Case 4: Metastatic Colon Cancer, MSI-High


EXPERT PERSPECTIVE VIRTUAL TUMOR BOARDShubham Pant, MD:For our next case we’re going to discuss a patient with metastatic colorectal cancer with microsatellite instability [MSI]. This is a 43-year-old male who presented to his physician with right abdominal pain and anemia. Of note, his father died of pancreatic cancer at age 64 and his sister was diagnosed with breast cancer at age 44. His physical examination reveals that there is diffuse direct abdominal tenderness and diminished bowel sounds. Lab findings are remarkable for a hemoglobin of 7.9. A CT [computed tomography] scan shows a large mass in the ascending colon and diffuse liver nodules. The CEA [carcinoembryonic antigen] is 980. A colonoscopy shows a nonobstructing mass in the hepatic flexure. His biopsy results reveal poorly differentiated adenocarcinoma. The testing that was done shows that the patient isKRAS,NRAS, andBRAFwild-type, but the microsatellite instability was high. The diagnosis is hereditary nonpolyposis colorectal cancer syndrome.

There are studies that have looked at PD-1 [programmed cell death protein 1] inhibitors for microsatellite unstable metastatic colorectal cancer. The CheckMate-142 trial was an open-label phase II study of nivolumab in MSI-high patients with metastatic or recurrent colorectal cancer. They received greater than 1 previous regimen, including fluoropyrimidine and oxaliplatin or irinotecan. Fifty-four percent of these patients had received 3 or more lines of therapy. The median follow-up was 12 months. The overall response rate by blinded independent central review was 36%. The disease control rate at 12 weeks or more was 70%.

The KEYNOTE-164 trial was a phase II study of pembrolizumab in, again, microsatellite unstable colorectal cancer. Ninety percent of these patients had received 2 or more prior therapies. The median follow-up was 7.4 months. The overall response rate was 26.2%, with a disease control rate of 50%.

There was another study for which nivolumab was combined with ipilimumab. This looked at 119 patients, and 76% had received 2 or more prior systemic therapies. The patient received 3 mg/kg of nivolumab plus ipilimumab, which is a CTLA4 [cytotoxic T-lymphocyte—associated antigen 4] inhibitor, at 1 mg/kg every 3 weeks. The overall response rate was 55%. The disease control rate at 3 months was 80%. The 12-month progression-free survival rate was 71%, and the overall survival rate was 85%. Grade 3/4 adverse events were seen in 32% of the patients, and treatment was discontinued in 13% of these patients. The overall response rate in those patients was 63%.

This was the Kaplan—Meier curve of nivolumab with ipilimumab or nivolumab monotherapy in these patients, and nivolumab with ipilimumab did have a higher response rate and disease control rate than nivolumab as a single agent. There were select adverse events in these patients. Specifically in the combination, there were hepatic events. These are all immunotherapy-related events. The rate of grade 3/4 events was 11%, and the rate of colitis, which was higher with anti–CTLA-4 therapy, was about 3% of the grade 3/4 events.

Transcript edited for clarity.

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