"Pembrolizumab works in non-randomized studies in this group of patients with advanced disease. This randomized study demonstrates a huge benefit in the first-line [setting] with pembrolizumab and should be the new standard of care."
Patients with newly diagnosed microsatellite instability–high (MSI-H)/mismatch repair deficient (dMMR) metastatic colorectal cancer (mCRC) treated in the phase 3 KEYNOTE-177 trial (NCT02563002), had a doubled progression-free survival following pembrolizumab (Keytruda) compared with chemotherapy.1
Finding were presented ahead of the 2020 ASCO Virtual Scientific Program. At the time of data cutoff, in February 2020, and at a median follow-up of 32.4 months, the median PFS was 16.5 months (95% CI, 5.4-32.4) with pembrolizumab (n = 153) versus 8.2 months (95% CI, 6.1-10.2) with standard chemotherapy with or without bevacizumab (Avastin) or cetuximab (Erbitux; n = 154) in patients with MSI-H/dMMR mCRC, leading to a 40% reduction in the risk of disease progression or death (HR, 0.60; 95% CI, 0.45-0.80; P = .0002).
“These long-awaited trial results will change clinical practice,” said lead author Thierry André, MD, of the Sorbonne Université and Hôpital Saint Antoine in Paris, in a press briefing ahead of the virtual conference.2 “Pembrolizumab works in non-randomized studies in this group of patients with advanced disease. This randomized study demonstrates a huge benefit in the first-line [setting] with pembrolizumab and should be the new standard of care.”
Approximately 5% of patients with mCRC have microsatellite instability, categorized by a high number of mutations in the tumor and decreased survival. Patients with metastatic MSI-H/dMMR tumors are less responsive to conventional chemotherapy and are in need of alternative treatment options.
In prior phase 2 trials, MSI-H status demonstrated predictive clinical benefit for pembrolizumab, as well as other PD-1 inhibitors, in patients with chemotherapy-refractory mCRC.
In May 2017, the FDA granted an accelerated approval to pembrolizumab for the treatment of adult and pediatric patients with unresectable or metastatic, MSI-H/dMMR solid tumors that have progressed after prior treatment and who have no satisfactory alternative treatment options, as well as for patients with MSI-H/dMMR CRC following progression on a fluoropyrimidine, oxaliplatin, and irinotecan.
The approval was based on data from 149 patients with MSI-H/dMMR cancers enrolled across 5 single-arm clinical trials, in which pembrolizumab demonstrated durable responses and prolonged survival.3
KEYNOTE-177 included 307 patients with treatment-naïve MSI-H/dMMR mCRC. To be eligible for enrollment, patients had to have confirmed MSI-H/dMMR stage IV CRC, an ECOG performance status of 0 or 1, and measurable disease.
Patients were randomized 1:1 to 200 mg of pembrolizumab every 3 weeks for up to 2 years or investigator’s choice of standard chemotherapy, including intravenous (IV) mFOLFOX6 [5-fluorouracil (5-FU), leucovorin, and oxaliplatin] every 2 weeks; mFOLFOX6 plus bevacizumab [5 mg/kg IV on day 1 of each 2-week cycle]; mFOLFOX6 plus cetuximab (400 mg/m2 IV, then 250 mg/m2 weekly in each 2-week cycle); FOLFIRI (leucovorin, 5-FU, and irinotecan); FOLFIRI plus bevacizumab (5 mg/kg IV on day 1 of each 2-week cycle); or FOLFIRI plus cetuximab (400 mg/m2 IV, then 250 mg/m2 weekly in each 2-week cycle).
Patients in the chemotherapy arm were allowed to cross over to the pembrolizumab arm at the time of disease progression.
Treatment was continued for up to 35 cycles in the pembrolizumab arm, until progressive disease, unacceptable toxicity, or patient/physician decision to withdraw.
PFS and overall survival served as the coprimary endpoints of the study; key secondary end points included overall response rate (ORR) and safety. All responses were evaluated according to RECIST v1.1 criteria by blinded independent central review.
Patients’ baseline and demographic characteristics were generally well balanced between arms.
Results also showed that the 12-month PFS rates were 55% in the pembrolizumab arm and 37% in the chemotherapy arm, and the 24-month PFS rates were 48.3% and 18.6%, respectively. The ORR was 43.8% with pembrolizumab, which consisted of an 11.1% complete response (CR) rate, 32.7% partial response (PR) rate, and 20.9% stable disease (SD) rate. The ORR was 33.1% with chemotherapy, which consisted of a 3.9% CR rate, 29.2% PR rate, and 42.2% SD rate.
Approximately 30% of patients in the pembrolizumab arm developed progressive disease versus 12.3% of patients in the chemotherapy arm, which were attributed to resistance to pembrolizumab, the preclusion of later CR, PR, or SD following any evidence of progression according to RECIST 1.1 criteria, or faulty determination of MSI-H status by polymerase chain reaction or immunohistochemistry, André explained during the press briefing.
The responses were also more durable with pembrolizumab compared with chemotherapy. The median duration of response was not reached with pembrolizumab versus 10.6 months with chemotherapy. Eighty-three percent of patients in the pembrolizumab arm had a response lasting at least 2 years versus 35% of patients in the chemotherapy arm.
In terms of safety, pembrolizumab showed an improved safety profile versus chemotherapy. The most common all-grade adverse events (AEs) occurring in at least 20% of patients in the pembrolizumab and chemotherapy arms, respectively, included diarrhea (25% vs 52%), fatigue (21% vs 44%), nausea (12% vs 55%), decreased appetite (8% vs 34%), stomatitis (5% vs 30%), alopecia (3% vs 20%), vomiting (3% vs 28%), decreased neutrophil count (1% vs 23%), neutropenia (0% vs 21%), and peripheral sensory neuropathy (0% vs 20%).
Grade 3 or higher treatment-related AEs were less common with pembrolizumab versus chemotherapy, at 22% and 66%, respectively. The most common immune-related AEs in the pembrolizumab arm included colitis and hepatitis.
“Immunotherapies like pembrolizumab have proved to be effective as second-line treatments for advanced disease. Now, in studies like this one, we are starting to see significant efficacy for immunotherapies as first-line treatment for advanced cancers with specific genetic signatures, in this case metastatic colorectal carcinoma with microsatellite instability–high/mismatch repair deficient mutations,” Howard A. Burris III, MD, FACP, FASCO, ASCO president, said during the presscast. “The data presented have the potential to change the standard of care.”
The study will continue to evaluate OS as the data mature in accordance with the recommendation from an Independent Data Monitoring Committee.
1. Andre T. Shiu Kai-Keen, Kim TW, et al. Pembrolizumab versus chemotherapy for microsatellite instability-high/mismatch repair deficient metastatic colorectal cancer: The phase 3 KEYNOTE-177 study. J Clin Oncol. 2020;38(suppl 15; abstr LBA4). doi:10.1200/JCO.2020.38.15_suppl.LBA4
2. ASCO press release. Pembrolizumab doubles time to disease progression in patients with advanced colorectal cancer with specific DNA mutations. Available from: https://www.asco.org/about-asco/press-center/news-releases/pembrolizumab-doubles-time-disease-progression-patients. Published May 28, 2020. Accessed May 28, 2020.
3. FDA grants accelerated approval to pembrolizumab for first tissue/site agnostic indication. Published May 23, 2017. https://bit.ly/3bI0DHK. Accessed May 28, 2020.