Effectiveness of Keytruda: Dutch Study Offers Clues for Prediction

A new Dutch study offers some clues that might help doctors predict the effectiveness of Keytruda (pembrolizumab) in individual mesothelioma patients. 

Keytruda is the brand name for pembrolizumab. It is an immunotherapy drug called an immune checkpoint inhibitor. It helps unmask mesothelioma cells so that the immune system can find and fight them. 

But the effectiveness of Keytruda is not consistent. Some patients respond well while others do not respond at all. The new study looked at how different people metabolize the drug. Understanding this could help doctors determine the best dose for each mesothelioma patient. 

Pembrolizumab and its Link to Mesothelioma Survival

Malignant pleural mesothelioma is a deadly form of lung cancer. Asbestos exposure is the main cause of mesothelioma. It can take decades for the disease to develop. But once mesothelioma takes hold, it usually grows and spreads quickly. One reason is that mesothelioma cells are very good at protecting themselves from immune system attack.

One way that mesothelioma cells protect themselves is with the protein PD-1. The effectiveness of Keytruda is based on disabling this protective function. The drug blocks the action of PD-1 to activate the immune system. 

Early studies suggested that Keytruda could help mesothelioma patients live longer, especially in combination with chemotherapy. But subsequent studies were not as promising. They showed that Keytruda only worked for select patients. 

The good news is that, in the right patients, the effectiveness of Keytruda can be very high. A study published earlier this year showed responders had a median survival of 17.7 months. With other treatments, pleural mesothelioma is often fatal in less than a year.

Drug Metabolism and its Impact on the Effectiveness of Keytruda

Dutch researchers wanted to understand how different patients process pembrolizumab and how that relates to its effectiveness. Their analysis included 588 blood serum samples from 122 advanced cancer patients. 

Patients had either lung cancer, pleural mesothelioma, melanoma, or bladder cancer. They received regular doses of Keytruda by itself. Researchers tracked their outcomes for 2.2 years. 

They discovered that how fast the drug leaves the body (called ‘drug clearance’) has a big impact on the effectiveness of Keytruda. In the mesothelioma and lung cancer patients, higher drug clearance led to shorter overall survival (OS). Body surface area (BSA) and albumin level (CL) affected drug clearance. 

“A strong inverse CL-OS relationship was demonstrated for non-small cell lung cancer and malignant pleural mesothelioma, which could not be observed for melanoma and UCC [bladder cancer],” writes lead author Daan Hurkmans, an oncologist at Erasmus University Medical Center, Rotterdam. 

For many drugs, Phase II trials help establish standard dosing. But the new study suggests that maximizing the effectiveness of Keytruda for mesothelioma may depend on a more tailored approach. This could include measuring their BSA and serum albumin.

“The findings suggest that personalized dosing should be prospectively explored,” the report concludes. 

Other researchers are looking for biomarkers to predict which mesothelioma patients will respond to immunotherapy. 

Source:

Hurkmans, D, et al, “Prospective real-world study on the pharmacokinetics of pembrolizumab in patients with solid tumors”, June 4, 2021, Journal for Immunotherapy of Cancer, https://jitc.bmj.com/content/9/6/e002344

Yap, et al, “Efficacy and safety of pembrolizumab in patients with advanced mesothelioma in the open-label, single-arm, phase 2 KEYNOTE-158 study”, April 6, 2021, https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30515-4/fulltext