Adjuvant Immunotherapy after RC improves Disease Free Survival - CheckMate-274

3 weeks 4 days ago #60697 by joea73
For muscle-invasive bladder cancer (MIBC) patients, neoadjuvant chemotherapy (NAC) has become the standard protocol before the surgery (RC) to remove the bladder to reduce recurrence (metastasis) and to improve the survival rate.  But, some
patients cannot complete NAC due to its side effects, and some patients will have RC without NAC for various reasons.  The disease-free (without metastasis) survival (DFS) for those who had RC without NAC is 40%.  The clinical trial CheckMate-274 ( NCT026324090, which started in 2016, has shown an improvement in DFS of the patients who did not have NAC before RC but had adjuvant immunotherapy.    Especially, those with PD-L1 expression (>= 1%) had improved DFS significantly from 40% to 60%.  Even those without PD-L1 expression (<1%), there was improved DFS.  

The clinical trial had 709 patients.  Of 709, 353 patients were administered into the vein with immunotherapy drug Nivolumab (also called Opdivo by Ono pharmaceutical & Bristol-Myers Squibb), and 356 patients received placebo (saline - saltwater) into
the vein. 

In terms of the side effects, grade 3 or 4 treatment-related adverse events occurred 17.9% among the patients who had received Nivolumab and 7.2% among those who had received placebo.  

The link to the announcement is below.

One of the hallmarks of cancer cells is their ability to disguise and prevents our immune system to kill cancer cells.  One such disguise is the PD-L1 ligand (a protein on the surface of the cancer cell).   Bladder cancer cells are known to produce antigens (some alerting signal), which our immune system recognizes and sends T-cells that recognize the cancer cells with the antigens and kill it.  But, when the cancer cells express (put on the surface of the cell) the protein called PD-L1 (Program Death Ligand 1), the dispatched T-cells do not kill the cancer cells.  T-cells have the protein called PD-1(Program Death -1). When PD-1 on T-cells touches PD-L1 on the cancer cells, T-cells do not kill the cancer cells even if the cancer cells are in front of the T-cells.  The immunotherapy drug Nivolumab will enable T-cells to kill the cancer cells by binding to (covering over) PD-1 protein on the T-cells so T-cells see the cancer cells.    Please note that PD-1 and PD-L1 are also important proteins to prevent T-cells to attack normal cells.   The cancer cells had learned (evolved) to survive by preventing to be norma cells in front of T-cells by showing PD-L1 as its own defense mechanism.   

PD-L1 expression tells what percentage of the cancer cells were detected with PD-L1 under a microscope.   PD-L1 >= 1% means there was at least one cancer cell of 100 cancer cells. 

Nivolumab ( the trade name Opdivo by Ono/BMS) is a PD-1 immune checkpoint inhibitor (blocker) drug.  Pembrolizumab (Keytruda by MERCK) is also a PD-1 immune checkpoint inhibitor.  They are very similar.  As a matter of Merck was sued for patent infringement by Ono/BMS and settled the case in 2017 by agreeing Merck will make an initial payment of $625 million to Bristol and Japan’s Ono. The company will also pay a 6.5 percent royalty rate on Keytruda sales from January 2017 to December 2023,
and a 2.5 percent rate for the subsequent three years.  Bristol will get 75 percent of the royalties and Ono will get the rest.   Also, Ono was sued by the 2018 Nobel prize winner Dr. Honjo for the discovery of the foundation of immunotherapy and helped Ono / BMS to develop the first immunotherapy drug Nivolumab (Opdivo), for $200 million.   I have thought it is an interesting background story. 

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