Neoadjuvant Immunotherapy Elicits Strong Responses in Localized dMMR/MSI-H Colorectal Cancer

Pei-Rong Ding, MD

Neoadjuvant treatment with anti–PD-1 inhibitors induced high rates of complete response (CR) and reduced recurrence rates, according to a retrospective analysis of patients with localized mismatch repair-deficient or microsatellite instability–high (dMMR/MSI-H) colorectal cancer (CRC).¹

Investigators need longer follow-up to confirm the survival benefits of neoadjuvant immunotherapy, but the regimen “has shown great promise as the new standard of care for locally advanced dMMR/MSI-H CRC.”

Data from 73 adult patients were included in the analysis; 62 (84.9%) achieved an objective response per radiologic assessment. Seventeen (23.3%) had a CR and 45 (61.6%) had partial responses (TABLE). One patient (1.4%) had progressive disease, and 10 (13.7%) had stable disease. Investigators observed responses irrespective of tumor location, RAS mutation status, Lynch syndrome status, and previous combination therapies.

The 2-year rates for tumor-specific overall survival (OS) and disease-free survival (DFS) were 100% for patients who underwent surgery following PD-1 blockade. There was no recurrence in patients who underwent surgery or who achieved CR.

“We need to keep in mind that our final goal is to cure patients long term, not just remove the tumor at the moment,” senior author Pei-Rong Ding, MD, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, said in a news release.² “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. With such a powerful option at hand, we have the duty to offer a safer surgery with better outcomes or a non-surgical, yet equally effective approach for this group of patients, especially for those who might suffer from function damage or organ sacrifice after surgery.”

Ding and colleagues conducted a retrospective review of patients with dMMR/MSI-H CRC who received neoadjuvant PD-1 inhibitors from October 2017 to December 2021 at 3 medical centers in China. The review included adults aged 18 to 75 years with histopathologically confirmed dMMR/MSI-H, unresected primary CRC. Patients were required to have an ECOG performance status of 0 or 1 and to have received at least 2 doses of PD-1 inhibitors. Patients who received previous chemotherapy and those with multiple CRC were also included.

Patients with suspected metastatic disease and those without radiographic assessment of treatment response were not eligible.

Nineteen patients (26.0%) had stage T4a disease, 29 (39.7%) had T4b, 3 (4.1%) had stage T2, and 22 (30.1%) had stage T3. Most patients (79.5%) received PD-1 inhibitor monotherapy.

The median patient age was 48 years (range, 19-78) and women made up 39.7% of the cohort. The most common primary tumor sites were the ascending colon and the rectum (24.7% each).

Twenty-five patients (34.2%) had a RAS mutation, and 16 (21.9%) had RAS wild-type disease. RAS status was unknown in 32 patients (43.8%).

Twenty-seven patients (37.0%) had Lynch syndrome, 15 (20.5%) did not, and Lynch status was unknown in 31 (42.5%). Sixty-six patients (90.4%) had positive nodal status, 24 (32.9%) had received prior chemotherapy, and 15 (20.5%) had received combined therapy.

The median follow-up was 17.2 months (range, 3.4-45.1). Sixteen patients were followed for more than 2 years. The median time to response was 9.6 weeks (range, 3.7-17.3).

The response rate was similar for patients with cT4a/4b disease (85.4%) and those with cT2-3 disease (84.0%) (TABLE). Investigators found that the ORR remained high even among patients with cT4b disease (n = 29; 93.1%). Patients with cT2-3 disease were more likely to achieve CR than those with cT4a/4b disease (52% vs 8.3%; P < .001).

Among forty-eight patients with locally advanced (cT4a/4b) disease, four (8.3%) had CR and 37 (77.1%) had PR with a median time to response of 9.1 weeks (range, 4.1–22). Thirty-eight of these patients (80.9%) proceeded to surgery. The median time from neoadjuvant treatment to surgery was 4.0 months (range, 1.4-12.2). All surgeries resulted R0 resection, and 22 (59.5%) patients achieved a pathologic CR (tumor regression grade [TRG] = 0).

Sixteen patients with cT4b disease received surgery; 66.7% of the resected tumors had pathologic CR. Six patients underwent multivisceral resection for suspected invasion, 4 of whom achieved a pathologic CR.

Among all patients, 23 did not receive surgery; 17 of those had a CR, 5 had a PR, and 1 had stable disease (SD). Two patients with a PR or SD were deemed resectable but still under treatment, 1 was deemed unresectable, and 3 refused surgery for unspecified reasons.

Investigators observed 8 grade 3/4 drug-related adverse effects during neoadjuvant treatment. The most common was bowel obstruction (n = 3), all of which required acute intervention. One patient underwent resection with preventive ostomy due to perforation. There were no deaths among these patients.

Ten patients experienced immune-related toxicities. The most common were hypothyroidism (n = 6), hypoadrenocorticism (n = 2), pneumonitis (n = 2), and encephalitis (n = 1). All these events were grade 1/2 except pneumonia.

Investigators analyzed postoperative complications in 51 patients undergoing surgery. There were 4 severe complications: adhesive intestinal obstruction (n = 1), abdominal infection (n = 1), anastomotic leak (n = 1), and abdominal bleeding (n = 1). Three patients required a second surgery, but there were no deaths within 1 month after surgery.

“This retrospective analysis highlights the potential for significant treatment responses with limited toxicities for these patients treated with immune checkpoint inhibitors,” Dustin A. Deming, MD, an associate professor with the University of Wisconsin Carbone Cancer Center and a member of the NCCN Guidelines Panel for Colon/Rectal/Anal Cancers, who was not involved in this study, said in a news release. “It will be exciting to see how these results, and other completed and on-going studies, will be utilized to incorporate anti–PD-1 treatments into the standard of care for locally advanced CRC.”

References

1. Xiao BY, Zhang X, Cao TY, et al. Neoadjuvant immunotherapy leads to major response and low recurrence in localized mismatch repair-deficient colorectal cancer. J Natl Compr Canc Netw. 2023;21(1):60-66.e5. doi:10.6004/jnccn.2022.7060
2. Surgery first for colon cancer? Not so fast, according to new study in JNCCN. News release. Journal of the National Comprehensive Cancer Network. January 11, 2023. Accessed January 12, 2023. https://prn.to/3ZuP5Br