Immunotherapy Makes History with Latest Cancer Approval

May 23, 2017, was an important day for cancer patients, and a historic day for the U.S. Food and Drug Administration (FDA). Eventually, it may even come to be regarded as a turning point in our overall approach to treating cancer in our society.

The recent accelerated approval of Keytruda® (pembrolizumab, Merck) wasn’t its first. It’s already approved for subsets of patients with melanoma, lymphoma, lung cancer, bladder cancer, and head and neck cancer.

With this announcement, however, the anti-PD-1 checkpoint immunotherapy became the first oncology treatment of any type to be granted FDA approval without any organ-specific strings attached.

Instead, this latest approval depends on biomarkers associated with the stability of a tumor’s genome, and makes Keytruda available to treat both adult and pediatric patients with all types of solid tumors. Now, patients with metastatic cancers that are characterized by high levels of microsatellite instability (MSI-hi) or deficient DNA mismatch repair (dMMR) can receive this immunotherapy, regardless of their tumor’s physical origin, if other available treatments aren’t working.

The FDA based its decision on results from five clinical trials, which involved a total of 149 patients with MSI-hi/dMMR tumors who were treated with pembrolizumab. Altogether, fifteen different tumor types were represented and, overall, nearly 40% of patients responded while 11 patients had their tumors disappear completely.

This high response rate appears to be due to the inability of these MSI-hi/dMMR tumors to repair their DNA, which causes them to accumulate mutations (sometimes as many as 10 to 100 times more mutations than “normal” cancer cells).

Some of these mutations produce abnormal proteins (“neo-antigens”) that can serve as targets for the immune system due to their “foreign” appearance. Oftentimes in patients with MSI-hi/dMMR tumors, T cells have already begun to recognize and respond to these tumor neo-antigens and in some cases have even infiltrated the tumor.

Unfortunately, tumors can also exhaust these T cells, in part through the PD-1/PD-L1 pathway that dampens their activity. In that circumstance, supporting T cell activity by blocking the PD-1 receptor (via an anti-PD-1 immunotherapy) is sometimes all that’s needed to tilt the scales in the immune system’s (and patient’s) favor.

While this immunotherapy is now available for patients with all types of solid cancers, this news likely to give new hope to patients with colorectal cancer (CRC)—the only cancer type explicitly mentioned in the approval—because it has one of the highest frequencies of MSI-hi/dMMR cases. In fact, 90 of the 149 previously mentioned patients had CRC. (Endometrial and gastrointestinal cancers also have relatively high MSI-hi/dMMR rates.)

Additionally, it was primarily in CRC that the relationship between dMMR status, high mutational loads, and pre-existing immune responses was discovered and validated.

Furthermore, in a global analysis of over 3,000 CRC patients using a metric called the Immunoscore (which measures the presence of T cells in and around tumors), a link between T-cell infiltrated tumors and higher patient survival rates has been elegantly demonstrated.

While MSI-hi/dMMR tumors represent only a small fraction of all cases (approximately 5% of metastatic CRC cases according to the FDA’s oncology director, Richard Pazdur, MD), the potential benefits of anti-PD-1 immunotherapy for this subset of patients will likely be great.

As for the other >95% of cancer patients who have MSS (microsatellite stable) tumors, while this approval doesn’t immediately change their treatment landscape, it did establish an important precedent that could enhance the future development, testing, and approval of drugs. In that respect, this landmark decision could help pave the way for the application of additional tumor-independent biomarkers for even larger patient populations.

If Neil Armstrong were a scientist, he might very well have described this as one small step for the MSI-hi/dMMR biomarker, but one giant leap for biomarkers in general.