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Oncology Xagena

High microsatellite instability metastatic colorectal cancer: Nivolumab alone or in combination with Ipilimumab has shown encouraging clinical activity


Interim data from the phase 2 CheckMate -142 trial evaluating Nivolumab ( Opdivo ) alone or in combination with Ipilimumab ( Yervoy ) in patients with previously treated metastatic colorectal cancer, including those with high microsatellite instability ( MSI-H ) was presented at the 52nd Annual Meeting of the American Society of Clinical Oncology ( ASCO ).

In these first-time clinical results, the primary endpoint of investigator-assessed objective response rate ( ORR ) was 25.5% ( 95% CI: 15.4-38.1 ) for Nivolumab monotherapy and 33.3% ( 95% CI: 18.6-50.9 ) for the Nivolumab and Ipilimumab combination regimen.
The six-month progression-free survival ( PFS ) rates were 45.9% ( 95% CI: 29.8-60.7 ) for Nivolumab monotherapy and 66.6% ( 95% CI: 45.5-81.1 ) for the Nivolumab and Ipilimumab combination.
MSI-H, a specific tumor biomarker, is present in approximately 15% of early stage metastatic colorectal cancers, and 4% of stage IV colorectal cancers.
The safety profile of Nivolumab alone or in combination with Ipilimumab was consistent with other tumor types and prior combination studies.

CheckMate -142

CheckMate -142 is an international phase 2, open-label, non-comparative trial evaluating Nivolumab as a single-agent or in combination with Ipilimumab in recurrent or metastatic colorectal cancer, including patients with and without high microsatellite instability ( MSI-H ).
The MSI-H patients received Nivolumab 3 mg/kg every two weeks ( n=70 ) or Nivolumab 3 mg/kg and Ipilimumab 1 mg/kg ( n=30 ) for four doses followed by Nivolumab 3 mg/kg every two weeks until an unacceptable toxicity occurred, or until disease progression.
Twenty-three microsatellite stable ( MSS ) patients received one of three doses of the Nivolumab and Ipilimumab combination.

The primary endpoint was investigator-assessed objective response rate in high microsatellite instability patients, and the secondary endpoint was independent radiology review of ORR in MSI-H patients.
Exploratory endpoints included safety and tolerability, progression-free survival and overall survival in MSI-H patients, as well as investigator-assessed ORR in microsatellite stable patients.

The investigator-assessed ORR for high microsatellite instability patients receiving Nivolumab 3 mg/kg with at least 12 weeks of follow up was 25.5% and 33.3% for the Nivolumab 3 mg/kg and Ipilimumab 1 mg/kg combination.
Median duration of response was not reached in either group.
The six-month progression-free survival rates were 45.9% ( 95% CI: 29.8-60.7 ) for Nivolumab 3 mg/kg and 66.6% ( 95% CI: 45.5-81.1 ) for the Nivolumab 3 mg/kg and Ipilimumab 1 mg/kg combination.
Survival data are also reported, with nine-month overall survival rates of 75.0% ( 95% CI: 58.5-85.7 ) for Nivolumab 3 mg/kg and 85.1% ( 95% CI: 65.0-94.2 ) for the Nivolumab 3 mg/kg and Ipilimumab 1 mg/kg combination.
At the time of analysis, 67.1% of MSI-H patients in the Nivolumab 3 mg/kg arm and 60.0% of those in the Nivolumab 3 mg/kg and Ipilimumab 1 mg/kg combination arm remained on treatment.

In MSI-H patients, treatment-related adverse events of any grade occurred in 58.6% of patients in Nivolumab 3 mg/kg group and 83.3% of patients in the Nivolumab 3 mg/kg and Ipilimumab 1 mg/kg group.
The most common adverse effects of any grade occurring in greater than or equal to 15% of MSI-H patients were fatigue ( 18.6% with Nivolumab 3 mg/kg; 20.0% with Ipilimumab 3 mg/kg and Ipilimumab 1 mg/kg ), diarrhea ( 14.3% with Nivolumab 3 mg/kg; 43.3% with Nivolumab 3 mg/kg and Ipilimumab 1 mg/kg ), pruritus ( 11.4% with Nivolumab 3 mg/kg; 16.7% with Nivolumab 3 mg/kg and Ipilimumab 1 mg/kg ), nausea ( 7.1% with Nivolumab 3 mg/kg; 20.0% with Nivolumab 3 mg/kg and Ipilimumab 1 mg/kg ), and pyrexia ( 4.3% with Nivolumab 3 mg/kg; 23.3% with Nivolumab 3 mg/kg and Ipilimumab 1 mg/kg ).
Grade 3/4 adverse effects occurred in 14.3% of patients in the Nivolumab 3 mg/kg group and 26.7% of patients in the Nivolumab 3 mg/kg and Ipilimumab 1 mg/kg group.
One patient in the Nivolumab 3 mg/kg group died due to a grade 5 treatment-related adverse effect of sudden death.
In microsatellite stable patients, adverse effects of any grade occurred in 80% of the patients with diarrhea ( 30% ), nausea ( 25% ), pyrexia ( 25% ), fatigue ( 20% ), vomiting ( 20% ), and pruritus ( 10% ) being the most common. ( Xagena )

Source: BMS, 2016

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