Oligometastatic Disease Status May Impact Treatment Decisions in mCRC

Van K. Morris, MD

Van K. Morris, MD

Multi-modality therapy has demonstrated long-term survival outcomes in patients with metastatic colorectal cancer (mCRC) with single-organ involvement, Van K. Morris, MD explained during a presentation at the 2020 Gastrointestinal Cancers Symposium (GI 2020). What oncologists are unsure of, however, is how to select the optimal regimen for patients with more than one site of organ involvement.

In an effort to develop a better understanding, Morris reviewed a pooled analysis of the phase III randomized TRIBE trial (NCT00719797) and the TRIBE 2 trial (NCT02339116), which both evaluated doublet/triplet cytotoxic chemotherapy regimens for the treatment of mCRC in the first- and second-line settings. The pooled analysis was presented separately by Gemma Zucchelli, MD, at GU 2020.

In his discussion, Morris set out determine prognostic implications of oligometastatic and non-oligometastatic disease in patients with unresectable metastatic colorectal cancer receiving standard therapies, if chemotherapy choice should be intensified or de-intensified, based on oligometastatic status, and if oligometastatic disease can identify the patients who are more likely to receive subsequent locoregional therapies.

In an interview withTargeted Oncology, Morris, assistant professor, Department of Gastrointestinal Medical Oncology, MD Anderson Cancer Center, discussed a pooled analysis of the TRIBE trials to determine how oligometastatic disease status impacts treatment decisions. He also discussed advances in the field, including novel treatments that are emerging for advanced CRC.

TARGETED ONCOLOGY:What are the most exciting advances we've seen for advanced CRC over the past 5 years?

Morris: It's been an exciting past 5 years for mCRC. For me, the most exciting advance is the understanding of the role of immunotherapy in patients with mCRC. As it stands right now, only about 3% to 5% of these patients appear to have benefit, and I am referring to the patients whose tumors have microsatellite instability. These patients can have very good long-term outcomes and tolerate treatment well.

The unmet need is how we can translate these findings into the remaining 95% of patients with microsatellite stable mCRC. We're working hard to try to answer that question. In the REGONIVO trial, early findings looking at the combination of regorafenib plus nivolumab in patients with microsatellite stable mCRC are encouraging. We're hoping to see more data in the coming months to see if this represents a true advance for patients with microsatellite stable disease.

What is also interesting in this space are the molecular characterizations of mCRC and how we can better treat patients according to their underlying molecular profiling. For example, we know that the patients withBRAF-mutated disease who represent approximately 8% to 10% of all patients with mCRC have poor prognoses. The median survival for these patients is 12 months. Whereas, when you look at all-comers in the mCRC population, survival is around 2.5 years. Most recently, we've seen that combinations of targeted therapies that focus on the MAP kinase pathway have improved survival outcomes specifically for this population. This is the first time ever that we've seen an effective treatment for patients withBRAF-mutated mCRC.

Another exciting abstract I've seen over the past year is on targeting patients withKRASG12C mutations with specific inhibitors for theKRASG12C oncoprotein. We know thatKRASmutations occur in more than half of patients with mCRC. Traditionally, these mutations we considered non-targetable , but for the first time, we're seeing that there is potential to targetKRASmutation. This brings a lot of excitement to us as providers because there is hope that RAS may be something that we can continue to target in the future.

Finally, another molecular subset that has been interesting to me is the HER2/neu over-amplified population, which also represents around 5% of patients with mCRC. We know that the drugs which target HER2 are effective in other solid tumors, but we are now starting to identify these patients and place them on important clinical trials that will further characterize the role of targeted therapies for this particular subset of patients in mCRC.

TARGETED ONCOLOGY:What novel strategies are emerging in CRC that appear promising?

Morris: In terms of novel treatment strategies, multiple exciting clinical trials are going on. Trials are looking at the role of surgical resection of traditionally unresectable disease in the oligometastatic setting. There are also trials looking at the role of definitive radiotherapy for 5 or fewer metastases in patients with unresectable mCRC.

TARGETED ONCOLOGY: Can you provide an overview of your presentation at the GI 2020?

Morris: At this year's GI symposium, I presented an abstract looking at patients with unresectable mCRC. I went over a pooled analysis from the two TRIBE trials, which were seminal clinical trials that were important in helping to define the role of triplet cytotoxic chemotherapy for patients with unresectable CRC.

The authors looked at a definition of oligometastatic disease and they looked at how patients did with unresectable mCRC based on whether they had oligometastatic disease or non-oligometastatic disease. There were several interesting findings. First, patients who had oligometastatic disease fared better in terms of survival outcomes relative to those who had non-oligometastatic disease. These findings make sense because if you have a lower total burden of disease, you're more likely to do better.

What was interesting though, is that when the investigators analyzed how patients did if they got 2 cytotoxic agents versus 3 cytotoxic agents, they didn't see any difference in the survival outcomes in the 2 groups.

Although this was a retrospective review, there are no data to this point that suggest that we should incorporate this definition of oligometastatic disease into our choice of whether to give doublet or triplet cytotoxic chemotherapy.

The authors also looked at the roles of local regional therapy in patients with unresectable mCRC, and in doing so, they saw a sizeable fraction of patients with both oligometastatic disease and non-oligometastatic disease who were able to undergo local regional therapies. But, as you would expect, those with oligometastatic disease were more likely to be able to receive more local regional therapies. Overall, the patients who got local regional therapies had very good survival outcomes. What wasn't clear from this study is whether or not these patients benefited from receiving local regional therapies or if what we're seeing is that patients who are able to undergo local regional therapies just have more indolent cancer biology and tumor biology, inherently.

I applaud the authors for considering oligometastatic disease in the management of surgically unresectable incurable mCRC. Their findings highlight the need for forthcoming randomized clinical trials that look specifically at the role of treatment benefit with local regional therapies in these patients who have what's traditionally considered unresectable with low burden mCRC. There are trials being conducted across the United States and Europe seeking to answer this question.

TARGETED ONCOLOGY: What is the key takeaway from your presentation?

Morris: Although patients with oligometastatic unresectable CRC have better prognoses, we should not be using this in our decisions of whether or not to give triplet or doublet cytotoxic chemotherapy at this time. Future clinical trials are ongoing and will help to answer that question.

Reference:

Morris, Van K. Are we moving the needle in advanced colorectal and anal cancers? Presented in an oral abstract session at: 2020 Gastrointestinal Cancers Symposium; January 23