Pembrolizumab as first-line in MSI-H mCRC

Featured video: Phase III Keynote-177 trial comparing pembrolizumab to standard therapy as first-line treatment for select patients with advanced 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), reported Prof. Thierry André (St Antoine Hospital, France) [1].

About 5% of all mCRC is characterised by MSI-H, often linked with germline mutations in Lynch syndrome. Mismatch repair status and MSI-H predict 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 tumours with MSI, regardless of the tumour type. Previously, KEYNOTE-164 evaluated the anti-tumour activity of pembrolizumab in previously treated, metastatic, microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) 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 randomised to either pembrolizumab (n=153; 200 mg every 3 weeks 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 RECIST 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 every 9 weeks thereafter per RECIST v1.1 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, see Figure). 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 medial 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 a new standard-of-care as first-line therapy in patients with MSI-H mCRC.”

Figure. Anti-tumour activity of pembrolizumab versus standard-of-care (chemo) in patients with high microsatellite instability (MSI-H) metastatic colorectal cancer (mCRC) [1]

 

1. André T, et al. ASCO Virtual Meeting, 29-31 May 2020, Abstract LBA4.
2. Le DT, et al. J Clin Oncol. 2020;38(1):11‐19.

Posted on 17 September, 202023 April, 2024