Phase II Open-Label Study of Pembrolizumab in Treatment-Refractory, Microsatellite Instability–High/Mismatch Repair–Deficient Metastatic Colorectal Cancer: KEYNOTE-164

Abstract

PURPOSE KEYNOTE-164 (NCT02460198) evaluated the antitumor activity of pembrolizumab in previously treated, metastatic, microsatellite instability–high/mismatch repair–deficient (MSI-H/dMMR) colorectal cancer (CRC). METHODS This phase II open-label study involved 128 centers worldwide. Eligible patients were age ≥ 18 years and had metastatic MSI-H/dMMR CRC treated with ≥ 2 prior lines of standard therapy, including fluoropyrimidine, oxaliplatin, and irinotecan with or without anti–vascular endothelial growth factor/epidermal growth factor receptor monoclonal antibody (cohort A) or ≥ 1 prior line of therapy (cohort B). MSI-H/dMMR status was assessed locally. Patients received pembrolizumab 200 mg every 3 weeks for up to 2 years until progression, unacceptable toxicity, or withdrawal. The primary end point was objective response rate by RECIST version 1.1 by independent central review. Secondary end points were duration of response, progression-free survival (PFS), overall survival, safety, and tolerability. RESULTS A total of 124 patients with MSI-H/dMMR CRC (61 in cohort A, 63 in cohort B) enrolled. At data cutoff, median follow-up was 31.3 months (range, 0.2-35.6 months) for cohort A and 24.2 months (range, 0.1-27.1 months) for cohort B. Objective response rate was 33% (95% CI, 21% to 46%) and 33% (95% CI, 22% to 46%), respectively, with median duration of response not reached in either cohort. Median PFS was 2.3 months (95% CI, 2.1 to 8.1 months) and 4.1 months (95% CI, 2.1 to 18.9 months). Median overall survival was 31.4 months (95% CI, 21.4 months to not reached) and not reached (95% CI, 19.2 months to not reached). Treatment-related grade 3-4 adverse events occurred in 10 patients (16%) in cohort A and 8 (13%) in cohort B, with the most common occurring in ≥ 2 patients being pancreatitis, fatigue, increased alanine aminotransferase, and increased lipase (2 patients each; 3%) in cohort A. CONCLUSION Pembrolizumab is effective with a manageable safety profile in patients with MSI-H/dMMR CRC.

Transcriptomic Analyses Revealed Systemic Alterations in Gene Expression in Circulation and Tumor Microenvironment of Colorectal Cancer Patients

“…With the rising success rates of immunotherapy on cancers such as melanoma and non-small-cell lung carcinoma (NSCLC), clinical trials on other solid tumor such as CRC suggest a combination therapy approach to tackling tumors that have undergone immune evasion. Food and Drug Administration (FDA) approved CTLA4 inhibitors such as ipilimumab, PD1 inhibitor nivolumab and PD-L1 inhibitor pembrolizumab in high mismatch repair-deficient high metastatic CRC [12], along with newly emerging drugs in combination with or without radiotherapy are just some of the ongoing clinical trials on CRC patients. Single cell transcriptome analysis of tumor infiltrating T cells (TILs) gave rise to the identification of 20 different T cell subsets, each with distinct functions, associations and clonalities, highlighting the complex and dynamic relationship between T cell function and cancer [13].…”

The Role of Palliative Surgery for Malignant Bowel Obstruction and Perforation in Advanced Microsatellite Instability-High Colorectal Carcinoma in the Era of Immunotherapy: Case Report

“…In colorectal cancer, checkpoint inhibitors such as pembrolizumab, nivolumab, and ipilimumab have been approved for MSI-H/dMMR metastatic colorectal cancer that has failed standard therapies (13)(14)(15)(16)(17). While studies on the benefits of palliative surgical interventions in the setting of malignant obstruction and fistula formation may have only suggested modest improvement in overall survival at best, these interventions were often followed by conventional chemotherapy or best supportive care in non-selected patients.…”

“…Profound and durable responses with immunotherapy, however, has changed the expected OS of MSI-H CRC patients. Le et al demonstrated in a phase II study that MSI-H/dMMR mCRC patients who received pembrolizumab (anti-PD-1) achieved a 90% disease control rate, 78% immune-related progression-free survival (PFS) at 20 weeks, and an objective response rate of 30-40% (13). Nivolumab (anti-PD-1) has also shown clinical benefit [overall response rate (ORR), 31%; disease control rate, 69%; 12 month OS, 73%] in previously treated patients with MSI-H/dMMR mCRC (14).…”

“…Additionally, unlike traditional cytotoxic therapies, time to response to immunotherapy can be longer. In recent clinical trials, for example, the median time to response for both nivolumab and nivolumab/ipilimumab was 2.8 months, and was 4.8 months for pembrolizumab (13,14). This creates the scenario where patients must first fail standard chemotherapy before starting immunotherapy, and once on immunotherapy, a clinical benefit may not be determined for weeks to months.…”

Immunotherapy in Metastatic Colorectal Cancer: Could the Latest Developments Hold the Key to Improving Patient Survival?

“…Currently, Pembrolizumab, Nivolumab as well as the combination of Nivolumab and Ipilimumab have been approved by the Food and Drug Administration (FDA) for the treatment of MSI-H or dMMR metastatic CRC cases progressing after treatment with fluoropyrimidine, oxaliplatin, and irinotecan. An overview of selected clinical trials regarding these drugs can be found in Table 1 [16][17][18]. At the time of this writing, the European Medicine Agency (EMA) has not yet approved any of the aforementioned medicine for the treatment of MSI-H CRC.…”