Neoadjuvant Pembrolizumab Yields High Responses for Advanced dMMR/MSI-H Solid Tumors

Article

Neoadjuvant pembrolizumab appears to improve outcomes in a cohort of patients with metastatic microsatellite instability–high, mismatch repair deficient solid tumors.

Neoadjuvant pembrolizumab (Keytruda) produced high response rates and was well tolerated in patients with advanced, metastatic microsatellite instability–high (MSI-H), mismatch repair deficient (dMMR) solid malignancies, according to data from a phase 2 study (NCT04082572) published in the Journal of Clinical Oncology.

The radiographic overall response rate (ORR) was 82% among the 33 evaluable patients, and included a complete response (CR) rate of 30% and partial response (PR) rate of 52% with a median time to response of 6 weeks (range, 4-24). A further 6 patients (18%) demonstrated stable disease.

“One of the most intriguing findings from this prospective trial is the suggestion that neoadjuvant PD-1–based therapy may represent a definitive approach for dMMR solid tumors enabling organ preservation,” according to the authors of a study published in the Journal of Clinical Oncology.

“One of the most intriguing findings from this prospective trial is the suggestion that neoadjuvant PD-1–based therapy may represent a definitive approach for dMMR solid tumors enabling organ preservation,” according to the authors of a study published in the Journal of Clinical Oncology.

Additionally, the pathologic CR (pCR) rate was 65% among the 17 patients who underwent surgical resection and 79% 14 patients diagnosed with colorectal cancer.

“Although several landmark trials have established the efficacy of checkpoint inhibitors in metastatic dMMR cancers, there is a paucity of data on neoadjuvant checkpoint inhibitors in dMMR cancers,” the investigators wrote. “To our knowledge, this single-center, phase II clinical trial demonstrates for the first time that neoadjuvant pembrolizumab is safe and feasible, and results in a high rate of complete pathologic response in patients with a range of localized dMMR solid tumor cancers.”

The open-label, single-center, phase 2 study enrolled 35 patients between October 31, 2019, and March 25, 2021, most of whom had colorectal adenocarcinoma (77%). The remainder had rectal (23%), pancreatic (6%), or duodenal adenocarcinoma (6%), or another type of cancer (11%). Most patients had stage III disease (74%) and a quarter had unresectable disease at presentation.

The median age in the study cohort was 62 years (range, 25-90). Most patients were men (57%) and White (94%).

Patients received a planned treatment course of intravenous pembrolizumab at 200 mg once every 3 weeks for 8 treatments with subsequent surgical resection. There was also the option of a nonsurgical treatment course, which entailed receipt of pembrolizumab for 16 treatments followed by observation.

A total of 18 patients underwent a non-surgical treatment course; 10 received the recommended year of pembrolizumab followed by surveillance, and the remaining 8 received less than a year of treatment.

There were no progression events among those who received treatment for a year. Among the remaining 8 patients, 5 pursued an organ-sparing approach, 3 of whom demonstrated radiographic CR and 2 achieved stable disease.

“One of the most intriguing findings from this prospective trial is the suggestion that neoadjuvant PD-1–based therapy may represent a definitive approach for dMMR solid tumors enabling organ preservation,” the investigators wrote. “We demonstrated that nonoperative management of dMMR/MSI-H localized solid tumors is promising and warrants continued exploration.”

Progression events were reported in 6 patients—4 of whom underwent salvage surgery—over the course of the study and follow-up periods.

All-cause adverse effects (AEs) affected all 35 patients. Grade 1/2 treatment-related AEs were observed in 37% and 6% had grade 3 events. No grade 4 events were reported. Two patients had died as of data cutoff from causes unrelated to treatment.

Of the 17 patients who underwent surgery, 3 developed postoperative complications, including 1 event of grade 3b surgical site abscess, 1 event of grade 2 diarrhea, and 1 event of grade 1 abdominal wall hematoma.

The small, single-institution sampling of patients limits the generalizability of these data, and the fact that surgical resection was elective may have biased some of the analysis, the investigators stated.

Nonetheless, the investigators concluded that these findings warrant larger studies on the subject.

Reference

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

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