Neoadjuvant Pembrolizumab Could Represent Avenue for Organ Preservation in Nonmetastatic, Unresectable dMMR CRC

Neoadjuvant treatment with pembrolizumab (Keytruda) led to clinical complete responses (cCRs) in patients with nonmetastatic, unresectable, mismatch repair–deficient (dMMR) colorectal cancer (CRC), marking a potential method for organ preservation in select patients, according to data from the single-center phase 2 PUMA trial (NCT05131919).

Findings presented in a posted at the 2025 ESMO Gastrointestinal Cancers Congress demonstrated that evaluable patients (n = 25) achieved an overall response rate (ORR) of 84%, including an ORR of 80% in patients with measurable disease per RECIST 1.1 criteria (n = 20).

Eight patients opted for organ preservation and forewent surgery; in this group, 7 completed treatment and were in cCR, and the final patient remained on treatment with a near cCR.

Among patients who underwent surgery (n = 17), 68% achieved a major pathologic response (MPR). Notably, 1 patient experienced disease progression during treatment with neoadjuvant pembrolizumab and received subsequent chemoradiotherapy prior to surgery; this patient achieved an MPR.

At a median follow-up of 23 months (range, 16-28) the 12-month relapse-free survival (RFS) rate was 94% (95% CI, 83%-100%). One patient who did not achieve a pathologic response had disease recurrence within 3 months of surgery, and another patient died due to a second primary tumor.

“Endoscopic [near] CR and tumor-negative biopsies were predictive of pathologic response,” lead study author Lauren van den Dungen, MD, and colleagues at the Netherlands Cancer Institute in Amsterdam, wrote in a poster presentation of the data.

PUMA Trial Rationale and Design

Although immune checkpoint inhibition given in the neoadjuvant setting has been an efficacious strategy for patients with locally advanced, dMMR CRC, those with unresectable, locally advanced dMMR tumors have generally been excluded from clinical trials evaluating regimens in the neoadjuvant and metastatic settings. As such, investigators of the single-arm, investigator-initiated trial conducted at Netherlands Cancer Institute sought to evaluate the efficacy and feasibility of organ preservation with neoadjuvant pembrolizumab in this patient population.

To enroll in PUMA, patients were required to have previously untreated, locally advanced, unresectable, dMMR colon or rectum adenocarcinoma. For this study, unresectable was defined as a requirement for multi-visceral surgery or induction therapy to achieve tumor-free resection.

After undergoing a colonoscopy, CT scan, and ECG during screening, patients received pembrolizumab at 200 mg once every 3 weeks for up to 2 years; until the tumor became resectable; or until they achieved a cCR. Follow-up colonoscopies were performed at 3, 6, 12, 18, and 24 months; follow-up CT scans were given once every 9 weeks during the first year of treatment, then once every 12 weeks during the second year.

ORR per RECIST 1.1/iRECIST criteria served as the trial’s primary end point. Secondary end points comprised MPR rate, endoscopic response assessment, circulating tumor DNA, and RFS.

At baseline, patients had a median age of 68 years (range, 37-70). The majority of the trial population was female (52%), had an ECOG performance status of 1 (56%), had stage cT4b tumors (72%), had positive lymph nodes (68%), and had primary tumors located in the colon (88%).

Reasons for unresectability at baseline stemmed from invasions of the abdominal wall (36%), adnexa (8%), bladder (4%), duodenum (24%), gallbladder (4%), iliacus muscle (12%), kidney (4%), liver (24%), major vessels including the iliac artery and superior mesenteric vein (8%), non-adjacent colon (8%), pancreas (4%), pelvic wall (8%), psoas muscle (8%), small bowel (48%), spleen (12%), stomach (12%), ureter/urethra (8%), and vaginal wall (4%).

Safety Data

Grade 3 immune-related adverse effects occurred in 2 patients (8%), and they included duodenitis and nephritis. Grade 1/2 endocrinopathies, including hypothyroidism and hypophysitis, were reported in 16% of patients.

R0 resection was reported in 16 of the 17 patients who underwent surgery. Notably, 3 responders experienced colonic obstructions.

Reference

van den Dungen LDW, de Gooyer PGM, Balduzzi S, et al. Efficacy of pembrolizumab and feasibility of organ preservation in non-metastatic, unresectable dMMR CRC: the PUMA study. Presented at: 2025 ESMO Gastrointestinal Cancers Congress; July 2-5, 2025; Barcelona, Spain. Abstract 107P.