Pembrolizumab Receives FDA Breakthrough Therapy Designation in Advanced Colorectal Cancer

Designation based on results in patients with metastatic colorectal cancer with high levels of microsatellite instability

On 2 November, 2015 Merck announced that the US Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation to pembrolizumab (KEYTRUDA®), the company’s anti-PD-1 inhibitor, for the treatment of patients with microsatellite instability high (MSI-H) metastatic colorectal cancer. This is the third Breakthrough Therapy Designation granted for pembrolizumab.

The data investigating the use of pembrolizuamb in patients with advanced colorectal cancer whose tumours have substantial evidence of mismatch DNA repair defects are encouraging. The FDA’s Breakthrough Therapy Designation is intended to expedite the development and review of a candidate that is planned for use, alone or in combination, to treat a serious or life-threatening disease or condition when preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints. Pembrolizumab was previously granted breakthrough status for advanced melanoma and advanced non-small cell lung cancer (NSCLC).

The Breakthrough Therapy Designation in advanced colorectal cancer is based on data from a phase II study evaluating the activity of pembrolizumab in cancers with microsatellite instability, a well-established feature seen in cells with certain types of DNA repair defects. Findings from the study, led by researchers from Johns Hopkins Kimmel Cancer Center, were presented at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting and were published simultaneously in the New England Journal of Medicine.

Testing tumours for microsatellite instability can identify patients with defective DNA mismatch repair (MMR) systems. DNA MMR is a process that permits cells to recognise and repair genetic mismatches generated during DNA replication. A defective MMR system allows mismatch mutations to persist. The average tumour has dozens of mutations; however tumours with DNA MMR deficiency may harbor thousands, especially in regions of repetitive DNA known as microsatellites. Tumours that are found to have mutations in select microsatellite sequences, called microsatellite instability (MSI), are considered DNA MMR-deficient. These tumours are referred to as being MSI high.

PD-1 blockade in tumours with MMR-deficiency

According to the results published in the NEJM, which consisted smaller sample than presentation at ASCO 2015, the immune-related objective response rate (ORR) and immune-related progression-free survival (PFS) rate were 40% and 78%, respectively, for MMR–deficient colorectal cancers and 0% and 11% for MMR–proficient colorectal cancers.

The median PFS and overall survival were not reached in the cohort with MMR–deficient colorectal cancer but were 2.2 and 5.0 months, respectively, in the cohort with MMR–proficient colorectal cancer (hazard ratio for disease progression or death, 0.10 [p<0.001], and hazard ratio for death, 0.22 [p=0.05]).

Patients with MMR–deficient noncolorectal cancer had responses similar to those of patients with MMR–deficient colorectal cancer (immune-related ORR, 71%; immune-related PFS rate, 67%).

Whole-exome sequencing revealed a mean of 1782 somatic mutations per tumour in MMR–deficient tumours, as compared with 73 in MMR–proficient tumours (p=0.007), and high somatic mutation loads were associated with prolonged PFS (p=0.02).

This study showed that MMR status predicted clinical benefit of immune checkpoint blockade with pembrolizumab.

Overall, DNA MMR-deficiency is present in approximately 15-20% in stage II colorectal cancer, 10% in stage III disease and approximately 5% or less in stage IV disease. In colorectal cancers, MMR-deficiency is seen in approximately 15-20% of non-hereditary colorectal cancers and in most hereditary colorectal cancers associated with Lynch Syndrome.

Merck is conducting a phase II registration study (KEYNOTE-164) to evaluate the efficacy and safety of pembrolizumab based on microsatellite instability status in patients with previously treated advanced colorectal cancers, and is also planning a phase III study (KEYNOTE-177) in a treatment naive patient population.

The pembrolizumab clinical development programme includes patients with more than 30 tumour types in more than 160 clinical trials, including more than 80 trials that combine pembrolizumab with other cancer treatments.