Neoadjuvant Immunotherapy Produces Promising Antitumor Response in Locally Advanced dMMR/MSI-H CRC

The use of neoadjuvant immune checkpoint inhibitors yielded promising pathological responses in patients with mismatch repair deficient (dMMR) and/or microsatellite instability–high (MSI-H) locally advanced colorectal cancer (CRC), according to findings from a study published in the British Journal of Surgery.

Eight patients of nine experienced a pathological complete response (CR) following treatment with immunotherapy, and the remaining patient had a near-complete response, with less than 1% of viable residual tumor remaining. The patient did not have a pathologic CR was 1 of 4 who received neoadjuvant chemotherapy prior to treatment with immune checkpoing inhibitor. Investigators evaluated a mean of 40.9 lymph nodes for each patient; they reported that just 1 patient had a single positive lymph node. Median follow-up was 11 months (range, 7-31 months). All patients were alive and free of recurrence at follow up.

The researchers evaluated 9 patients with locally advanced nonmetastatic colorectal cancer who were treated at MD Anderson Cancer Center. All patients received neoadjuvant immune checkpoint inhibitor therapy, including pembrolizumab (Keytruda), nivolumab (Opdivo), and a combination of nivolumab and ipilimumab (Yervoy). Moreover, patients had stage II to stage III confirmed dMMR or MSI-H disease. All visible tumors were resected following neoadjuvant immunotherapy. Data were collected retrospectively from April 2017 to May 2020.

“A subset of patients diagnosed with colorectal cancer represents a biologically distinct population, characterized by [dMMR] or [MSI-H] tumors,” lead author Anai Kothari, MD, MS, an assistant professor of the Department of Surgical Oncology at the Froedtert Hospital Cancer Center, Medical College of Wisconsin, wrote. “Although these patients benefit less from conventional chemotherapy than those with proficient mismatch–repair [and/or] microsatellite-stable disease, a significant fraction will respond to checkpoint inhibitors. In the metastatic setting, checkpoint inhibitors are used regularly to treat [dMMR CRC] based on several clinical trials demonstrating a high frequency of durable clinical response. The role of neoadjuvant [checkpoint inhibitors] in the setting of locally advanced potentially resectable disease, however, remains to be fully defined.”

The main outcomes were radiographic and pathological responses. Investigators defined a pathological CR as an absence of cancer cells in surgical specimens. Additionally, lymph nodes were evaluated for the possible presence of cancer. Secondary outcomes included toxicities associated with immune checkpoint inhibitors, perioperative adverse effects that occurred within 30 days of surgery, and recurrence-free survival.

In total, 4 patients were men and 5 were women, with ages ranging from 37 to 75 years. Four of the patients received neoadjuvant chemotherapy before immunotherapy; these patients underwent a mean of 4 chemotherapy cycles. Moreover, patients received a median of 5 immunotherapy doses (range, 1-16). A median of 5 months elapsed from the beginning of immunotherapy to resection, and a median of 48 days passed between the end of immunotherapy and the date of surgery. Seven patients received pembrolizumab, 1 received nivolumab alone, and 1 received a combination of nivolumab and ipilimumab. Four patients underwent extended or multivisceral resection and 6 had bulky tumors measuring 5 cm or greater. Following treatment, investigators observed residual intraluminal mass and mucin in 8 of 9 patients. Progressive homogeneity of mucin pools of immunotherapy was reported in 5 of 8 patients and 5 of 9 patients were partial responders by Response Evaluation Criteria in Solid Tumours version 1.1.

“The use of checkpoint inhibitor therapy for patients with locally advanced, non-metastatic colorectal cancer offers a promising new strategy for dMMR [and/or] MSI-H tumors,” the authors wrote.

Notably, the study was limited by its small sample size, retrospective nature, and short follow-up.

“Ultimately, larger prospective studies will also be needed to confirm the generalizability of these findings and their application as standard of care. Nevertheless, a consecutive series in which all patients achieved a complete or near-complete pathological response to neoadjuvant checkpoint inhibitor treatment is remarkable,” the investigators concluded

Reference

Kothari A, White MG, Peacock O, et al. Pathological response following neoadjuvant immunotherapy in mismatch repair-deficient/microsatellite instability-high locally advanced, non-metastatic colorectal cancer: Neoadjuvant checkpoint inhibition in locally advanced colorectal cancer. Bri J Surg. 2022;109(6):489-492. doi:10.1093/bjs/znac050