FDA Accelerates Development of Keytruda in Genetic Subtype of CRC


The designation, which will expedite the development and review of Keytruda in this space, was based on findings from an ongoing phase 2 study.

The FDA has granted a breakthrough therapy designation to the immunotherapy Keytruda (pembrolizumab) as a potential therapy for patients with microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC), according to a statement from Merck.

The designation, which will expedite the development and review of Keytruda in this space, was based on findings from an ongoing phase 2 study, which demonstrated high response rates with Keytruda in patients with heavily pretreated CRC with mismatch repair (MMR) deficiency, a condition that causes MSI. Findings from the analysis were published in The New England Journal of Medicine (NEJM). Data from a more up-to-date analysis were simultaneously presented at the 2015 annual meeting of the American Society of Clinical Oncology (ASCO), a gathering of nearly 30,000 oncology professionals in May.1,2

In the findings presented at ASCO, the objective response rate was 62 percent with Keytruda in MMR-deficient mCRC compared with 0 in patients with MMR-proficient tumors. Median progression-free survival (PFS) and overall survival (OS) were not reached, with many patients responding to treatment for longer than 12 months in the MMR-deficient arm.

“We are committed to understanding the full potential of Keytruda to help patients with a broad range of difficult-to-treat cancers,” Roger M. Perlmutter, president, Merck Research Laboratories, said in a statement. “The data investigating the use of Keytruda in patients with advanced colorectal cancer whose tumors have substantial evidence of mismatch DNA repair defects have been encouraging, and we appreciate the opportunity that this FDA breakthrough therapy designation provides us to accelerate our effort to bring Keytruda to these patients.”

In the three-arm study that was the basis for the new designation, Keytruda was administered at 10 mg/kg every two weeks to patients with CRC who were MMR-deficient (13 patients) and MMR-proficient (25 patients). Additionally, a separate arm looked at Keytruda in patients with MMR-deficient non-CRC malignancies (10 patients). MMR and microsatellite instability testing was conducted using polymerase chain reaction and immunohistochemistry, which are standard tests conducted for patients with CRC in order to detect Lynch syndrome.

Defects in MMR commonly lead to microsatellite instability, which can be found in most cancers, including a majority of patients with 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.

The primary endpoint of the study was immune-related progression-free survival (PFS) and response rate at 20 weeks. Secondary endpoints focused on overall survival, PFS, and disease control rate (complete response, partial response, plus stable disease). Response and survival were assessed by RECIST criteria in addition to immune-related criteria.

In the 48 patients analyzed from the study for the ASCO presentation, those with MMR-deficient CRC experienced a disease control rate of 92 percent compared with 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. In patients with MMR-deficient non-CRC tumors, the overall response rate was 60 percent and the disease control rate was 70 precent.

OS and PFS were not reached in the MMR-deficient group versus a median PFS of 2.3 months and an overall survival of 7.6 months in the MMR-proficient group.

In the analysis published in NEJM, which contained data from fewer patients, the overall response rate with Keytruda was 40 percent in patients with MMR-deficient mCRC (10 patients). In this same group, the PFS rate with Keytruda at 20 weeks was 78 percent.

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

"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 when the findings were presented. "Mismatch repair deficient tumors are highly responsive to checkpoint blockade with anti-PD-1."

Interestingly, patients with Lynch syndrome (11 patients) 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 overall response rate was 27 percent with Keytruda compared with 100 percent in those with MMR that was unrelated to Lynch syndrome (six patients).

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.

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+ lymphoid cells. However, the researchers noted that neither PD-L1 nor CD8 were significantly associated with PFS and overall survival.

"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, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, said in an interview with CURE at the conference. "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."

After announcing the positive news at the ASCO meeting, Merck launched the phase 2 KEYNOTE-164 study to evaluate the effectiveness of MMR and MSI-H as a predictive marker in patients with pretreated mCRC. This study is meant to support a regulatory filing for Keytruda in MMR/MSI-H-deficient mCRC, if results are positive.

In addition to the phase 2 study, Merck is planning to launch a phase 3 trial to assess patients with treatment-naive MMR-deficient mCRC. In this study, patients will receive Keytruda or one of six standard chemotherapy regimens. PFS will be the primary endpoint of the study, which is labeled KEYNOTE-177.


  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; 372:2509-2520.
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