Frontline pembrolizumab significantly delays the disease progression of patients with metastatic colorectal cancer and a high microsatellite instability
Phase II trials of pembrolizumab previously demonstrated a durable anti-tumour activity and acceptable safety profile in patients with previously treated microsatellite instability-high (MSI-H) metastatic colorectal cancer. The Keynote-177 trial was the first phase III trial assessing the potential of pembrolizumab as a first-line treatment option for these patients. Initial progression-free survival (PFS) results of this trial indicate that, compared to the current standard of care, pembrolizumab delays the disease progression with more than 8 months. In addition, also the duration of the responses obtained with pembrolizumab and the safety of the therapy compared favourably to standard of care. As such, these data indicate that pembrolizumab might well become the novel standard-of-care first-line treatment option for these patients.
Microsatellite instability (MSI) is caused by a deficiency in the mismatch repair system and occurs in cells with high levels of mutation in short, repeated DNA sequences. In metastatic colorectal cancer (mCRC) around 5% of patients have a high microsatellite instability (MSI-H mCRC) profile. As mismatch repair status and MSI-H status are predictive for the clinical benefit of immune checkpoint blockade with pembrolizumab and other anti-PD-1 agents, pembrolizumab has been studied in patients with MSI-H or mismatch repair deficient (dMMR) CRC. In previously published phase II studies, pembrolizumab demonstrated a durable anti-tumour activity with an acceptable safety profile in patients with previously treated MSI-H mCRC. Based on these positive findings, the phase III Keynote-177 trial compared pembrolizumab to standard-of-care (chemotherapy with or without bevacizumab or cetuximab) in the frontline treatment of these patients.
In total, Keynote-177 trial enrolled 307 patients with confirmed MSI-H or dMMR stage IV CRC across 23 countries. All patients were treatment naïve, had an ECOG performance status of 0 or 1 and had measurable disease. Patients were randomised (1:1) to pembrolizumab 200 mg once every three weeks or to investigator-choice of chemotherapy (options include mFOLFOX6 or FOLFIRI alone or in combination with bevacizumab or cetuximab). Upon centrally verified disease progression in the chemotherapy arm, patients could crossover to the pembrolizumab arm. Treatment was given for up to 35 cycles of pembrolizumab or until unacceptable toxicity, disease progression or patient/physician decision to withdrawal. The two co-primary endpoints of Keynote-177 were progression-free survival (PFS) and overall survival (OS). In the plenary session of ASCO 2020, the first PFS results of the study were presented.
After a median follow-up of 32.4 months, the median PFS was 16.5 months in the pembrolizumab arm, as compared to 8.2 months in the chemotherapy arm. This represents a highly significant 40% reduction in the risk of disease progression or death (HR [95%CI]: 0.60 [0.45-0.80], p=0.0002). At the 2-year landmark, 48% of the patients in the pembrolizumab arm were still alive and free of progression as compared to only 19% in the chemotherapy arm. The overall response rate (ORR) was 43.8% (of whom 11.1% achieved a complete response) for patients treated with pembrolizumab versus 33.1% (of whom 3.9% had a complete response) for patients treated with chemotherapy. The median duration of response was not reached in the pembrolizumab arm and was reported at 10.6 months in the chemotherapy arm. In total, 83% of the patients who received pembrolizumab had a duration of response of at least two years (versus 35% of the patients who received chemotherapy).
Treatment-related adverse events of grade 3 or higher were reported in 22% of the patients in the pembrolizumab arm, versus 66% of the patients in the chemotherapy arm. Toxicity was different between both arms, with immune-mediated adverse events and infusion reactions being characteristic for patients treated with pembrolizumab. Classical chemotherapy toxicity was observed in the chemotherapy arm (diarrhoea, neutropenia, fatigue, nausea, alopecia, etc.).
Compared to chemotherapy, pembrolizumab provides a clinically meaningful and statistically significant improvement in the PFS for previously untreated patients with MSI-H mCRC. In addition, responses were more durable with pembrolizumab as compared to chemotherapy and pembrolizumab also had a more favourable safety profile. Pembrolizumab should therefore be considered a new standard-of-care first-line treatment in patients with MSI-H mCRC.
André T, Shiu KK, Kim TW, et al. Pembrolizumab Versus Chemotherapy for Microsatellite Instability-High/Mismatch Repair Deficient Metastatic Colorectal Cancer: The Phase 3 KEYNOTE-177 Study. Presented at ASCO 2020; Abstract LBA4.