Combination therapy with two HER2 inhibitors plus chemotherapy could be a promising strategy for patients with locally advanced HER2-positive rectal adenocarcinoma, based on results of a small pilot study.

Six of eight evaluable patients (75%) responded to trastuzumab and tucatinib plus chemotherapy, including four clinical complete responses, according to a study presented by lead author Michael Foote, MD, a gastrointestinal medical oncologist at Memorial Sloan Kettering Cancer Center, New York City, at the American Association for Cancer Research (AACR) Annual Meeting 2026.

“Over a third of patients with rectal cancer require a total mesenteric excision of their tumor, which is a very morbid procedure that necessitates a permanent ostomy bag. It’s a life-changing experience,” said Foote. “We asked ourselves, looking at the landscape of targetable alterations in metastatic colorectal cancer, if targeting some of these alterations up front in early disease could help improve clinical complete response rates to avoid surgery.”

Foote and colleagues ultimately selected HER2 as their target. Although HER2-amplified tumors are relatively rare in colorectal cancer, a recent phase 2 trial reported compelling responses to combination therapy with trastuzumab and tucatinib among patients with metastatic disease.

“Based on this exciting data, we saw a strong rationale for including these treatments up front in patients with early-stage rectal cancer,” Foote said, during his presentation.

The investigators conducted a prospective, single-arm study involving 10 patients with locally advanced rectal adenocarcinoma. All cases were RAS wild-type, mismatch repair-proficient, and HER2 positive (immunohistochemistry [IHC] 3+ or IHC 2+ with a fluorescence in situ hybridization ratio of ≥ 2). No patients with KRAS mutations were enrolled.

“This is a high-risk population,” Foote said, of the enrolled population, noting that 70% had lymph node-positive disease. “These were big tumors that were close to the sphincter. So a lot of these patients — the majority of them — would have required a large rectal surgery on their tumor.”

The study regimen comprised 6 weeks of trastuzumab and tucatinib followed by 15 weeks of these same agents plus chemotherapy (FOLFOX or CAPOX). Patients who achieved a clinical complete response transitioned to active surveillance without surgery or radiation, whereas those without a complete response proceeded to standard-of-care chemoradiation or surgery.

In what Foote called a “very impressive” overall response rate, seven of nine patients (78%) who completed 6 weeks of dual HER2 therapy responded to treatment.

“This is much higher than expected,” Foote said.

Six of eight patients (75%) who completed the subsequent 15 weeks of HER2 inhibition plus chemotherapy responded to treatment, four of whom (50%) demonstrated a clinical complete response.

“No patient progressed on this treatment during this introductory period,” Foote noted.

One additional patient achieved a clinical complete response after undergoing radiation.

Clinical complete responses were observed only in patients with HER2 IHC 3+ tumors. HER2 gene copy number was also notably higher among complete responders, Foote noted, suggesting this metric “may be a more robust biomarker” for predicting responses.

After a median follow-up of 26 months, all of the clinical complete responders remained free of metastatic disease. Three of these patients experienced local recurrence within a median of 4 months, but all were successfully salvaged without surgery.

Among all, 90% of patients had a grade 1 or 2 adverse event, but grade 3 events were relatively uncommon and transient, including liver enzyme elevations, which occurred in 30% of patients taking the HER2 combination alone. No grade 4 or 5 events occurred.

Following the presentation, a conference attendee asked how generalizable this strategy might be to other targetable alterations in colorectal cancer.
“I think it certainly could be applied,” Foote said. “HER2-targeted treatments in advanced metastatic colorectal cancer were very successful. You could argue [in favor of evaluating] BRAF and EGFR inhibitors.”

Kenneth Tanabe, MD, professor of surgery at Harvard Medical School and chief of the Division of Gastrointestinal and Oncologic Surgery at Massachusetts General Hospital, both in Boston, suggested the neoadjuvant window is becoming more than an opportunity to shrink tumors before surgery.

“Finding the right drug for the right molecular subset has incredible potential,” Tanabe said. “By identifying the specific HER2 population and matching it with the targeted therapy, it provides opportunity for less surgery that results in organ preservation, and possibly even a watch and wait pathway that avoids surgery completely.”

Foote disclosed having relationships with Genzyme, Bristol Meyers Squibb, Intera, and others.