ctDNA, Total Neoadjuvant Therapy, and TAS-102 Signal a Shift in CRC Management

Circulating tumor DNA (ctDNA) and total neoadjuvant therapy (TNT) are reshaping the landscape of early-stage colorectal cancer (CRC), explained Tony Philip, MD, who added that the paradigm shift in the advanced setting came from moving less-intensive treatment to the first-line setting.

“We should keep an eye on what’s going to come out with ctDNA, because it’s exciting stuff. It’s nice to have these new toys to play with. We’ve just got to figure out how and when to use them,” said Philip. “Total neoadjuvant therapy for rectal cancer is really changing the landscape. For patients who have distal rectal cancers, we really should think about nonoperative management. How do we [avoid] a permanent colostomy [in some patients]? How can we preserve organ function for some of those patients?”

In the advanced setting, the addition of trifluridine/tipiracil (TAS-102; Lonsurf) to bevacizumab (Avastin) led to an improvement in overall survival (OS) vs capecitabine/bevacizumab in the frontline treatment of patients with unresectable metastatic CRC who are not eligible for standard chemotherapy, according to data from the phase 2 TASCO1 trial. In results presented during the 2021 Gastrointestinal Cancers Symposium, patients in the TAS-102/bevacizumab arm had a median OS of 22.31 months (95% CI, 18.00-23.69) vs 17.67 months (95% CI, 12.58-19.81) in the capecitabine/bevacizumab arm (HR, 0.78; 95% CI, 0.55-1.10).

“Based on the TASCO1 trial, we do have options for patients that are not able to get aggressive treatment,” said Philip.

In an interview with OncLive^® during an Institutional Perspectives in Cancer webinar on gastrointestinal malignancies, Philip, a medical oncologist at Monter Cancer Center of the North Shore, LIJ Cancer Institute, and an assistant professor of medicine at Hofstra-North Shore LIJ School of Medicine and New York Institute of Technology College of Osteopathic Medicine, provided insight into the utility of ctDNA in the early-stage setting, trials that could determine its role in clinical practice, and detailed the shift toward nonoperative and less-intensive interventions in the early-stage and advanced settings, respectively.

OncLive^®: What is the role of ctDNA in early-stage CRC, and how could it be used to detect MRD and inform a patient’s risk of recurrence?

Philip: Some of the data that was presented at [the 2021 Gastrointestinal Cancers Symposium] suggests that ctDNA may be able to pick up disease recurrence approximately 8 months prior to traditional methods, such as carcinoembryonic antigen tumor markers, or even CT scan. It lays the groundwork for some interesting data and may change how we do things moving forward. However, we definitely need a lot more clinical trials to validate whether that’s truly the case and how to use it in a day-to-day setting.

Several clinical trials are ongoing [in that regard]. Some of the trials are looking at [ctDNA] in stage II/III disease and [are studying] whether giving chemotherapy and changes in ctDNA validate its use [as] both a predictive test and a prognostic test. BEACON and COBRA are some of the trials that are ongoing, amongst many others.

How have the RAPIDO and OPRA trials contributed to our understanding of how to manage patients with locally advanced rectal cancer?

[It’s] interesting timing for RAPIDO because in the COVID-19 environment that we’re in currently, the ability to do short-course radiation might reduce patients’ time in the hospital or clinic. The outcomes for response to treatment might be preserved, so that’s one benefit.

In terms of OPRA, as we evolve the nonoperative management of distal colorectal cancers, [the data] suggest that the nonoperative management route, which was not even considered many years ago, of up-front chemoradiation followed by chemotherapy may be a better strategy.

What research is being done to improve care for patients who aren’t eligible for intensive therapy?

The TASCO1 trial is interesting because we normally think of TAS-102 as one of the last resorts of treatment. The drug is generally thought to be fairly well tolerated, but traditionally, given its approval in the fourth- or fifth-line setting, people don’t think of it as effective. However, when we look at this drug for patients that have disease, but are not really eligible for aggressive treatment, this presents an option and may be better than what we perceive to be some of the standards before, without any added toxicity. It allows us to treat some of those patients that can’t get more aggressive chemotherapy. It gives them those options as well. Many trials are ongoing, trying to figure out how to harness immunotherapy for MSS [microsatellite stable] CRC and other treatment options.

What ongoing efforts have the potential to impact practice?

Ongoing trials looking at ctDNA are really going to change practice. In trying to figure out for patients that have stage II/III disease that we think based on traditional markers of risk recurrence make them high risk, [we’ll ask whether we] can we tease out patients that may be cured from just surgery alone and don’t need chemotherapy. That would be a great practice changing result from all of this [research].

For those who we think may be cured from surgery, but truly aren’t: Should those patients benefit from chemotherapy and prevent metastatic disease from developing down the road? That’s one of the more exciting things: How do we better determine who should get adjuvant therapy and who shouldn’t? Clearly, we’re not there yet, but this lays some of the groundwork for that.

Reference

1. Van Cutsem E, Danielewicz I, Saunders MP, et al. Phase II study evaluating trifluridine/tipiracil + bevacizumab and capecitabine + bevacizumab in first-line unresectable metastatic colorectal cancer (mCRC) patients who are noneligible for intensive therapy (TASCO1): results of the final analysis on the overall survival. J Clin Oncol. 2021;39(suppl 3):14. doi:10.1200/JCO.2021.39.3_suppl.14