ctDNA-Guided Approaches Reveal Effective Adjuvant Agents in MRD+ CRC

Tanios S. Bekaii-Saab, MD

Recent data on guided approaches with circulating tumor DNA (ctDNA) for patients with colorectal cancer (CRC) who displayed minimal residual disease (MRD)-positivity following surgery have shown that trifluridine/tipiracil (Lonsurf) does not significantly improve outcomes and the anti-inflammatory drug celecoxib (Celebrex) plus fluorouracil, leucovorin, and oxaliplatin (FOLFOX) does, according to Tanios S. Bekaii-Saab, MD.1,2

In the phase 3 CALGB/SWOG 80702 study (NCT01150045), patients with ctDNA-positive stage III colon cancer achieved an estimated 5-year overall survival rate of 61.6% (95% CI, 52.4%-72.4%) when given adjuvant celecoxib plus FOLFOX (n = 99) compared with 39.9% (95% CI, 29.6%-53.8%) when treated with placebo (n = 74; HR, 0.58; 95% CI, 0.38-0.90%-53.8%; P = .0135).1 Additionally, patients who were ctDNA-positive following curative resection that received chemotherapy with trifluridine/tipiracil vs placebo did not experience a statistically significant disease-free survival (DFS) benefit in the phase 3 ALTAIR study (NCT04457297).2 However, as the median DFS was 9.30 months (95% CI, 7.92-10.84) compared with 5.55 months (95% CI, 4.17-7.33), respectively, a numerical benefit was observed (HR, 0.79; 95% CI, 0.60-1.05; P = .107).

“Where the data have been most consistent [are] specifically with the tumor-informed tests—those are the ones that seem to have the highest level of sensitivity,” Bekaii-Saab said in an interview with OncLive®. “For those [examinations], the presence of MRD-negative disease could suggest a lack of benefit from adjuvant chemotherapy. I say ‘could’ because it still needs to be validated in randomized settings, whereby patients with positive disease may somewhat benefit from some chemotherapy.”

In the interview, Bekaii-Saab detailed studies of ctDNA-guided strategies that are elucidating the role of adjuvant therapies in CRC and he highlighted agents of promise. Bekaii-Saab is leader of the gastrointestinal cancer program at the Mayo Clinic Comprehensive Cancer Center, as well as the medical director of the Cancer Clinical Research Office and vice chair and section chief for medical oncology at Mayo Clinic in Phoenix, Arizona.

OncLive: What is the role of ctDNA in MRD detection for patients with CRC?

Bekaii-Saab: It’s an interesting subject. Assessment of MRD has made its way into CRC, specifically in the earlier stages of the disease, but also more into oligometastatic disease. Now, the role continues to be explored further. Most of the data we’ve had so far, except [for from] a couple of studies, were from large observational studies. But the results continue to be consistent across [the board] whether it’s the CIRCULATE-Japan GALAXY trial [UMIN000039205], [the observational] BESPOKE study [NCT04264702] from the US, or other smaller studies—they all suggest that patients who have MRD assessment may benefit at least from a discussion about whether to [move forward with] or forego treatment.

What studies are helping to elucidate the role of ctDNA?

One that was a bit disappointing was the ALTAIR study [NCT04457297]. The ALTAIR study was part of CIRCULATE-Japan, and it looked at patients who were MRD-positive [following curative resection] and randomly assigned them to trifluridine/tipiracil or [placebo]. There was not a significant difference between the 2 groups. For patients with MRD-positive disease, it wasn’t clear whether switching to trifluridine/tipiracil vs observation would make a difference. That was a bit disappointing. However, on the other side, one would ask the question: Is trifluridine/tipiracil the right agent? It is a fluoropyrimidine, and patients were already exposed to capecitabine. Does that make sense? Should we go more toward targeted approaches? [For example], if a patient has a BRAF V600E mutation, do we go to BRAF-targeted strategies, rather than just switch to another chemotherapy? That study, unfortunately, tells us that another chemotherapy may not cut it.

Where things got a bit interesting was from the CALGB/SWOG 80702 study, which was looking at chemotherapy [with] 3 years of celecoxib or placebo. This study was negative for celecoxib’s effect vs placebo following adjuvant therapy, but there were hints that there is a small subgroup of patients who may benefit. In the follow-up study, approximately less than half of the patients had enough material that they could assess their MRD [with], and those who had MRD-positive disease appeared to benefit from the addition of celecoxib vs those who did not.

How will data from CALGB/SWOG 80702 inform care?

The question is would that change our standard today? Does it mean that patients who are MRD-positive should be put on celecoxib? Celecoxib does come with its own toxicities. This study was a post-hoc analysis, it was also a retrospective look, and less than half of the patients had materials [available to examine for MRD]. All these limitations have to be taken into account before making a decision, but I believe it’s worth discussing with patients. I’m finding myself at least having some level of discussion with patients about this [therapy], giving the pros and the cons, and the fact that the data are still soft and further study needs to be assessed.

On that front, we’ve had some interesting data from the phase 3 ALASCCA study [NCT02647099] that looked at PIK3CA mutations as predictors of effectiveness of aspirin, and it did show that there may be some benefit. It was a randomized study, [and] it certainly has its limitations, but the effect was powerful. Historically, we’ve known that there may be some benefits from these agents, whether COX-2 inhibitors or NSAIDs, in patients with CRC following resection, and that may cut down on the risk of recurrence. But the problem today is we don’t have a positive study large enough [and] prospective enough to take us in one [direction] or the other. [However], the data are looking promising, [and] it changes the discussion, and that’s important.

References

1. Nowak JA, Shi Q, Twombly T, et al. Prognostic and predictive role of circulating tumor DNA (ctDNA) in stage III colon cancer treated with celecoxib: findings from CALGB (Alliance)/SWOG 80702. J Clin Oncol. 2025;43(suppl 4):LBA14. doi:10.1200/JCO.2025.43.4_suppl.LBA14
2. Bando H, Watanabe, Kotaka M, et al. A randomized, double-blind, phase III study comparing trifluridine/tipiracil (FTD/TPI) versus placebo in patients with molecular residual disease following curative resection of colorectal cancer (CRC): the ALTAIR study. J Clin Oncol. 2025;43(suppl 4):LBA22. doi:10.1200/JCO.2025.43.4_suppl.LBA22