11 patients with patients with ongoing responses of six months or longer.
SIDE EFFECTS: Most common side effects observed in the clinical trial were fatigue, decreased appetite, dyspnea, and cough. However, it is important to note that immunotherapeutic agents may be associated with immune-mediated side effects in the lungs, colon and hormone-producing glands. Immune-mediated adverse reactions observed with Pembrolizumab in the KEYNOTE-001 trial included pneumonitis, colitis, hepatitis, hypophysitis, hyperthyroidism, hypothyroidism, type 1 diabetes mellitus, and nephritis. Based on the severity of the adverse reaction, Pembrolizumab should be withheld or discontinued and corticosteroids should be administered. Based on its mechanism of action, Pembrolizumab 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.
It is important to note that Pembrolizumab has been approved by the FDA under its accelerated approval program, that ensures promising therapies are available to patients sooner. Pembrolizumab’s accelerated approval by the FDA is based on the tumor response rate and durability of response seen in non-small lung cancer patients treated with Pembrolizumab in the KEYNOTE-001 trial. An improvement in survival or disease-related symptoms has not yet been established. Continued approval for Pembrolizumab in this indication is contingent upon verification and description of clinical benefit in the confirmatory trials that are ongoing.
PRICE: Merck has shared that the price of Pembrolizumab for health insurers and other payers is approximately $12,500 per month, or ~$150,00 per year.
ACCESS: Merck has programs that ensure patients who are prescribed Pembrolizumab have access to the therapy. The Merck Access Program provides reimbursement support for eligible patients receiving Pembrolizumab, including help with out-of-pocket costs and co-pay assistance. Merck also offers financial assistance for eligible patients who are uninsured through their patient assistance program. More information is available by calling 1-855-257-3932 or visiting www.merckaccessprogram-keytruda.com.
GOING FORWARD: This is a great advance and another win for lung cancer patients, who now have two new immunotherapeutic drugs in their arsenal to tackle this disease! Pembrolizumab is also being evaluated in multiple Phase 3 clinical trials in small cell lung cancer and other disease indications. Harnessing the power of the body’s own immune system has shown promise in treating several cancers in addition to lung cancer, such as melanoma. On Thursday, the FDA approved the use of a combination of two immunotherapeutic drugs, Opdivo and Yervoy for the treatment of melanoma, a first in the use of immunotherapeutic combinations. This combination is being evaluated in lung cancer as well.