ctDNA Could Become the Next Pillar of Treatment Selection in mCRC

Kanwal Raghav, MBBS, MD

Treatment sequencing in metastatic colorectal cancer (CRC) is guided by the results of up-front molecular profiling, tumor sidedness, and the toxicity profile of an agent, explained Kanwal Raghav, MBBS, MD, who added that the ongoing TACT-D (NCT03844620) could help to further refine patient selection in the salvage setting where patients have a lower likelihood of benefit with available therapies.

“In TACT-D, we’re trying to see whether by monitoring the circulating tumor DNA [ctDNA] early, we can we distinguish responders from non-responders in a salvage-line setting. That’s where it’s more critical, because your chance of benefit is lower, and your chance of risk is higher,” said Raghav.

In an interview with OncLive, Raghav, an associate professor in the Department of Genitourinary Medical Oncology and Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, discussed current sequencing approaches in mCRC.

OncLive: How do you stratify patients for treatment in the metastatic setting?

Raghav: You have to account for clinical and molecular factors in mCRC. We approach resectable colon cancer a little bit differently than unresectable [colon cancer] in purely a palliative setting. In [mCRC], we prefer to do up-front molecular profiling on all our patients at diagnosis. This helps us in multiple ways. If the tumor is microsatellite instability high or is mismatch repair deficient, these patients would benefit from pembrolizumab [Keytruda]. A patient with a RAS mutation would benefit from bevacizumab [Avastin]/FOLFOXIRI or bevacizumab/FOLFOX followed by bevacizumab/FOLFIRI. If the patient is RAS and BRAF wild type and left sided, then we try to bring anti-EGFR therapy up front in treatment.

On the other hand, if you are RAS and BRAF wild type and right sided, many people tend to use anti-EGFR therapy in a later line of therapy. We also test every patient for HER2 expression and amplification. For the BRAF-mutant population, the standard of care would be the BEACON CRC regimen. However, I would recommend going to clinical trials first before we recommend that regimen to those patients.

In what situations would you consider giving patients a chemotherapy-free interval?

The chemotherapy-free options in CRC colorectal cancer are provided by multiple methods. You can either do single-agent biological therapies like an EGFR inhibitor, for example. You can give a complete chemotherapy break—you can use regorafenib [Stivarga], which is one of our agents that is approved after standard chemotherapies have failed in the third-line setting as a bridge, because it does give you a chemotherapy-free interval.

The biggest advantage of a chemotherapy-free interval is letting the patient’s bone marrow recover. Moreover, a good use of a chemotherapy-free interval does not mar the outcomes for patients and preserves their bone marrow. It’s very sad to see when patients are not able to participate on clinical trials because of exclusion parameters, so that’s one reason why we would use a chemotherapy-free interval.

How do you choose between TAS-102 (trifluridine/tipiracil; Lonsurf)and regorafenib once a patient has reached the third-line setting?

Both of these drugs have been approved in CRC in pretty much the same setting. There is no true rationale for choosing one over the other because the trials were done in a similar population. However, there are some reasons why we generally use regorafenib earlier than TAS-102. There are data regarding the efficacy of TAS-102 in regorafenib-pretreated patients, but not vice versa. The majority of patients who are eligible for both these treatments are just coming off a large amount of systemic chemotherapy, which is 5-FU based, and many of them have already cytopenias. That’s not to say that regorafenib doesn’t have its toxicity, but those toxicities are slightly different from what they are for TAS-102. With TAS-102, I’ve seen bone marrow suppression as a major dose-limiting toxicity. Sometimes, giving that regorafenib bridge helps their bone marrow recover so that they can go to TAS-102.

With regard to regorafenib, is the goal to reach the maximum-tolerated dose of 160 mg?

For most patients, we adopt the ReDOS criteria, and as in the study, we try to push it to the maximum dose of 160 mg. Now, the majority of patients will not reach that dose, but there are some patients who get to that dose, and that’s the whole point of escalating that treatment rather than starting it at full dose. Somebody who is doing very well on 120 mg is probably going to be okay with 160 mg. However, somebody who went from 80 mg to 120 mg and started having problems is probably not the right candidate for 160 mg.

Has the COVID-19 pandemic affected your likelihood of recommending patients for clinical trials?

[COVID-19] has not really changed my approach. I’m a firm believer of clinical trials, not just in the third-line setting, but in the second-line setting, and even, if possible, in the first-line setting. Unless and until we come up with something that can really benefit a very large subset of patients in all these settings, trials are required, irrespective of COVID-19.

It’s an exciting time, and there are lots of good, great trials and drugs––immunotherapy, targeted therapy, antibody-drug conjugates [ADCs]––that are coming up. My advice to patients and physicians alike, is to identify patients for clinical trials as early in their course of treatment as possible.

We have been involved with regorafenib and nivolumab, which generated a lot of excitement. That study is currently under way. We are a part of the U3-1402 study, which is an anti-HER3 ADC. This drug has shown significant benefits in lung cancer as well as breast cancer.

Fam-trastuzumab deruxtecan-nxki (Enhertu) has generated a lot of excitement as a potential pan-tumor HER2-directed therapy. The agent received an approval in gastric cancer earlier this year. Could we soon see an approval in CRC?

The technology has improved with the ADCs. ADCs have been there for a long period of time, but the technology has improved. Trastuzumab deruxtecan has come through for breast cancer, gastric cancer, and we also presented the data for CRC at the 2020 ASCO Virtual Scientific Program, which also showed very promising responses. It’s been included as part of the guidelines. There is a bigger study ongoing, which will hopefully lead to FDA approval of this drug in CRC.

It’s a very exciting drug, although it has some toxicities that you have to watch out for, especially interstitial lung disease. However, it is really great to see a drug work across multiple indications—anywhere where there is HER2 amplification.

It’s always good to have all these successes, but we need to do a little bit better when it comes to patient selection. We’re really good at getting drugs through the FDA, but we still have not worked out an ideal way of figuring out which patients are really benefiting from these treatments.