Opdivo Is Promising for Microsatellite Instability-High mCRC

Patients with microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC) had sustained antitumor activity with Opdivo (nivolumab), according to an update of the phase 2 CheckMate-142 trial presented at the 2017 Gastrointestinal Cancers Symposium.

At a median follow-up of 7.4 months (range, 0.3-25.3), the overall response rate (ORR) with single-agent Opdivo was 31.1 percent. The median progression-free survival (PFS) was 9.6 months and the 12-month PFS rate was 48.4 percent. The median overall survival (OS) had not been reached and the 12-month OS rate was 73.8 percent.

“These results suggest that nivolumab should be considered a new standard of care for patients with previously treated MSI-H advanced CRC,” said lead study author Michael J. Overman, M.D., associate professor, department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center.

“This is in line with a recent amendment to the NCCN Guidelines which recommends that all metastatic colorectal cancer patients have testing for MSI-H, and that after initial therapy, those patients with MSI-H disease should be considered for pembrolizumab or nivolumab monotherapy,” added Overman.

The open-label, international, phase 2 CheckMate-142 study enrolled patients with recurrent or mCRC, including MSI-H patients and microsatellite stable (MSS) patients. Patients were randomized to receive either single-agent Opdivo or Opdivo combined with Yervoy (ipilimumab).

The data Overman presented at the GI Symposium were for 74 MSI-H patients who received 3 mg/kg of Opdivo every two weeks. The primary endpoint was ORR, with additional outcome measures including PFS, OS and safety.

For the 74-patient cohort, the median age was 52.5 years (range, 26-79), 59.5 percent of patients were male, and 87.8 percent of patients were white. All patients had an ECOG performance status of 0 or 1. The majority of patients (54.1 percent) had at least three prior lines of therapy.

A history of Lynch syndrome was reported for 31.1 percent of patients and 16.2 percent had BRAF mutations. Among the 66 patients for whom PD-L1 status was evaluable, 28.4 percent (21 patients) had PD-L1 expression of at least 1 percent. The median number of doses was 13 (range 1-54) and forty patients (54.1 percent) remained on treatment.

The ORR by investigator assessment was 31.1 percent, comprising 23 partial responses. The stable disease rate was 39.2 percent, the progressive disease rate was 24.3 percent, and the response was not determinable for 5.4 percent. The disease control rate of at least 12 weeks was 68.9 percent.

Among the 23 investigator-assessed responders, the median time to response was 2.8 months, the median duration of response was not yet reached, and 83 percent (19 patients) of responses were ongoing.

The ORR by blinded independent review was 27 percent, comprising two complete responses and 18 partial responses. The stable disease rate was 37.8 percent, the progressive disease rate was 27 percent and the response was not determinable for 11.1 percent. The disease control rate of a 12 weeks was 62.2 percent.

Overman noted that there was response and clinical benefit regardless of PD-L1 expression, BRAF mutation status, KRAS mutation status, and clinical history of Lynch Syndrome.

The rate of all-grade adverse events (AEs) was 68.9 percent, with the most common being fatigue (23 percent), diarrhea (21.6 percent), pruritus (13.5 percent), lipase increased (12.2 percent) and rash (10.8 percent). Grade 3/4 AEs occurred in 20.3 percent of patients, including lipase increased (8.1 percent), fatigue (1.4 percent) and diarrhea (1.4 percent).

Among the 45.9 percent of patients who discontinued treatment, the reasons included disease progression (36.5 percent), treatment-related toxicity (5.4 percent), maximum clinical benefit (1.4 percent), patient decision (1.4 percent) and withdrawn consent (1.4 percent). The were no deaths associated with treatment-related toxicity.

Overman also noted that, “Patient-reported outcome analyses showed clinically meaningful improvements in functioning, symptoms, and quality of life.”