ASCO 2020: Keytruda Shines as New Quality of Care in Treating metastatic Colorectal Cancer

By Pavel Ryzhov, Ph.D.

The KEYNOTE-177 trial results announced at the ASCO virtual meeting demonstrated the benefits of Keytruda as a first-line treatment of microsatellite instability-high (MSI-H) /mismatch repair deficient (dMMR) metastatic colorectal cancer.

Colorectal Cancer

Colorectal cancer (CRC) annually affects over 1 million people and is the second cause of cancer-related deaths in the world. The underlying genetic instabilities lead to a succession of mutations that result in the conversion of benign polyps into malignant tumors which then metastasizes into the distal organs. Early screening procedures and novel treatments have significantly benefited patients. However, advanced stages of CRC like metastatic CRC (mCRC) have a typically poorer prognosis, rendering currently available treatments less effective.

Genetic Instability in CRC

CRC is typically characterized by broad genetic instabilities. One such is microsatellite instability (MSI), which is characterized by the impairment of DNA mismatch repair (MMR) mechanisms. Specifically, microsatellites are composed of repeat DNA sequences that experience insertion or deletion mutations when replication errors remain uncorrected.

MSI-high or MSI-H subgroup refers to the higher amount of instabilities in CRC and can be hereditary or sporadic in nature. Hereditary non-polyposis colorectal cancer (HNPCC) or Lynch syndrome, characterized by germline mutations in one of the MMR genes, while sporadic MSI-H CRC is associated with methylation of MMR MLH1 gene promoter.

Standard of Care for MCI-H mCRC

While early stages of CRC are typically treatable with interventions where polyps may be surgically removed, advanced metastatic stages require further adjuvant chemotherapy. Depending on the type of genetic instability, and the specifics of the pathways affected, treatment options would vary. Therefore the MMR gene mutations that contribute to MSI-H status of CRC are of crucial importance. Several studies have reported that MSI-H phenotype is associated with resistance against conventional fluoropyrimidines, such as 5-fluorouracil (5-FU) and capecitabine, typically used for first-line treatment of CRC. This is likely due to the overexpression of one of the enzymes involved in the metabolism of 5-FU.

Furthermore, it has been reported that immune co-receptor programmed death 1 (PD-1) and other inhibitory checkpoints are upregulated in the MSI-H subset of CRC as compared to MSI-negative types of cancer. As a result, cancer immunotherapy against PD-1 has been investigated and shown to have clinical benefit in treating these patients.

The current standard of care for metastatic CRC include multi-drug chemotherapies like FOLFOX (combination of 5-FU, leucovorin, and oxaliplatin), FOLFIRI (combination of 5-FU, leucovorin, and irinotecan) and several monoclonal antibody-based therapies like anti-VEGF bevacizumab for inhibition of angiogenesis and anti-EGFR cetuximab. As a second-line treatment, Merck’s Keytruda (pembrolizumab), an anti-PD 1 mAb has been approved by the FDA in 2017 for the treatment of adult or pediatric MSI-H cancers that are unresectable or metastatic.

Keytruda, a “Trial” blazer

Merck’s Keytruda has been previously approved for a number of disease indications, including non-small cell lung cancer, gastric, cervical cancers, and others. The PD-1/PD-L1 pathway functions in limiting the over-activation of T lymphocytes in the body. However, in a cancer setting, immune checkpoint proteins are often overexpressed by the cancers themselves. PD-1 inhibitors like Keytruda block the pathway, thereby activating T-cells and restoring anti-tumor response.

After it was discovered that MSI-H tumor microenvironment contains overexpressed immune checkpoint-related proteins, immunotherapeutic treatment by administration of pembrolizumab was investigated in 5 clinical trials. The trials established the efficacy of the drug across multiple different cancer localizations that have MSI-H status. This led to the Breakthrough Therapy Designation by FDA in 2015 for treatment of mCRC and in 2016 for non-CRC cancers, and an Accelerated Approval in 2017.

This marked the first time that a cancer treatment was approved in lieu of a common biomarker in multiple types of solid tumors. As a result of this accelerated approval, Merck was required to conduct additional studies in MSI-H patients.

KEYNOTE-177

Encouraged by the early success of using targeted immunotherapy to treat MSI-H mCRC as a second-line therapy, Merck initiated the subsequent clinical trial, KEYNOTE-177, to investigate the benefit of pembrolizumab as a first-line treatment as compared to standard of care (SoC) combination chemotherapy and other available immunotherapies.

Originally started in 2015, this Phase III parallel assignment randomized open-label study enrolled 307 patients that had confirmed MSI-H Stage IV CRC and were not subject to any previous treatment regimen. The patients were divided into two arms, where 153 patients received pembrolizumab and 154 received the investigator’s choice of chemotherapy, such as FOLFIRI, FOLFOX, FOLFIRI + bevacizumab, FOLFIRI + cetuximab, FOLFOX + bevacizumab or FOLFOX + cetuximab.

The dual primary endpoints investigated in the study were progression-free survival (PFS) up to 24 months and overall survival (OS) up to 36 months, and the secondary endpoint is overall response rate (ORR). The results reported at the plenary session of the ASCO virtual meeting showed that the PFS rate at 12 months was 55% for pembrolizumab and 37% for SoC, and at 24 months was 48% vs. 19% respectively.

The median PFS rate for patients treated with pembrolizumab was 16.5 months with 5.4-32.4 months confidence interval (CI) as compared to 8.2 months for SoC (6.1-10.2 CI). OS rate at 24 months cutoff was 83% for pembrolizumab vs. 35% for SoC, and 43.8% vs. 33.1% overall respectively. The investigators concluded that the trial successfully met one of its primary endpoints (PFS), and the investigation of OS will continue in the future.

Grade ≥3 adverse events were reported in 22% of the cases of the pembrolizumab arm vs. 66% in the SoC arm. The presenter, Thierry Andre, MD, Professor of Medical Oncology at the University Pierre et Marie Curie (UMPC) said that “toxicity is different between both arms, but clearly, pembro[lizumab] is less toxic compared to chemo”. Interestingly, in the pembrolizumab arm, immune-mediated side effects were reported in more cases as compared to standard chemotherapy where typical side effects like diarrhea, nausea, fatigue, alopecia, etc. were more prevalent.

Based on these results, the investigators recommended the use of pembrolizumab as a new first-line standard of care and highlighted that biomarker-driven studies, such as KEYNOTE-177 is an important step forward in treating MSI-H mCRC patients as adjuvant therapy.

Editor: Rajaneesh K. Gopinath, Ph.D.

References

1. https://meetinglibrary.asco.org/record/186928/abstract
2. https://investors.merck.com/news/press-release-details/2020/Merck-Announces-KEYTRUDA-pembrolizumab-Significantly-Improved-Progression-Free-Survival-as-First-Line-Treatment-for-Advanced-Microsatellite-Instability-High-MSI-H-or-Mismatch-Repair-Deficient-dMMR-Colorectal-Cancer/default.aspx

Author

Pavel Ryzhov