Metastatic Colorectal Cancer Treatments Continue to Change

The treatment landscape for metastatic colorectal cancer (mCRC) underwent a drastic change with the approval of checkpoint inhibitors for microsatellite instability-high (MSI-H) tumors.

Moving forward, researchers are now trying to find regimens that will have similar success for patients who are microsatellite stable or mismatch repair-proficient. However, that is proving to be easier said than done.

“We know that immunotherapy works exceedingly well in patients with mismatch repair deficient (dMMR) tumors. Unfortunately, that accounts for only about 5% of all patients with CRC, so we don’t get to use immunotherapy as much as we would like to,” said Anthony Shields, MD, PhD, professor in the Department of Oncology and the Molecular Imaging and Diagnostics Program at Barbara Ann Karmanos Cancer Institute, said in an interview with OncLive, a sister publication of Oncology Nursing News.

Regimens Under Investigation

Shields mentioned the IMblaze370 trial, where investigators compared atezolizumab (Tecentriq) alone or in combination with cobimetinib (Cotellic) to regorafenib (Stivarga) in patients with unresectable, locally advanced mCRC who had at least 2 lines of prior chemotherapy. To Shields’ surprise, the immunotherapy regimens proved no better than regorafenib.

However, he —and others in the field– are staying optimistic: “With that being said, investigators are trying every such combination in the world. I am opening a trial with pembrolizumab (Keytruda) plus an Interleukin-2-enhancing drug. It’s going to be a while because it wasn’t the quick hit we thought it would be, but immunotherapy will eventually find a way into this patient population.”

Additional immunotherapy combinations, such as adding these drugs to targeted agents, other checkpoint inhibitors, and bispecific antibodies, are also being explored.

Patients Who Respond to Immunotherapy

For patients with mCRC who do respond to immunotherapy, they tend to see disease improvements quickly.

“For some of the patients, [this approach] makes an amazing difference for a short period of time; it doesn’t necessarily last forever,” Shields said, mentioning that some patients do see benefit for years to come. “When you get wins like that, you think, ‘Immunotherapy is going to change your practice.’”

However, the adverse events (AEs) of some of these regimens can often be troublesome — something the oncology nurse should always look out for. Healthcare providers may also be unable to decipher whether the toxicity is coming from the disease itself, an infection, or the immunotherapy.

“Patients can get a wide range of AEs that are unpredictable and really hard to diagnose,” Shields said.

The Importance of Genetics

The first step in determining whether or not a patient may respond to immunotherapy is to conduct genetic testing.

At a minimum, Shields explained, all patients undergo mismatch repair (MMR) testing for conditions such as Lynch syndrome. For those with stage IV disease, large gene panels are run. These can be costly, but are worth it, he explained.

“These [panels] cost a few thousand dollars, but that’s equivalent to 1 dose of my drugs these days,” he said. If you tell me a new drug that works or doesn’t work, it’s worth it by far. Those panels keep getting better and better, and we just instituted full transcriptome. I expect that within the year we’ll be doing full sequencing of DNA.”

Further, liquid biopsies are entering the CRC field, with some trials suggesting that patients with positive liquid biopsies or circulating tumor DNA (ctDNA) tend to do worse if they have stage II or stage III disease.

“There are questions here about [disease] biology that still need to be answered,” Shields said.

A version of this article originally appeared on OncLive as, “Shields Sheds Light on Complex mCRC Landscape.”