Pembrolizumab Granted Breakthrough Status for Microsatellite Instability-High mCRC


The FDA has granted a breakthrough therapy designation to pembrolizumab as a potential therapy for patients with microsatellite instability-high metastatic colorectal cancer.

Roger M. Perlmutter, MD, PhD

The FDA has granted a breakthrough therapy designation to pembrolizumab (Keytruda) as a potential therapy for patients with microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC), according to a statement from the company developing the PD-1 inhibitor, Merck.

The designation was based on findings from an ongoing phase II study, which demonstrated high response rates with pembrolizumab 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); however, data that were simultaneously presented at the 2015 ASCO Annual Meeting were from a more up-to-date analysis.1,2

In the findings presented at ASCO, the objective response rate (ORR) was 62% with pembrolizumab 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, MD, 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 3-arm study that was the basis for the new designation, pembrolizumab was administered at 10 mg/kg every 2 weeks to patients with CRC who were MMR-deficient (n = 13) and MMR-proficient (n = 25). Additionally, a separate arm looked at pembrolizumab in patients with MMR-deficient non-CRC malignancies (n = 10). MMR and microsatellite instability testing was conducted using PCR and IHC, 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% of patients in the MMR-deficient arm were positive for Lynch syndrome.

The primary endpoint of the study was 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 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 DCR of 92% compared with 16% 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 ORR was 60% and the DCR was 70%.

OS and PFS were not reached in the MMR-deficient group versus a median PFS of 2.3 months (HR, 0.10; 95% CI, 0.03-0.37; P <.001) and an OS of 7.6 months in the MMR-proficient group (HR, 0.22; 95% CI, 0.05-1.00; P = .05).

In the analysis published in NEJM, which contained data from fewer patients, the ORR with pembrolizumab was 40% in patients with MMR-deficient mCRC (n = 10). In this same group, the PFS rate with pembrolizumab at 20 weeks was 78%.

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

"This is the first study to use genetics in a prospective manner to guide immunotherapy," lead author Dung T. Le, MD, 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 (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% with pembrolizumab compared with 100% in those with MMR that was unrelated to Lynch syndrome (n = 6).

In total, 1782 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%) 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 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, MD, associate professor of Oncology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, said in an interview with OncLive at the conference. "Follow-up studies are looking at the mutations. We did have 4 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 II 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 pembrolizumab in MMR/MSI-H-deficient mCRC, if results are positive (NCT02460198).

In addition to the phase II study, Merck is planning to launch a phase III trial to assess patients with treatment-naive MMR-deficient mCRC. In this study, patients will receive pembrolizumab or 1 of 6 standard chemotherapy regimens. PFS will be the primary endpoint of the study, which is labeled KEYNOTE-177 (NCT02563002).


  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.

Related Videos
Chun Chao, PhD, MS
Jonathan C. Trent, MD, PhD
5 KOLs are featured in this panel.
5 KOLs are featured in this panel.
Mary Philip, MD, PhD
Rom S. Leidner, MD
Sarwish Rafiq, PhD
Efficacy and Safety of Fruquintinib in Patients With Metastatic Colorectal Cancer According to Prior Treatment Sequence in the Refractory Setting: Results From FRESCO and FRESCO-2
5 KOLs are featured in this panel.
Richard Kim, MD