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Patients with untreated heavily mutated metastatic colorectal cancer (mCRC) lived twice as long without disease progression when they received an immune checkpoint inhibitor instead of chemotherapy, a randomized trial showed.

As Thierry Andre, MD, of Sorbonne University in Paris, reported in a late-breaker abstract at the , the median progression-free survival (PFS) was 16.5 months with pembrolizumab (Keytruda) and 8.2 months with chemotherapy. More than twice as many patients were alive without disease progression at 24 months with pembrolizumab.

The PD-1 inhibitor also was better tolerated, as grade 3 or greater adverse events (AEs) occurred in 22% of patients versus 66% in the chemotherapy arm, Andre noted.

"Pembrolizumab provided a clinically meaningful and statistically significant improvement in PFS versus chemotherapy in patients with MSI-H [microsatellite instability-high] disease," he said during an ASCO press briefing. "Responses were more durable with pembrolizumab versus chemotherapy. We observed an improved safety profile with pembrolizumab versus chemotherapy."

"Pembrolizumab should be considered a new standard-of-care as first-line therapy with MSI-H metastatic colorectal cancer," he added.

The findings represent a compelling addition to the evidence of anti-PD-1/L1 activity in tumors with numerous mutations (MSI-H or mismatch repair deficiency [dMMR]). Pembrolizumab has "tumor-agnostic" FDA approval for previously treated MSI-H/dMMR solid tumors, and nivolumab (Opdivo) and the combination of nivolumab and ipilimumab (Yervoy) are approved for .

Pembrolizumab demonstrated durable antitumor activity and acceptable safety in several phase II trials involving patients with previously treated MSI-H mCRC, which supported the FDA's then-unprecedented tumor-agnostic approval. The studies and FDA approval provided a rationale for continued investigation of the drug in the first-line setting of metastatic MSI-H/dMMR CRC. About 5% of mCRC tumors are associated with MSI-H/dMMR.

Andre reported findings from the phase III randomized trial comparing pembrolizumab and chemotherapy. After confirmation of MSI-H/dMMR tumor status, he and his colleagues allocated 307 patients to receive pembrolizumab or one of six standard-of-care chemotherapy regimens with or without bevacizumab (Avastin) or cetuximab (Erbitux).

Treatment continued until disease progression or unacceptable toxicity, and patients assigned to chemotherapy had the option to cross over to pembrolizumab at disease progression.

The trial had co-primary endpoints of PFS, as assessed by blinded independent central review, and overall survival (OS). After a median follow-up of 28.4 months, patients who received pembrolizumab had a 40% reduction in the hazard ratio for disease progression or death compared with those who received chemotherapy (95% CI 0.45-0.80). The data remained immature for a definitive analysis of OS, Andre said.

More patients in the pembrolizumab arm remained alive without disease progression at 12 months (55.3% vs 48.3%) and 24 months (37.3% vs 18.6%). Treatment with the PD-1 inhibitor resulted in an objective response rate of 43% vs 33.1% for chemotherapy.

Median duration of response had yet to be reached in the pembrolizumab arm versus 10.6 months in the chemotherapy arm, and 83% of responses in the pembrolizumab arm persisted for at least 24 months compared with 35% of responses in the chemotherapy arm, Andre reported.

The most frequently reported AEs in the pembrolizumab arm (all grades) were diarrhea (25%), fatigue (21%), and nausea (12%). In the chemotherapy arm, the most common AEs were nausea (55%), diarrhea (52%), fatigue (44%), decreased appetite (34%), and stomatitis (30%).

About 25% of patients in the chemotherapy arm had decreased neutrophil count (17% grade ≥3), and about 20% developed neutropenia (15% grade ≥3). In contrast, those rates were much lower in patients in the pembrolizumab arm: 1% incidence of decreased neutrophil count and 0% neutropenia.

The results probably will not surprise many oncologists in the United States, where pembrolizumab's activity in MSI-H/dMMR tumors is pretty well established, said ASCO President Howard A. "Skip" Burris, MD, of Vanderbilt University Medical Center in Nashville, who moderated the press briefing.

"I think the encouraging thing about this abstract is that we are moving the safer therapy into the first-line setting, avoiding putting people on chemotherapy before moving on to this treatment," he said. "I also think investigators and practitioners will be happy to see that the impact [of first-line pembrolizumab] is pretty substantial."

"This study is part of the overall concept of not saving a therapy but moving it earlier in the treatment line and identifying specific groups that will benefit," Burris added. "As a drug developer, that's music to my ears."

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