Challenges Remain With Personalized Medicine in CRC

Pashtoon M. Kasi, MD, MBBS, MS

Researchers are aiming for a more individualized approach to the treatment of patients with metastatic colorectal cancer (mCRC), but progress on this front remains a challenge, said Pashtoon M. Kasi, MD, MBBS, MS.

CRC is a highly heterogeneous disease, and outside of standard chemotherapy, many patients with mCRC still do not have effective treatment options available to them. However, progress has been made in the smaller subsets of patients with mCRC. For example, immunotherapy has improved outcomes in those with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumors.

In July 2018, the FDA approved the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) for this patient population. The decision was based on data from a cohort of 119 patients with MSI-H/dMMR mCRC who received this approach in the phase II CheckMate-142 study. Here, 82 patients received prior treatment with a fluoropyrimidine, oxaliplatin, and irinotecan, and the overall response rate was 46% (95% CI, 35-58). Among the 38 responders, there were 3 complete responses and 35 partial responses. The median duration of response was not reached (range, 1.9-23.2+ months).

Beyond new treatments, Kasi explained that other key components to advancing personalized medicine in CRC include genetic testing and tumor sidedness.

OncLive: What is the current treatment approach for patients with advanced CRC?

In an interview with OncLive, Kasi, an assistant professor of Oncology and senior associate consultant in the Division of Hematology/Oncology, Mayo Clinic, discussed advances and unmet needs in mCRC.Kasi: CRC is a very heterogeneous disease; in my opinion, it is the poster child for individualized medicine because even though we think of CRC as 1 entity, even the left side of the colon behaves differently than the right side. Mutations also factor into play, as well as age and other characteristics that make the patient's tumor unique. [When it comes to the treatment of patients with] advanced CRC, we have to differentiate between those with widespread metastatic disease or oligometastatic disease. For example, if a patient only has a few metastases in the liver, we start off with chemotherapy first, and if they indeed have these few spots, we can then use a multidisciplinary approach.

Beyond that, when we talk about mCRC in general, in terms of individualizing care based on the tumor, the patients who are important are the ones who have RAS mutations because these mutations can render some treatments ineffective. Even the size of the colon can make a difference.

All of these factors come into play when choosing the right chemotherapy cocktail, and usually this cocktail is paired with a biologic. When we talk about other treatment options, immunotherapy used to have no effect in this space, but now, we have a subset of patients we know can have benefit from this approach. Those with MSI-H/dMMR tumors can respond [to immunotherapy]. We are seeing promising data not only with single-agent PD—1 inhibitors, but with the combinations as well. The combination of nivolumab and ipilimumab is approved [by the FDA] in this patient population for those who have progressed on standard chemotherapy. Unfortunately, this is a pretty rare subset of patients with CRC, at best representing 4% or 5% of patients.

What have been the biggest data that have come out recently?

Is there anything you would like to add?

By default, we now check every patient for MSI-H/dMMR. One thing that is important to know, and is what causes these tumors to be responsive to immunotherapy, is that dMMR [is linked with a high] number of mutations.Many of the advancements made recently have been under the umbrella of individualized medicine. One key aspect from a tumor-based genetic testing perspective is recognizing the different subsets of CRC. The other intriguing thing is that [the tumors] also change over time. Practically speaking, doing repeated biopsies is not very rational; it is an invasive procedure. Liquid biopsies, which employ circulating tumor DNA testing, is a less invasive procedure. There is a chance for these biopsies to be more precise as well. Liquid biopsies are not yet ready for primetime, but they are getting there. Multi-gene testing is making a huge difference.From an individualized medicine approach, although a lot of people would not consider this standard of care, there were data presented at the 2018 ESMO Congress and other meetings regarding pharmacogenomics, which is determining what drugs are a good idea and which ones aren't. We are increasingly using combination regimens in practice, but cost is an issue.

Bristol-Myers Squibb’s Opdivo (nivolumab) + Low-Dose Yervoy (ipilimumab) is the First Immuno-Oncology Combination Approved for MSI-H/dMMR mCRC Patients Who Progressed Following Treatment with a Fluoropyrimidine, Oxaliplatin and Irinotecan. Published July 11, 2018. Accessed July 11, 2018. https://bit.ly/2uaofBD?rel=0" .