When a devil brings a good omen

James Fleck: Anticancerweb 15(06), 2020

Considering both genders, colorectal cancer (CRC) is the second most common cause of cancer death in the world. According to the most recent epidemiological data from IARC, CRC contributes to a crude mortality rate and an age-standardized rate of 11.5 and 8.9, respectively. Despite the effectiveness of colonoscopy as a method for the early diagnosis of CRC, about 21% are still diagnosed as stage IV disease. CRC is a very heterogeneous disease, expressing several molecular subtypes that harbor distinct genetic and clinical characteristics. Approximately 5% of metastatic patients have a high level of microsatellite instability (MSI-H) as a consequence of a DNA deficiency in mismatch repair (dMMR), which leads to a hypermutable state. The sporadic MSI-H/dMMR CRC often originates in the right side of the colon, is strongly associated with BRAF V-600E mutation and  has the worse prognosis. This phenotype is associated with a lower response rate to chemotherapy with Fluoropyrimidines, both in adjuvant and palliative setting. Fortunately, preliminary reports have shown durable responses with immunotherapy, using a single-agent PD-1 (programmed-death-1) blockade. A 52% objective response rate (ORR) has been reported using pembrolizumab (PD-1 inhibitor) in the palliative treatment of MSI-H/dMMR CRC. This is a huge progress towards personalized medicine, not only because this molecular subtype is predictive of an increased response rate to immunotherapy, but also because it avoids adverse events associated with chemotherapy.

Recently presented at the American Society of Clinical Oncology Virtual Meeting 2020, the prospective randomized phase III trial Keynote-177 showed a doubled progression-free survival (PFS) in  metastatic CRC MSI-H / dMMR treated in the pembrolizumab arm when compared to the chemotherapy arm. A total of 307 metastatic MSI-H/dMMR CRC patients were randomly assigned 1:1 to the experimental arm (pembrolizumab 200 mg Q3W) or to the control arm (mFOLFOX6 or FOLFIRI Q2W  bevacizumab or cetuximab). Crossover was allowed, and primary outcomes were PFS and overall survival. Secondary endpoints were ORR and safety. The interim analysis after a medium follow-up around 28 months, showed a median PFS of 16.5 months in the pembrolizumab arm versus 8.2 months in the control arm (HR=0.60, P=0.0002). ORR was also superior in the experimental arm (43.8% versus 33.1%) and grade 3-5 treatment-related adverse events were lower in the pembrolizumab arm (22% versus 66%). The study is not mature enough to evaluate OS differences, but the magnitude of the PFS benefit anticipated a new standard of care for metastatic CRC MSI-H / dMMR. In contrast, the pembrolizumab arm showed a higher rate of disease progression compared to chemotherapy (29.4% versus 12.3%). This unexpected result should be further investigated eventually adding more light in this ambiguous biological behavior of metastatic MSI-H/dMMR CRC. Identification of predictive markers would be especially important before moving pembrolizumab to trials exploring adjuvant setting. 

References:

1.     International Agency for Research on Cancer (IARC) – World Health Organization, 2018 (https://www.iarc.fr)

2.     Zoran Gatalica,  Semir Vranic, Joanne Xiu, et all: High microsatellite instability (MSI-H) colorectal carcinoma: a brief review of predictive biomarkers in the era of personalized medicine, Familial Cancer15:405–412, 2016

3.     Dung T. Le, Tae Won Kim, Eric Van Cutsem, et all: Phase II Open-Label Study of Pembrolizumab in Treatment-Refractory, Microsatellite Instability–High/Mismatch Repair–Deficient Metastatic Colorectal Cancer: KEYNOTE-164 J Clin Oncol 38:11-19, 2019

4.     Thierry Andre, Kai-Keen Shiu, Tae Won Kim, et al: Pembrolizumab versus chemotherapy for microsatellite instability-high/mismatch repair deficient metastatic colorectal cancer: The phase 3 KEYNOTE-177 study, ASCO Meeting Abstract LBA4, 2020