Neoadjuvant Pembrolizumab Elicits Deep Responses in Localized MSI-H/dMMR Solid Tumors

Neoadjuvant pembrolizumab was found to have high clinical activity and an acceptable safety profile in patients with localized microsatellite instability–high/deficient mismatch repair solid tumors.

Kaysia Ludford, MD

Kaysia Ludford, MD

Neoadjuvant pembrolizumab (Keytruda) was found to have high clinical activity and an acceptable safety profile in patients with localized microsatellite instability–high/deficient mismatch repair (dMMR) solid tumors, according to data from a single-center phase 2 trial (NCT04082572) published in the Journal of Clinical Oncology.1

Of the 35 patients enrolled to the trial, 27 had colorectal cancer (CRC) and 8 had non-colorectal cancer. The primary efficacy end point was evaluable in 15 patients; 10 of the patients experienced a pathologic complete response (pCR) of 67% (95% CI, 38%-88%).

In addition to the 15 patients who underwent surgery after 3 cycles of pembrolizumab, 2 more patients received surgery after 1 and 2 cycles of the immunotherapy, respectively, with 1 of the patients achieving a pCR. In these 17 patients, the pCR rate was 65%; 6 patients did not achieve a pCR. Fourteen of these patients had CRC; in this patient subset, the pCR was 79%. Notably, treatment response with pathologic downstaging was observed in 5 patients.

Ten patients received 1 year of pembrolizumab followed by surveillance without surgical resection, and an additional 8 patients did not undergo surgical resection and received less than 1 year of the immunotherapy. The median follow-up for these 18 patients was 38 weeks (range, 0-103) from the last pembrolizumab dose received. Of those who completed less than 1 year of the immunotherapy (n = 8), 5 elected to pursue an organ-sparing approach; 3 patients experienced a complete response (CR) and 2 had stable disease (SD).

“To our knowledge, this single-center phase 2 clinical trial demonstrates for the first time that neoadjuvant pembrolizumab is safe and feasible, and results in a high rate of pCR in patients with a range of localized dMMR solid tumor cancers,” wrote lead study author Kaysia Ludford, MD, of The University of Texas MD Anderson Cancer Center, in Houston, TX, and colleagues, in the paper.

Anti–PD-1 therapy has transformed the treatment of patients with metastatic dMMR cancers. Although the role of this approach in those with localized dMMR cancers is not fully defined, encouraging data have been reported in those with dMMR CRC.

For example, the phase 3 KEYNOTE-177 trial (NCT02563002) proved that pembrolizumab is superior to chemotherapy with regard to progression-free survival (PFS) when used as a first-line treatment in this population.2 The median PFS with the immunotherapy was 16.5 months vs 8.2 months with chemotherapy (HR, 0.60; 95% CI, 0.45-0.80; P = .0002).

Because the intact primary tumor provides a source of antigens for immune priming and expansion of activated tumor-specific T cells, neoadjuvant immunotherapy is thought to hold promise. Investigators have hypothesized that the approach is promising for pairing with surgery but may also allow for nonoperative care.

To explore this concept further, the investigator-initiated, open-label, phase 2 trial was conducted at The University of Texas MD Anderson Cancer Center. To be eligible for enrollment, patients needed to have a locally advanced, histologically confirmed dMMR/MSI-H solid tumor. They were also required to be at least 18 years of age and have measurable disease by RECIST v1.1 criteria.

The planned treatment for participants was pembrolizumab administered intravenously at a dose of 200 mg once every 3 weeks for 8 treatments and subsequent surgical resection. However, a nonsurgical option was available in which patients could receive the immunotherapy for 16 treatments and then enter an observation period.

The co-primary end points of the trial were safety and pCR rate. Secondary end points comprised best overall response, rate of organ-sparing at 1 year for those who received the nonsurgical approach, and pCR rate in all patients examined. Exploratory end points included endoscopic response rates and circulating tumor DNA kinetics.

Of the 25 patients enrolled to the trial, the median age was 62 years (range, 25-90) and 57% were male. Most patients were White (94%) and had an ECOG performance status of 0 or 1 (94%). Seventy-four percent of patients had resectable disease. Most patients (74%) did not receive prior therapy, but 11% had prior radiation, 9% had prior surgery, and 6% had prior chemotherapy.

Participants had colon (54%), rectal (23%), pancreatic (6%) or duodenal adenocarcinoma (6%); 11% of patients had another tumor type, which included gastric cancer (n = 1), ampullary cancer (n = 1), meningioma (n = 1), and endometrial cancer (n = 1). Seventy-four percent of patients had stage III disease, and the remaining 23% had stage II disease.

At the time of the data cutoff date of March 31, 2022, 17 patients had undergone surgical resection and 18 patients did not.

Additional data showed that the best overall radiographic response rate achieved in evaluable patients (n = 33) was 82% (n = 27); this comprised a CR rate of 30% and a partial response rate of 52%. Eighteen percent of patients had SD.

Thirty patients had luminal gastrointestinal cancers and 19 were determined to be response evaluable. Sixty-three percent of evaluable patients (n = 12) achieved an endoscopic CR; 37% experienced incomplete responses. The median time to response in complete responders was 17 weeks (range, 6-31). Five of the complete responders received surgery and all achieved a pCR. Three of the incomplete responders received surgery and 2 of them achieved a pCR.

Regarding safety, 35 patients experienced all-cause toxicities. Grade 1 or 2 treatment-related adverse effects (TRAEs) were reported in 37% of patients, and 6% experienced TRAEs that were grade 3. No grade 4 toxicities were observed. By the time of the data cutoff, there were 2 deaths, but neither were attributed to the study treatment.

Additionally, 3 of the patients underwent surgery developed post-operative complications, which included grade 3b site abscess, grade 1 abdominal wall hematoma, and grade 2 diarrhea (n = 1 each).

“The study design, in which the patient and/or treating physician chose whether or not to proceed with surgical resection, could have introduced bias into our analysis of the primary and secondary end points of pCR and organ-sparing rate,” the study authors concluded. “Furthermore, the study size is small and represents the experience of a single institution. Larger prospective studies are warranted.”


  1. Ludford K, Ho WJ, Thomas JV, et al. Neoadjuvant pembrolizumab in localized microsatellite instability high/deficient mismatch repair solid tumors. J Clin Oncol. Published online January 9, 2023. doi:10.1200/JCO.22.01351
  2. André T, Shiu K-K, Kim TW, et al. Pembrolizumab in microsatellite-instability-high advanced colorectal cancer. N Engl J Med. 2020;383(23):2207-2218. doi:10.1056/NEJMoa2017699
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