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CheckMate 142 Update: Prolonged Disease Control With Nivolumab in Deficient Mismatch Repair Colorectal Cancer


With 6 additional months of follow-up since the initial presentation of results, in the phase II CheckMate 142 trial, 74% of heavily pretreated patients with metastatic colorectal microsatellite instability–high (MSI-H) cancers are alive after single-agent treatment with nivolumab (Opdivo).1


Nivolumab monotherapy provided durable responses, disease control, and long-term survival in this population [patients with DNA mismatch repair deficient/microsatellite instability–high metastatic colorectal cancer].
— Michael J. Overman, MD

“Nivolumab monotherapy provided durable responses, disease control, and long-term survival” in this population, reported Michael J. Overman, MD, of The University of Texas MD Anderson Cancer Center, Houston. He suggested nivolumab is a “new standard of care” in this tumor type.

At the 2017 Gastrointestinal Cancers Symposium, follow-up of 19 of 23 patient responders (83%) is ongoing at a median follow-up of 7.4 months. Responses have been observed regardless of tumor or immune cell expression of the programmed cell death ligand 1 (PD-L1), BRAF or KRAS mutation status, or clinical history of Lynch syndrome. Almost half the patients are progression-free at 12 months, Dr. ­Overman reported.

About 4% of patients with metastatic colorectal cancer have tumors with a high degree of microsatellite instability (MSI-H) due to a deficiency in the DNA mismatch repair system (MMR). These patients may be less responsive to conventional chemotherapy than are patients whose tumors are MMR-proficient.

MMR-deficient/MSI-H tumors are hypermutated and associated with elevated levels of tumor neoantigens and tumor-infiltrating lymphocytes and upregulated expression of checkpoint regulators in immune cells, including programmed cell death protein 1 (PD-1) and PD-L1. That means they may be exquisitely responsive to immune checkpoint inhibition, and this appears to be the case. The use of antibodies targeting PD-1 have, in fact, shown strong efficacy, and pembrolizumab (Keytruda) has received Breakthrough Therapy status by the U.S. Food and Drug Administration in this setting. Emerging data for nivolumab are also robust.

Study Details

CheckMate 142 is evaluating nivolumab (3 mg/kg) with and without ipilimumab (Yervoy; 1 mg/ kg) in patients with metastatic MMR-deficient/MSI‑H colorectal cancer. Dr. ­Overman presented updated data on 74 patients treated in the monotherapy arm; the combination arm is still enrolling. The primary endpoint is objective response rate by investigator assessment.

Most patients (54%) had received at least three prior lines of therapy. BRAF was mutated in 16% of patients; 35% had KRAS-mutated disease; 28% had ≥ 1% expression of PD-L1; and 31% had Lynch syndrome. More than half the patients remain on the study.

Outcomes

The objective response rate was 31.1%, and 68.9% of patients demonstrated disease control for at least 12 weeks. Responses occurred early, at a median of 2.8 months, and the median duration of response has not been reached. “Both in responding and stable disease patients, we saw significant durability of those benefits,” Dr. ­Overman revealed.

Nivolumab in Colorectal Cancer

  • CheckMate 142 is evaluating single-agent nivolumab and nivolumab plus ipilimumab in patients with metastatic colorectal cancer whose tumors are microsatellite instability–high.
  • Among 74 patients receiving the single agent, 31.3% responded; 83% of responses are ongoing at a median follow-up of 7.4 months.
  • Median progression-free survival was 9.6 months, and median overall survival has not been reached.

There were four deaths among patients with stable disease, and no deaths among responders. The majority of patients achieving stable disease at ≥ 18 weeks remain on study, and 19 of 23 responses (83%) are ongoing.

Treatment beyond disease progression was allowed, and one such patient showed a “marked benefit,” Dr. ­Overman noted. This patient had rectal adenocarcinoma and extensive liver metastases. He responded to single-agent nivolumab, but upon worsening pain, he was found to have clinical progression of his rectal primary tumor; it was irradiated and resected. Based on a continued response in the liver, the patient stayed on nivolumab beyond disease progression. On study day 573, he underwent an exploratory laparotomy for an anastomotic leak at his rectal stump; it revealed two liver lesions, both of which demonstrated a pathologic complete response to treatment. The patient currently is being followed off therapy without any evidence of progression.

Median progression-free survival in the CheckMate 142 update was 9.6 months, with a 12-month rate of 48.4%. Median overall survival has not been reached, and 73.8% of patients are alive at 1 year, reported Dr. Overman.

Reduction in target lesions was observed regardless of PD-L1 expression, BRAF mutation status, KRAS status, or presence of Lynch syndrome.

Toxicity

Single-agent nivolumab was well tolerated, with grade 3/4 treatment-related adverse events reported in 20.3% of patients. The safety profile was in keeping with that in other studies of nivolumab.

By a number of patient-reported outcomes scales, clinically meaningful improvements were reported in quality of life, functioning, and symptoms as early as week 13. On the EuroQol 5 dimension (EQ-5D) scale—a generic health-related quality-of-life instrument—patients who continued treatment for 19 weeks achieved “a level of health that would be regarded as equal to or exceeding the general health of many populations,” he ­reported.

Ongoing studies are evaluating the use of PD-1 blockade as initial treatment of metastatic disease in the MMR-deficient/MSI-H subset. “Our current front-line therapy in metastatic colorectal cancer patients is fairly active, but this is a question we need to answer,” he said. “I encourage physicians to enroll their patients on these trials.” ■

Disclosure: Dr. Overman has served as a consultant or advisor to Merrimack, Bristol-Myers Squibb, Roche, and Sirtex Medical and has received research funding from Amgen, Bristol-Myers Squibb, Celgene, MedImmune, Merck, and Roche.

Reference

1. Overman MJ, Lonardi S, Leone F, et al: Nivolumab in patients with DNA mismatch repair deficient/microsatellite instability high metastatic colorectal cancer. 2017 Gastrointestinal Cancers Symposium. Abstract 519. Presented January 21, 2017.


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