Keytruda: a new hope for patients with molecular abnormality
For decades, cancer drugs have typically been approved and used to treat site-specific tumors like those of the brain, lung or breast. With the site-agnostic approach, “instead of the classical way of treating patients based on their tumor type, one can treat based on a genetic alteration”. Patients whose tumors are laden with the genetic defect have an abundance of abnormal proteins that look more foreign to immune cells, triggering them to search out and destroy the cancer cells. FDA’s first “site-agnostic” approval for a cancer drug (Keytruda) indicates a potential shift in cancer treatment approach with PD-1 inhibitors. Some of the inhibitors involved in this approach are:
Pembrolizumab (Merck): Pembrolizumab (Keytruda) is a humanized monoclonal antibody against PD-1. Keytruda is approved for multiple specific cancer like melanoma, NSCLC, bladder cancer and lymphoma etc and is also in clinical trials for multiple other indications. Recently, FDA approved Keytruda to treat tumors with genetic defects known as “microsatellite instability” or “mismatch repair” deficiencies. The FDA action was based on results from clinical trials on approximately 150 patients with the genetic defect. Nearly 40% of patients experienced significant tumor shrinkage. This also supports the concept of involvement of MSI and MMR and approach for treatment including them.
Nivolumab (BMS): Nivolumab (Opdivo) is a fully human immunoglobulin (Ig) G4 monoclonal antibody directed against PD-1 with immune checkpoint inhibitory activity. According to data from ASCO-17 the similar clinical activity between patients locally and centrally confirmed as microsatellite instability-H suggest local testing is appropriate for identifying the dMMR/MSI-H patients who may benefit from nivolumab monotherapy. Initial analysis demonstrated a manageable safety profile and clinical activity with the combination of nivolumab and ipilimumab in the treatment of patients with deficient DNA mismatch repair (dMMR)/high microsatellite instability (MSI-H) metastatic colorectal cancer.
Various other companies are also developing PD-1 inhibitors eg. PF-6801591 (Pfizer), BGB-A317 (BieGene), JS-001 (Shanghai Junshi), MEDI0680 (Medimmune), PDR-001 (Novartis), REGN-2810 (Regeneron), SHR-1210 (Jiangsu Hengrui) and TSR-042 (Tesaro) and are in various clinical phases. Boehringer is new in the PD-1 inhibitor space and has a monoclonal antibody BI-754091 in its pipeline. Currently BI-754091 is under clinical study of NSCLC, myeloma and solid tumors. Boehringer Ingelheim and Sarah Cannon Research Institute, the global cancer institute of HCA collaborated to develop BI-754091 and BI-754111 (anti-LAG-3) for the combination treatment of multiple cancers. With the approval of Keytruda based on a patient’s’ specific genetic traits, regardless of where in the body the disease originated, a new approach has been opened for other players also who are targeting site specific tumors with their PD-1 inhibitors.
By Dr. Rupesh Tyagi
Senior Research Analyst, Science and Research @ Innoplexus