Κυριακή, 13 Αυγούστου 2017

NIVOLUMAB FOR MSI-H METASTATIC COLORECTAL CANCER

The immune checkpoint inhibitor nivolumab (Opdivo, Bristol-Myers Squibb) may provide a new treatment option for patients with metastatic colorectal cancer with a certain genetic defect — DNA mismatch repair–deficient (dMMR)/microsatellite instability-high (MSI-H).
Results from a phase 2 trial (CheckMate 142) showing benefit from nivolumab in this tumor subtype were published online July 19 in Lancet Oncology.
"Nivolumab provided promising and durable responses with prolonged survival relative to the anticipated median survival in patients with dMMR/MSI-H metastatic colorectal cancer," write first author, Michael J. Overman, MD, from the University of Texas MD Anderson Cancer Center, Houston, and colleagues.
Nivolumab has just been approved by the US Food and Drug Administration (FDA) for this indication.
Another similar drug, pembrolizumab (Keytruda, Merck & Co), has also been approved for this indication. This approval was hailed at the time as a paradigm shift for cancer care because it was the first FDA approval of a cancer drug for treating tumors with a certain genetic defect regardless of where the tumor appears in the body, rather than for a specific tumor type.
"The results of the CheckMate 142 trial, which are broadly consistent with previous findings of studies of pembrolizumab, are notable in view of the generally poor prognosis of patients with dMMR/MSI-H metastatic colorectal cancer," commented Francesco Sclafani, MD, from the Royal Marsden NHC Foundation Trust (Sutton, Surrey, United Kingdom), writing in an accompanying
MMR/MSI testing…should now be routinely offered to all patients with metastatic colorectal cancer. Dr Francesco Sclafani 
"Therefore, despite the small numbers and non-randomised study design, the
results establish a new treatment option in this setting and confirm that MMR/MSI testing can no longer be considered as an ad-hoc screening procedure for genetic susceptibility or treatment selection in early-stage
tumours, but should now be routinely offered to all patients with metastatic colorectal cancer," he added.

Nivolumab Study Details 

CheckMate 142 was a multicenter, open-label phase 2 study and is the largest so far to evaluate an immune checkpoint inhibitor in patients with dMMR/MSI-H metastatic colorectal cancer, note the researchers.
dMMR/MSI-H tumors are found in about 15% of early-stage and 5% of metastatic colorectal cancer, and they carry a poor prognosis when treated with conventional chemotherapy, the authors comment.  However, this type of cancer has high levels of tumor neoantigens, tumor-infiltrating lymphocytes, and checkpoint regulators, all of which respond to immune checkpoint blockade. Immune checkpoint inhibitors such as nivolumab activate the immune system to help fight cancer and are already used in other types of tumors.
To see how well this type of cancer responds to nivolumab, researchers recruited 74 adults with histologically confirmed metastatic dMMR/MSI-H colorectal cancer. Patients either were intolerant to at least one past line of chemotherapy or had progressive cancer despite treatment. Fifty-four percent (n = 40) had received three or more past rounds of chemotherapy. Participants were recruited at 31 sites in eight countries (Australia, Belgium, Canada, France, Ireland, Italy, Spain, and the United States) between March 2014 and March 2016.   
Participants received 3 mg/kg intravenous nivolumab monotherapy every 2 weeks until tumor progression, death, unacceptable toxicity, study withdrawal, or end of the study.
The primary endpoint was investigator-assessed objective response according to Response Evaluation Criteria in Solid Tumors (RECIST) guidelines. Response was evaluated by local investigators and blinded independent central review.
During a median follow-up of 12 months, 31.1% of patients (n = 23 of 74; 95% confidence interval [CI], 20.8% to 42.9%) reached the primary endpoint, all of whom showed partial response. Disease control of 12 weeks or longer was achieved by 69% (n = 51; 95% CI, 57% to 79%).
By 1 year, no participants had reached median duration of response, and all responders remained alive. Eight participants had responses that lasted 12 months or more.
Participants had a median progression-free survival of 14.3 months (95% CI,
4.30 months to not estimable), with 12-month progression-free survival of 50% (95% CI,  38% to 61%). Twelve-month overall survival was 73% (95% CI, 62% to 82%).
Forty-one percent of patients (n = 31) experienced grade 3 adverse events, and 14% (n = 10) developed grade 4 adverse events, the most common of which included increased lipase (6 patients [8%]) and amylase (2 patients [3%]). Seven percent of patients discontinued nivolumab because of drug-related adverse events.
Twenty-three (31%) participants died during the study, but no deaths were thought to be related to nivolumab.
Further analyses showed that programmed cell death (PD) ligand 1 expression (linked to increased tumor aggressiveness) and biomarkers for colorectal cancer (BRAF and KRAS) did not predict response to nivolumab, nor did a history of Lynch syndrome (a genetic disease that greatly increases the risk for colorectal cancer).
"These findings strongly suggest dMMR/MSI-H is a marker for response
to PD-1 checkpoint inhibition in metastatic colorectal cancer. These findings are in line with the recent amendment to the National Comprehensive Cancer
Network guidelines, which recommend universal testing for dMMR/MSI-H in all patients with metastatic colorectal cancer," the authors write.
In the editorial, Dr Sclafani says that more work is needed, but he predicts that the treatment algorithm for dMMR/MSI-H colorectal will rapidly evolve. Continuing research on immune checkpoint inhibitors in dMMR/MSI-H metastatic colorectal cancer "will prompt the gastrointestinal oncology community to look at the potential of immunotherapy with renewed enthusiasm," he concludes.
Ongoing research is looking at combination therapy with nivolumab plus ipilimumab, which has shown preliminary efficacy in dMMR/MSI-H colorectal cancer. Studies are also looking at combinations of nivolumab with other immunotherapies, as well as the safety and efficacy of nivolumab with other anticancer therapies. Researchers are also evaluating other biomarkers for clinical outcome with nivolumab.

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