Pembrolizumab had a favorable safety profile in patients with advanced colorectal cancer (CRC) expressing programmed death ligand 1 (PD-L1) in a recent study, although antitumor activity was limited. The findings were published in PLoS ONE.
Bert H. O’Neil, MD, from the Indiana University Simon Cancer Center, in Indianapolis, and colleagues, evaluated the safety and antitumor activity of pembrolizumab in a cohort of patients with advanced PD-L1–positive CRC, including those with microsatellite instability (MSI) and microsatellite-stable (MSS) status.
The study was part of KEYNOTE-028, an international, multicenter, open-label, nonrandomized, single-arm, phase Ib trial designed to assess the safety and antitumor activity of pembrolizumab in 20 types of PD-L1–positive advanced solid tumors.
Patients with CRC expressing PD-L1 have a poor prognosis because it is a heterogeneous disease driven in part by loss of genomic stability. Molecular phenotypes of CRC are defined by the mutational status of genes encoding mismatch repair (MMR) proteins.
High levels of MSI due to MMR deficiency are found in approximately 15% of CRC tumors. These are known as MSI-high (MSI-H) tumors, and are generally thought of as a positive prognostic marker for early-stage CRC when compared with those with MSS disease. However, MSI status is considered a negative prognostic marker in metastatic CRC.
Pembrolizumab is a highly selective monoclonal antibody designed to directly block the PD-1:PD-L1/PD-L2 interaction by binding to PD-1. It has demonstrated robust antitumor activity with several tumor types.
Participants in the study had CRC with tumor samples assessed for MMR proficiency. In addition, either the patient’s previous treatment was ineffective or standard therapy did not exist or was inappropriate for the locally advanced or metastatic PD-L1-positive adenocarcinoma.
Patients received pembrolizumab 10 mg/kg intravenously every 2 weeks for 24 months or until confirmed disease progression. Response was assessed by CT or MRI every 8 weeks for the first 6 months, and every 12 weeks thereafter. Tumors were assessed for PD-L1 expression.
Primary end points were safety and overall response rate (ORR) defined as proportion of patients experiencing complete or partial response.
Several secondary end points were investigated: progression-free survival (PFS), defined as time from enrollment to the first documented instance of disease progression; overall survival (OS), which was the time from enrollment to death from any cause; and duration of response (DOR), defined as time from first response to disease progression in patients who experienced partial response or better.
A total of 23 patients were enrolled. The median age was 57 years. Most patients (57%) were men, and 15 (65%) received three or more prior therapies. One patient (4%) had MSI-H CRC.
The median follow-up duration as of the data cutoff date was 5.3 months (range, 1.0–26.2 months). Treatment-related adverse events were reported for eight patients (35%). Events that occurred in more than one patient were fatigue (13%), stomatitis (9%), and asthenia (9%).
In this cohort, the ORR was 4%. One patient experienced partial response by investigator review, with a time to response of 1.7 months. Four patients (17%) experienced stable disease with a median duration of 5.1 months, 15 patients (65%) had progressive disease, and three patients were not assessed for efficacy. There was no obvious discernible pattern with regard to number of lines of prior therapy or location of metastases between the patient with partial response, the four patients with stable disease, and the remaining patients.
Overall, 13% of patients had a clinical benefit (ie, complete response, partial response, or stable disease for more than six months). There was a decrease from baseline in the size of the target lesions in 16% of patients with an evaluable post baseline tumor assessment.
For the patient who experienced partial response to pembrolizumab treatment, the response was maintained over multiple assessments, with a response duration of 22.7 months as of the data cutoff date. The 54-year-old male was the only patient in this cohort with MSI-H CRC; he also had a BRAFV600E mutation.
Median PFS was 1.8 months, and the 6-month and 12-month PFS rates were 17.4% and 4.3%, respectively. Median OS was 5.3 months, and the 6-month and 12-month OS rates were 43.5% and 29.8%, respectively.
“Pembrolizumab monotherapy has an acceptable safety profile but limited antitumor activity in patients with heavily pretreated PD-L1–positive advanced CRC,” concluded the authors.
Moreover, antitumor activity was observed in MSI-H CRC (n=1/1) but not in MSS CRC (n=22/23). Ongoing studies will assess the role of pembrolizumab in treating these patients.
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