Response rate of 85% argues against surgery-first approach in mismatch repair-deficient tumors

Neoadjuvant immunotherapy with PD-1 inhibitors led to objective responses in 85% of patients with localized and locally advanced colorectal cancer (CRC) with mismatch repair deficiency (dMMR)/high microsatellite instability (MSI-H), a retrospective study from China showed.

Overall, 62 of 73 patients achieved objective responses, primarily with single-agent PD-1 inhibition. Response rates were similar across the range of stages T2 to T4a/4b disease. The treatment led to pathologic complete response (pCR) in a majority of the patients.

After a median follow-up of 17.2 months, median recurrence-free and overall survival (OS) had yet to be reached in patients who deferred surgery. Patients who underwent surgery had a median 2-year tumor-specific disease-free survival and OS of 100%, as reported in the Journal of the National Comprehensive Cancer Network opens in a new tab or window(JNCCN).

The findings have clear implications for current clinical practice regarding dMMR CRC, according to study author Pei-Rong Ding, MD, of Sun Yat-sen University Cancer Center in Guangzhou.

“We need to keep in mind that our final goal is to cure patients long term, not just remove the tumor at the moment,” Ding said in a statementopens in a new tab or window.

“I think care providers, especially surgeons, should refrain from scheduling immediate surgery for patients with locally advanced, or even early-stage dMMR/MSI-H colorectal cancer,” he continued. “With such a powerful option at hand [immunotherapy], we have the duty to offer a safer surgery with better outcomes or a nonsurgical yet equally effective approach to this group of patients, especially for those who might suffer from function damage or organ sacrifice after surgery.”

The study represents the “highly active area of research” into new treatment strategies for dMMR/MSI-H locally advanced CRC, said Dustin A. Deming, MD, of the University of Wisconsin Carbone Cancer Center in Madison.

“This retrospective analysis highlights the potential for significant treatment responses with limited toxicities for these patients treated with immune checkpoint inhibitors,” said Deming, a member of the NCCN guidelines panel for colon, rectal, and anal cancer, in a press release. “It will be exciting to see how these results, and other completed and ongoing studies will be utilized to incorporate anti-PD-1 treatments into the standard of care for locally advanced colorectal cancers.”

As Ding and coauthors noted in their introduction to the results, PD-1 inhibition has proven highly effectiveopens in a new tab or window in the treatment of unresectable and metastatic dMMR/MSI-H CRC and has become standard of careopens in a new tab or window. The success has led to interest in neoadjuvant immunotherapy strategies for less advanced disease. Neoadjuvant cytotoxic chemotherapy often achieves substantial tumor downstaging in mismatch repair-proficient CRC but has failed to duplicate the activity in dMMR tumors.

The first studyopens in a new tab or window of neoadjuvant nivolumab (Opdivo) plus ipilimumab (Yervoy) for localized dMMR CRC showed that almost all patients had objectives responses, and 60% achieved pCR. A follow-up studyopens in a new tab or window showed major pathologic response in 95% of patients after two cycles of immunotherapy. Another recent study showed a 100% rate of complete responseopens in a new tab or window at 6 months in patients with localized dMMR rectal cancer treated with a PD-1 inhibitor. Retrospective studies have provided additional evidence of anti-PD-1 efficacy in localized/locally advanced dMMR CRC.

Ding and colleagues added to the evidence with a retrospective analysis of 73 patients with localized/locally advanced CRC with dMMR/MSI-H. The patients were treated from October 2017 through December 2021 with a variety of PD-1 inhibitors at three centers in southern China.

Colon cancer accounted for 48 cases, followed by rectal cancer with 18 and mixed CRC in seven. Two-thirds of the patients had locally advanced disease (T4a/4b). In 79.5% of cases, treatment consisted of single-agent PD-1 inhibition.

Overall, the treatment led to an objective response rate of 84.5% (84.0% in T4a/4b disease, 85.4% in T2/3 disease), including complete responses in 17 (23.3%) patients. Among 50 patients who had undergone surgery at the time of publication, 57.1% had pCR, including 59.5% in the 38 patients with T4a/4b tumors. Patients who had a complete response did not undergo immediate surgery, and all 17 remained alive and recurrence-free at last follow-up.

Grade 3/4 adverse events (AEs) related to neoadjuvant therapy occurred in eight patients (including three bowel obstructions and one bowel perforation), four of whom required acute intervention. None of the eight patients died. Immune-related AEs (all grades) occurred in 10 patients (hypothyroidism in six).

Four patients had severe postoperative complications (one case each of adhesive intestinal obstruction, abdominal infection, anastomotic leak, and abdominal bleeding). Three of the four patients required a second surgery. No patients died within 1 month of surgery.

“Although longer follow-up is needed to validate its survival benefits, neoadjuvant immunotherapy has shown great promise as the new standard of care for locally advanced dMMR/MSI-H CRC,” the authors concluded.