Experts highlight ctDNA-guided strategies, ADCs, and targeted therapies shaping CRC research in the first quarter of 2026.
The early months of 2026 have been marked by continued momentum in the field of colorectal cancer (CRC) research, with multiple late- and early-phase trials exploring novel antibody-drug conjugates (ADCs), biomarker-driven strategies, and immunotherapy combinations.
We asked several experts to give a quick look at some of the most highly anticipated ongoing clinical research in CRC so far this year. According to our experts, investigators are increasingly refining CRC into molecularly defined subsets, with HER2, MET, and circulating tumor DNA (ctDNA)–directed approaches emerging as key areas of focus. Concurrently, large cooperative group efforts are aiming to clarify long-standing questions regarding adjuvant therapy selection and treatment intensification.
Read our recap below for insights on how these studies may shake out and help shape the future of CRC management.
The phase 2/3 CIRCULATE-NORTH AMERICA trial (NRG-GI008; NCT05174169) is evaluating ctDNA-guided de-escalation or intensification strategies using mFOLFOX6 (modified leucovorin, 5-fluorouracil [5-FU], and oxaliplatin), CAPOX (capecitabine and oxaliplatin), or mFOLFIRINOX (irinotecan, oxaliplatin, leucovorin, and 5-FU).1 The study is actively accruing patients with high-risk stage II or stage III resected colon cancer and has expanded study participation to Canada.
After undergoing central ctDNA testing, eligible patients with ctDNA-negative disease (cohort A) will be stratified by colon cancer stage and intended chemotherapy treatment before being randomly assigned to receive the standard-of-care (SOC) treatment; or be monitored via serial ctDNA testing without chemotherapy unless they convert to ctDNA-positive status. Those with ctDNA-positive disease (cohort B) will be stratified by intended chemotherapy treatment and postoperative ctDNA status, then randomly assigned to receive either SOC or mFOLFIRINOX.
“I am excited about this study because I think it is very well designed and has the forethought to answer key questions that [are going to come up],” Jeremy Kortmansky, MD, explained in an interview with OncLive®. “These include questions around whether everyone needs adjuvant chemotherapy based on their ctDNA profile, and if there is a role for increasing the intensity of chemotherapy based on ctDNA. It has become an even more important study because when the [phase 2/3] DYNAMIC-III study [ACTRN12617001566325] was presented—which is the Australian version of the CIRCULATE study—it did not show a real advantage to increasing the intensity of therapy based on ctDNA expression. There was some concern that patients who were ctDNA negative and did not receive chemotherapy may have had a higher recurrence risk. This raised questions about whether we should be omitting chemotherapy in these patients. Having a follow-up study with a much better design is important. In the DYNAMIC-III study, the chemotherapy choices were based much more on the investigator’s choice regarding what ‘intensification’ meant, whereas in CIRCULATE, it is very clear what that means. It may be a couple of years before we see results, but [this study is important to follow].”
Kortmansky is an associate professor of clinical medicine (medical oncology), associate chief medical officer of Network Medical Services, chief of ambulatory services, clinical director of the Division of GI Medical Oncology at Yale Cancer Center, and the chief network officer for the Smilow Cancer Hospital and Yale School of Medicine in New Haven, Connecticut.
“There is a lot of interest in patients with MET amplification, which is a target for therapy,” Kortmansky added. “We have not talked about it as much in colorectal cancer as we do in lung cancer, but it represents close to 50% of patients who have some increase in their MET expression. There are a couple of drugs further along in development, such as the ADC Temab-A. This drug showed promise in heavily pretreated patients in a phase 1 study [NCT05029882], and it is now being studied in several advanced clinical trials. The benefit of that drug is not necessarily related to the level of MET expression, so it might be a drug with all-comer potential.”
Ongoing evaluations are examining Temab-A as part of combination regimens in metastatic CRC.
“One of the areas in CRC where we're really seeing improvement is with HER2-targeted therapies for CRC, [such as] fam-trastuzumab deruxtecan-nxki [T-DXd; Enhertu], which has been approved in other settings [and showed clinical benefit in the final analysis of the phase 2 DESTINY-CRC02 trial (NCT04744831)],”5 Shubham Pant, MD, MBBS, a professor in the Department of Gastrointestinal (GI) Medical Oncology and director of Clinical Research at The University of Texas MD Anderson Cancer Center in Houston, stated. “CRC trials that are ongoing with [HER2-targeted ADCs] are really something to watch out for. In that subset of treatment, we should be able to do the same thing we did [for patients with BRAF-mutated disease, which accounts for] 3% to 5% of CRCs. The way I see CRC in the future is like a big pie [that we can] cut into little slices. [For a patient in the] up-front [setting with BRAF/]KRAS wild-type, left-sided [disease], they should get EGFR-targeted therapy; [if they have BRAF mutations], they get the BRAF-targeted therapy; [if they harbor] HER2 [mutations], they get the HER2-targeted therapy, and so forth. That's what I'm excited about.”
Key ongoing studies are looking at novel and next-generation HER2-targeted ADCs in CRC, including the following:
The phase 3 STELLAR-303 trial (NCT05425940) evaluated zanzalintinib in combination with atezolizumab (Tecentriq) compared with regorafenib in previously treated non–microsatellite instability–high (MSI-H) metastatic CRC and demonstrated a 20% reduction in the risk of death (HR, 0.80; 95% CI, 0.69-0.93; P = .0045) in the intention-to-treat population, although toxicity remains a key consideration.11
“The STELLAR-303 trial showed what I thought was a modest improvement in survival in the third line at the cost of a lot of toxicity,” Kortmansky stated. “I'm not sure that that combination is quite ready for prime time, although there's probably more to come as they parse out and give us the subset analyses from that study, but toxicity management is going to be important, and so I think that that's what the horizon is.”
These results support the phase 3 STELLAR-316 trial, which will evaluate zanzalintinib with and without an immune checkpoint inhibitor in patients with resected stage II/III CRC, representing a key effort to translate efficacy signals from metastatic disease into earlier lines of therapy.12 The study is expected to initiate in mid-2026.
Lastly, Marc Lehrer Greenwald, MD, highlighted recent data showing the increasing importance of molecular selection, particularly the role of immunotherapy in MSI-H disease, as well as the need to align trial design with real-world patient heterogeneity to improve outcomes across CRC subtypes.
“The biggest thing we are finding in CRC is the use of checkpoint inhibitors with MSI-high cancers, because that is a game changer for those patients,” Greenwald, who is the chief of colorectal clinical services and surgeon-in-chief at North Shore University Hospital in Great Neck, New York, stated. “We conducted a study where we looked at lymph node involvement on CT scans. In rectal cancer, we perform clinical staging before treatment, and we are looking at whether there will eventually be clinical staging for locally advanced, lymph node–positive colon cancers before treatment. Unfortunately, we did not find the correlation that we really wanted to find, but imaging is only going to get better, and there will be other testing. That is a paradigm that may shift.
“When patients have metastatic disease to the liver or the lungs, we treat them with chemotherapy first, because surgery delays the systemic therapy they really need. We know that primaries decrease in size, and something that may be partially obstructing often improves because the patients need systemic therapy. One of the things that will probably happen as we move forward is learning how to better define those patients with colon cancer who should receive systemic therapy before surgery or local therapy. We are doing a pretty good job of figuring that out with rectal cancer because there are so many new data sets coming out every day that change the way we do things.”
