Total neoadjuvant therapy (TNT) followed by rectal surgery is the standard of care in proficient mismatch repair (pMMR) locally advanced rectal cancer, but studies are finding that patients with clinical complete response may often avoid surgery and be followed “nonoperatively.” In the first results of the NO-CUT trial, presented at the European Society for Medical Oncology (ESMO) Congress 2024, patients assigned to total neoadjuvant therapy followed by intensive nonoperative management achieved a distant recurrence–free survival of almost 97%.¹

Alessio Amatu, MD

“In NO-CUT, one of four patients with locally advanced pMMR adenocarcinoma of the low-to-mid rectum benefited from TNT. Nonoperative management did not jeopardize distant relapse–free survival…. In patients achieving clinical complete response after TNT, nonoperative management consisting of intensive follow-up can be proposed as an alternative to rectal surgery,” said Alessio Amatu, MD, a researcher and oncologist at Niguarda Cancer Center, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy.

A clinical complete response was noted in 26% of patients, which enabled them to proceed with nonoperative management; 90% of patients with an incomplete response underwent surgery. The distant relapse–free survival rate was 96.9% in those who had nonoperative management and 76.7% in all patients. Additionally, 85% of patients who underwent nonoperative management had organ preservation, and all patients with local regrowth (which occurred within 4–18 months) underwent rescue surgery, almost half with a sphincter-sparing approach, he reported.

Study Details

NO-CUT is a multicenter single-arm phase II trial in patients with pMMR locally advanced rectal cancer that assessed whether nonoperative management would jeopardize distant relapse–free survival. It also aimed to find predictive biomarkers of clinical complete response that can be identified by multiomic analyses in tumor and blood samples. The primary study endpoint was the percentage of patients alive and distant relapse–free survival at 30 months.

Patients with cT3–4N0/cTxN1–2 lower/middle pMMR tumors underwent total neoadjuvant therapy consisting of four cycles of capecitabine and oxaliplatin (CAPOX) followed by long-course chemoradiotherapy over 5 weeks. After total neoadjuvant therapy, patients were assigned to rectal surgery or surveillance based on clinical complete response parameters. Multiomics correlative analyses and circulating tumor DNA (ctDNA) testing were performed.

In the population of 180 patients who underwent total neoadjuvant therapy, 164 (91%) completed treatment per protocol, and 46 (25.5%) were assigned to nonoperative management with intensive follow-up. Patients were followed for a median time of 26 months and 10 months, respectively. Local regrowth occurred in less than 20% of the group that had nonoperative management.

Key Findings by ctDNA Status

Circulating tumor DNA by liquid biopsies taken after total neoadjuvant therapy predicted clinical response and distant relapse–free survival, with an absence of ctDNA significantly associated with tumor response. Among patients with a complete response, 92% were ctDNA-negative, and 8% were ctDNA-positive. Among patients with an incomplete response, 31% were ctDNA-positive, and 69% were ctDNA-negative.

In an assessment of distant relapse, at 3 years, 85.8% of the ctDNA-negative patients were free of distant relapse, compared with 64.0% of ctDNA-positive patients (hazard ratio = 3.23; P = .035). After surgery, in incomplete responders, ctDNA status also predicted progression-free survival, with ctDNA positivity associated with a sevenfold hazard of disease progression.

Complete multiomics correlative analyses are in progress and will be informative. At this point, along with ctDNA’s predictive power, the patient’s transcriptomic profile at diagnosis was also associated with outcome. Such multiomics studies should help to improve total neoadjuvant therapy strategies and increase response rates by refining treatment candidates.

EXPERT POINT OF VIEW

David Sebag-Montefiore, MD

“Over the past 25 years, there’s been increasing interest in whether patients who experience a complete clinical response can safely avoid surgery and the need for a temporary or permanent stoma. We are now entering a new era where systemic and radiotherapy-based treatments alone or in combination have the potential to change the treatment paradigm within the next 5 to 10 years,” said David Sebag-Montefiore, MD, Professor of Clinical Oncology and Health Research at the University of Leeds in the United Kingdom and Director of the Leeds Cancer Research UK Radiation Centre of Excellence, the invited discussant of the NO-CUT trial.

More and more early-phase/phase II studies are showing that clinical complete response rates of up to 60% can be achieved, and patients can be successfully followed, with successful surgical salvage should local relapse occur. “In the NO-CUT trial, the 26% complete clinical response rate, the 20% local regrowth rate, and the very impressively high 97% distant relapse–free survival rate are reassuring and confirm oncologic safety,” Dr. Sebag-Montefiore said, noting that quality-of-life and functional outcome data from these patients will be important. He also lauded the investigators for their embedded translational research, “which is critically important for our scientific understanding.”

There are ongoing questions about the best sequence of the total neoadjuvant therapy, the best background for radiotherapy, the best use of immunotherapy in the majority of patients who have mismatch repair–proficient disease (recent studies showed robust responses in the small mismatch repair–deficient subset), optimal patient selection, mechanisms of treatment response and resistance, and ways to increase the clinical complete response rate further.

“We also need to avoid overtreatment and offer organ-preservation strategies to patients who want them,” Dr. Sebag-Montefiore said, explaining the need to move from an “opportunistic” approach that depends on response to total neoadjuvant therapy to a more planned approach upfront. “We are on the verge of a new era for organ preservation. Much of the groundwork has been done, and we now have a platform to build upon…to change the treatment paradigm.”

DISCLOSURE: Dr. Amatu reported financial relationships with Amgen/Italfarmaco. Dr. Sebag-Montefiore has received research funding from Cancer Research UK, Yorkshire Cancer Research, and Adlai Nortye.

REFERENCE

1. Amatu A, Zampino MG, Bergamo F, et al: Total neoadjuvant treatment with non-operative management for proficient mismatch repair locally advanced rectal cancer: First results of NO-CUT trial. ESMO Congress 2024. Abstract 509O. Presented September 16, 2024.