Some of the most successful approaches to immuno-oncology have dealt with inhibition of the immune checkpoints expressed on cancer cells. These immune checkpoint inhibitor drugs include Keytruda and Opdivo, two of the most popular immunotherapies on the market. Keytruda has been approved as a treatment for metastatic melanoma and non-small cell lung cancer, as well as head and neck squamous cell cancer. Opdivo is approved to treat metastatic melanoma, renal cell carcinoma, and urothelial carcinoma. However, the indications for these drugs continue to grow as clinical trials prove them effective (at least in some cases) at treating situations with few other viable treatment options.
FDA Approves Opdivo for Liver Cancer Therapy
The first line of treatment for hepatocellular carcinoma—the most common form of liver cancer—is Nexavar, although not all patients will respond to this drug. However, the US Food and Drug Administration (FDA) recently approved Opdivo for use in patients who have not responded to Nexavar. The approval was granted through the accelerated process after a Phase I/II trial demonstrated favorable tumor response rate and durability for the drug. Due to the nature of this approval, continued use of Opdivo for treating liver cancer will depend on additional data about the drug and its effectiveness. The approval was likely based, at least in part, on the fact that patients with advanced-stage hepatocellular carcinoma have very few other options.
The data that the FDA used to justify its approval came from the multicenter CheckMate-040 trial, which is an open-label investigation sponsored by Opdivo’s manufacturer. The study involves 154 patients, of which 22 patients responded to the drug. Three of the patients actually experienced eradication of the liver tumor. Furthermore, the majority of participants had a sustained response for more than a year. The drug has a relatively manageable safety profile and an acceptable tolerability, with liver inflammation occurring in only 5 percent of patients.
Keytruda Receives Accelerated Approval for Gastric Cancer
In September, the FDA also approved Keytruda for the treatment of advanced or metastatic gastric cancer, as well as gastroesophageal junction adenocarcinoma. The accelerated approval requires that patients have PD-L1-positive tumors and that they have progressed in their disease despite receive two or more other treatment options, such as fluoropyrimidine and platinum-based chemotherapy or HER2-targeted therapy. The Phase II KEYNOTE-059 trial showed acceptable tumor response rate and durability of response to qualify the treatment for accelerated approval.
Gastric cancer has proven very difficult to treat. While several different treatment modalities are available, it is still hard to elicit a response from the tumor. The trial named above included 259 patients across several studies in an open-label study. All participants had experienced progression of disease after two other treatments. After receiving Keytruda, 13.3 percent of patients had tumors that responded and 1.4 percent of patients experienced complete disappearance of the cancer. After six months, more than half of the responses were sustained, although this number fell by half after a full year. At the same time, the effects of taking the drug are mild with no life-threatening issues arising.
How Immune Checkpoint Inhibitors Work
The preliminary results from the two trials mentioned above show that checkpoint inhibitors can produce extraordinary results for a small number of patients and at least some response in others. How exactly do these treatments work? To understand this, individuals need to know how the immune system functions. Several different sorts of white blood cells, each with a specialized function, make up the main offensive part of the immune system. One of the most important immune cells is called the T cell, which includes cytotoxic T cells that kill tumor cells directly and helper T cells that boost other parts of the immune system. These T cells recognize specific antigens on the surface of cells to determine which ones they should attack. T cells are constantly circulating in the blood and looking for these tumor antigens.
Once T cells are activated, they need to be inactivated or they will continue to attack cells. Checkpoints expressed on the surface of T cells seek out these inactivation signals. Cancers have evolved to express factors that bind to the inactivation receptors and shut down the cells prematurely. Checkpoint inhibitors work by binding to the inactivation receptors so that the factors excreted from the tumor cells cannot bind. Importantly, the checkpoint inhibitors do not affect the same inactivation response. Thus, the T cell does not become inactivated by the tumor cells and is free to attack as it normally would.
What is important to understand about tumor cells is that they tend to have a wide range of other strategies for avoiding the normal immune response. Thus, it is perhaps not too surprising that drugs like Opdivo and Keytruda have limited efficacy. Cancers can often switch to a different method of avoiding immune detection. This fact is the reason that these drugs are often used in combination with other therapies to attack the cancer from multiple angles and improve the chances of the tumor responding.