Pembrolizumab superiority shown as first-line in MSI-H mCRC

The first phase 3 study of pembrolizumab versus standard-of-care demonstrated superiority for first-line pembrolizumab in patients with high microsatellite instability (MSI-H) metastatic colorectal cancer.

The first phase 3 study of pembrolizumab versus standard-of-care (i.e. chemotherapy + bevacizumab or cetuximab) demonstrated superiority for first-line pembrolizumab in patients with high microsatellite instability (MSI-H) metastatic colorectal cancer (mCRC), Prof. Thierry André (St Antoine Hospital, France) reported [1].

About 5% of all mCRC are characterized by MSI-H, often linked with germline mutations in Lynch Syndrome (also known as hereditary non-polyposis colorectal cancer or HNPCC). Mismatch repair status and MSI-H predict the clinical benefit of immune checkpoint blockade with pembrolizumab as first-line therapy for MSI-H mCRC and has been FDA-approved for adults and children with metastatic tumors with MSI, regardless of the tumor type. Previously, KEYNOTE-164 evaluated the anti-tumor activity of pembrolizumab in previously treated, metastatic, microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) colorectal cancer (CRC) [2]. In the current study, treatment-naïve MSI-H patients were treated with first-line pembrolizumab.

KEYNOTE-177 studied 307 stage IV treatment-naïve CRC patients with confirmed MSI-H/dMMR with good performance status. Patients were randomized to either pembrolizumab (n=153; 200 mg Q3W for up to 35 cycles) or investigator-choice chemotherapy (n=154; mostly mFOLFOX6- or FOLFIRI-based, plus bevacizumab or cetuximab). There was an optional crossover to the pembrolizumab regimen for patients with centrally verified disease progression by RECIST v1.1. The dual primary endpoints were progression-free survival (PFS) per RESIST v1.1 by blinded independent central review (BICR) and overall survival. Secondary endpoints were overall response rate and safety. Tumour response was assessed at week 9 and Q9W thereafter per RESIST cv1.1 by BICR.

With a median follow-up of 32.4 months (range 24.0-48.3), pembrolizumab was superior to chemotherapy in terms of PFS: 16.5 months in the pembrolizumab group versus 8.2 months in the chemotherapy control arm (HR 0.60; 95% CI 0.45-0.80; P=0.0002). Overall survival data are still immature. The overall response rate was 43.8% in the pembrolizumab arm as compared with 33.1% in the chemotherapy control arm (P=0.0275). The median duration of response was not reached in the pembrolizumab arm but was 10.6 months in the chemotherapy arm.

Treatment-related adverse events of grade 3 or higher were reported in 22% of the patients in the pembrolizumab arm, as opposed to 66% of the patients in the chemotherapy arm. No new toxicities with pembrolizumab were observed.

In short, pembrolizumab provided a clinically meaningful and statistically significant improvement in PFS versus chemotherapy in patients with MSI-H mCRC. Responses were also more durable with pembrolizumab. Furthermore, there was an improved safety profile with pembrolizumab versus chemotherapy. Prof. André concluded that “pembrolizumab should be considered ta new standard-of-care as first-line therapy in patients with MSI-H mCRC.”

1. André T, et al. Phase III Keynote-177 trial comparing pembrolizumab to standard therapy as first-line treatment for select patients with advanced colorectal cancer. ASCO Virtual Meeting, 29-31 May 2020, Abstract LBA4.
2. Le DT, et al. Phase II Open-Label Study of Pembrolizumab in Treatment-Refractory, Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer: KEYNOTE-164. J Clin Oncol. 2020;38(1):11‐19.