CRC Treatment Enters New Era Where Personalized Care Is King

Nilofer S. Azad, MD

Colorectal cancer (CRC) treatment has entered an era that is both exciting and challenging, according to Nilofer S. Azad, MD, who emphasized that as new strategies continue to be explored, treatment decisions should be informed by tumor location, the alterations present, and tolerability.

“In CRC, a number of emerging therapies are being explored in the third-line setting, which underscores the importance of referring patients to clinical trials early and often,” said Azad. “Notably, when selecting for second- and third-line treatment, we must pay close attention to whether a patient’s tumor is right- or left-sided.”

Beyond tumor sidedness, the identification of actionable alterations is also important, said Azad, as several options are now available for use. For example, patients who have KRAS wild-type disease can be given EGFR inhibitors, while those with BRAF mutations, can be given BRAF/EGFR combinations. Regorafenib (Stivarga) and TAS-102 (trifluridine/tipiracil; Lonsurf) have also entered the treatment arsenal.

In an interview with OncLive® during the 2020 Institutional Perspectives in Cancer webinar on Gastrointestinal Malignancies, Azad, an associate professor of oncology at Johns Hopkins ​University School of Medicine and director of the Developmental Therapeutics Clinical Trials Program at Johns Hopkins Sidney Kimmel Cancer Center, spotlighted recent advances made in CRC care, the significance of tumor sidedness in informing treatment decisions, and emerging efforts that seek to propel progress even further.

OncLive®: What are some of the recent advances that have been made in CRC?

Azad: CRC has entered a new era that is both exciting and challenging. We’re starting to make some real inroads in bringing down the incidence of the disease through excellent screening [practices] and more awareness of these efforts. A couple of new drugs have also been approved in the past few years for patients with advanced disease; these were the first few approvals that we have seen after [utilizing] the same tools for over a decade.

[Despite this progress], we’re seeing that in the vast majority of patients with advanced disease, our newer approvals are only modestly beneficial. We’re happy that there is benefit [with these agents] and that patients are living longer, but we definitely have more [work to do] before we are able to turn this into a truly chronic illness. Those are some of the challenges that we are still [faced with] but we are [developing a much better] understanding of what CRC is and how we can target it better.

How is tumor sidedness being used to inform treatment decisions?

For many years, it has been clear that right-sided CRC is more aggressive and resistant; this has been shown in many large epidemiological studies that evaluated the difference [in outcomes] between [those with] right- versus left-sided tumors.

As such, we knew that there was something biologically different about these cancers; however, it was not translating back to the way we treated patients. It was just something that we considered prognostically, but we [used] the same treatment options for both sides.

About 5 years ago, a series of important trials came out that demonstrated that these tumors are not only biologically different; they should be treated differently, as well. As such, now, when a patient has right- versus left-sided CRC, some data suggest that they may benefit from more aggressive chemotherapy.

Additionally, if a patient does not have a KRAS, BRAF or NRAS alteration and they have left-sided CRC, they may benefit more from EGFR inhibitors in the first-line setting for metastatic disease. Meanwhile, for patients with right-sided disease, that is not the case.

Speaking of using the presence of alterations to inform decisions, could you speak to the significance of germline testing in CRC?

The most common hereditary cancer syndrome is Lynch syndrome or hereditary nonpolyposis CRC. This is present in 1% to 2% of patients but is still the most common. That is the syndrome that we now know, in advanced cancers, is extremely sensitive to immunotherapy. There are other cancer types and other hereditary syndromes that are even more uncommon but, if you go to a genetics counselor, they will test broadly for all of these. Patients with strong family histories of many cancers over many generations should be tested, along with those who are younger. Although they have a low chance of having a hereditary syndrome, people who are diagnosed under the age of 50 should be assessed.

Moving to the third-line setting, what are some of the options that have emerged?

We have multiple third-line options available for patients. Patients who have KRAS wild-type disease can receive agents that target EGFR. For patients who have a BRAF mutation, there are combinations therapies that actually target these mutations comprised of a BRAF inhibitor and an EGFR inhibitor. For garden-variety CRC that does not fall into one of those subsets, we have regorafenib and TAS-102. These agents are relatively new, but we continue to gain more experience with them.

In your own practice, how do you choose between regorafenib and TAS-102 in the third- and fourth-line settings?

I have found that this [decision] is very provider dependent. If you look at both of these drugs, they have overlapping survival curves. In terms of the clinical benefits they provide, they're very similar. On the other hand, everyone has a different sense of how easy it is to dose these drugs and how well patients tolerate them. 

I find TAS-102 to be far more tolerable, so I start with this agent. We now have data from a small study [showing the benefit of] the combination of TAS-102 with bevacizumab (Avastin), which is an approach that I use in my practice. This was not a large, randomized phase 3 trial, but it was a randomized trial nonetheless.

In the initial study that was published in the New England Journal of Medicine and led to the approval of the agent, investigators looked at how long patients were able to maintain their fitness and performance status; that was not done with regorafenib. Compared with those who received placebo, patients who were given TAS-102 felt better for a longer period of time. I find these data to be very convincing.

How do the safety profiles of TAS-102 and regorafenib differ?

TAS-102 is a more traditional chemotherapy agent in both the way it works and the adverse effects (AEs) that patients experience. Common AEs include fatigue and low blood counts.

Regorafenib is a multi-kinase TKI; thus, its safety profile is much broader. Some of the common AEs include fatigue, nausea, hepatitis, diarrhea, and rash. Although there are many AEs, patients will not experience all of them.

What ongoing research efforts are you most excited about?

There is a lot of exciting research being done in CRC. For example, several immunotherapy strategies are being utilized in an attempt to make [this approach] work for the vast majority of patients [with CRC]. There are also emerging targeted agents that are hitting molecular [alterations] that are found in CRC. Finally, several new chemotherapy agents are also being explored.

Some of these research efforts are going to pan out while others will not. Even so, all of this work is equally exciting and truly emphasizes the importance of enrolling patients onto clinical trials [to continue to move the needle].