Keytruda Works Well in Cancers Marked by Faulty DNA Repair Mechanism

Patients with heavily pretreated colorectal cancer who harbored genetic defects in DNA mismatch repair (MMR) experienced high response rates when treated with the PD-1 inhibitor Keytruda (pembrolizumab) in a recent study.

Errors in mismatch repair allow defective strands of DNA to go uncorrect­ed, compromising the integrity of cells. In the study, when the immunotherapy Keytruda was used in patients with MMR deficiencies, the objective response rate (ORR) was 62 percent compared with 0 percent in patients with MMR-proficient tumors. Median progression-free survival (PFS) and overall survival (OS) had not been reached, with many patients responding to treatment for longer than 12 months in the MMR-deficient arm.

The findings from the ongoing phase 2 study of Keytruda — which inhibits the protein PD-1 in order to stimulate the immune system to fight cancer — were presented May 29 during the 2015 annual meeting of the American Society of Clinical Oncology (ASCO), a Chicago gathering of nearly 30,000 oncology professionals.

"This is the first study to use genetics in a prospective manner to guide immunotherapy," lead author Dung T. Le, an assistant professor of oncology at Johns Hopkins Kimmel Cancer Center, said during a press briefing. "Mismatch repair-deficient tumors are highly responsive to checkpoint blockade with anti-PD-1."

Findings from the analysis were simultaneously published in The New England Journal of Medicine (NEJM); however, data at the ASCO meeting were from a more up-to-date analysis that was conducted on May 8, 2015.

In the three-arm study, Keytruda was administered at 10 mg/kg every two weeks to patients with colorectal cancer (CRC) who were MMR-deficient (n = 13) and MMR-proficient (n = 25). The third arm looked at Keytruda in patients with MMR-deficient non-CRC malignancies (n = 10). Testing for MMR and resulting microsatellite instability was conducted using polymerase chain reaction and immunohistochemistry, which are standard tests conducted for patients with CRC in order to check for the rare and hereditary Lynch syndrome.

"Mismatch repair deficiency is easily determined using an existing commercially available test," Le said. "In terms of cost, the tests run in the hundreds of dollars, not the thousands that panels cost."

The primary endpoints of the study were immune-related PFS and response rate at 20 weeks. Secondary endpoints focused on OS, PFS and disease control rate (DCR; complete response, partial response, plus stable disease). Response and survival were assessed by Response Evaluation Criteria In Solid Tumors (RECIST) criteria in addition to immune-related criteria.

In the first 48 patients analyzed from the study, those with MMR-deficient CRC experienced an overall response rate (ORR) of 62 percent and a DCR of 92 percent. The ORR was 0 percent and the DCR was 16 percent in MMR-proficient tumors. After a median treatment duration of 5.9 months, no patients in the MMR-deficient group who responded had progressed.

OS and PFS were not reached in the MMR-deficient group, versus a median PFS of 2.3 months and an OS of 7.6 months in the MMR-proficient group. In patients with MMR-deficient non-CRC tumors, the ORR was 60 percent and the DCR was 70 percent.

The side effects seen in the study were consistent with those reported in other studies of Keytruda. The most common were rash/itchiness (17 percent), pancreatitis (15 percent) and thyroiditis/hypothyroidism (10 percent).

"Responses were durable in a treatment-refractory patient population, and many of these responses were ongoing for over a year," said Le. "These data suggest that genomics are more influential than histology for mismatch repair-deficient tumors treated with anti-PD-1."

Defects in MMR commonly lead to microsatellite instability, which can be found in most cancers, including a majority of cases of hereditary nonpolyposis CRC (Lynch syndrome). Without this repair mechanism, the mutational burden is generally higher, suggesting a higher likelihood of developing cancer. In total, more than 80 percent of patients in the MMR-deficient arm were positive for Lynch syndrome.

"Mismatch repair deficiency is represented in approximately 4 percent to 5 percent of many tumor types, so it has broad applicability," Le said. "We saw responses in colorectal cancer, endometrial cancer, stomach cancer, small bowel cancer and bile duct cancers."

Interestingly, patients with Lynch syndrome (n = 11) were less likely to respond compared with those with other forms of MMR, according to the data published in NEJM. In those with Lynch syndrome, the ORR was 27 percent with Keytruda compared with 100 percent in those with MMR that was unrelated to Lynch syndrome (n = 6).

In total, 1,782 somatic mutations were identified per patient in the MMR-deficient arm compared with 73 in those with MMR-proficient tumors. Predominately, these tumors were found to alter amino acids (63 percent), and 578 of the somatic mutations in the deficient arm were associated with the immune system.

Overall, membranous PD-L1 expression was only identified in patients with MMR-deficient tumors. Additionally, tumors with MMR deficiencies were more likely to contain a greater density of CD8-positive lymphoid cells. However, the researchers noted that neither PD-L1 nor CD8 were significantly associated with PFS and OS.

"PD-L1 was done on all patients. There was a trend for PD-L1 expression, but nothing was stronger than the mutational burden," senior author Luis A. Diaz, Jr., associate professor of oncology at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, said in an interview with OncLive, a sister publication to CURE. "Follow-up studies are looking at the mutations. We did have four non-responders, and so we're trying to understand who those non-responders were and what their mutational profiles were."

Keytruda, which was the first PD-1 inhibitor to gain approval from the U.S. Food and Drug Administration, is the topic of multiple presentations at the ASCO meeting. More than 40 abstracts being presented at the meeting mention the highly selective humanized monoclonal IgG4 antibody. An application for Keytruda’s use in the treatment of non-small cell lung cancer is pending. It is currently approved for the treatment of patients with advanced or unresectable melanoma following progression on prior therapies.

Merck, the developer of Keytruda, plans to launch a phase 2 study (KEYNOTE-164) to evaluate the effectiveness of MMR as a predictive marker in patients with locally advanced unresectable or metastatic colorectal cancers. The study is expected to begin enrolling patients later this year.

1.Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch repair deficiency. J Clin Oncol. 2015;(suppl; abstr LBA100).

2. Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015. doi:10.1056/NEJMoa1500596