Checkpoint blockade in MSI High cancers
Continuing part two of our mini-series on colorectal cancer, today we move from the big scale Immunoscore study to small subsets of disease that are looking interesting in several ways.
For years, advanced colorectal cancer has been dominated by chemotherapy (FOLFOX or FOLFIRI) with and without targeted therapies (VEGF and EGFR antibodies), with very little new to talk about. Part of the challenge here is how do you add something the existing standard of care and move the needle significantly. In front-line, for example, the OS is already out 2-plus years, so these are long and risky trials to undertake. Not surpisingly, many companies have sought to evaluate their agents in tumour types where they consider the risk of development to be lower.
Unless… we can find creative approaches that turn the paradigm on its head and identify a clearly defined niche that can be carved out separately from allcomers.
This is where we’re at now – identifying subsets that might respond exquisitely to novel approaches based on a rational understanding of the underlying biology. One obvious subset might be BRAF, which can be treated with a BRAF inhibitor with or without other targeted therapies as Dr Pietrantonio and colleagues (2016) literally just showed for example, but what about others of potential interest?
Colorectal cancer with microsatellite stable (MSS) disease represents 95% of metastatic patients. These are people whose mismatched repair system is proficient and actively functional in fixing the DNA strand breaks that occur during the course of life.
In contrast, those with microsatellite instability (MSI) are the minority of people with colon cancer (and some other cancers too) whose mismatched repair system is deficient and unable to adequately repair the DNA strand breaks. Ironically, this leads to thousands of mutations that can be recognised by the immune system to help detect the presence of cancer. It also tends to occur in hereditary cancers such as Lynch Syndrome.
We’ve been following the MSI vs MSS story for a while now, but at ASCO this year there was more data available and things appear to be getting clearer on the commercial front too.
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