Neoadjuvant immunotherapy a potential new standard of care for localized colorectal cancer
Key findings:
- Immunotherapy with PD-1 inhibitors before surgery appeared highly effective for patients with localized mismatch repair-deficient or microsatellite instability-high colorectal cancer.
- Patients who underwent surgery after neoadjuvant anti-PD-1 therapy had 2-year tumor-specific DFS and OS rates of 100%.
Neoadjuvant treatment with immune checkpoint inhibitors for colorectal cancer induced clinical responses that helped delay or prevent surgical resection, results of a study in Journal of the National Comprehensive Cancer Network showed.
The retrospective analysis of patients with localized mismatch repair-deficient or microsatellite instability-high (dMMR/MSI-H) disease revealed short-term effectiveness of neoadjuvant anti-PD-1 therapy, in addition to longer-term survival benefits and a low recurrence rate when compared with historical results using standard-of-care immediate surgical resection.
The safety and efficacy of neoadjuvant immunotherapy may establish it as a new standard of care for adults with locally advanced dMMR/MSI-H colorectal cancer, the investigators noted.
Background
Anti-PD-1 therapy has proved highly effective among patients with metastatic dMMR/MSI-H colorectal cancer, for whom it has become the established standard of care. However, efficacy in the neoadjuvant setting among patients with localized dMMR/MSI-H colorectal cancer has not yet been validated through clinical studies, according to Pei-Rong Ding, MD, PhD, and colleagues from Sun Yat-sen University Cancer Center in China.
“[Previous] studies are subject to some common limitations, such as a small sample size and a lack of long-term follow-up,” Ding and colleagues wrote. “Whether neoadjuvant anti-PD-1 treatment could reduce tumor recurrence and prolong survival for patients with dMMR [colorectal cancer] remains unknown.”
Methodology
Ding and colleagues conducted a retrospective analysis to evaluate the feasibility and efficacy of neoadjuvant anti-PD-1 therapy for patients with localized dMMR/MSI-H colorectal cancer.
The study group included 73 adults aged 75 years or younger (median age, 48 years; range, 19-78; 39.7% women) who received anti-PD-1 therapy at one of three medical centers in Southern China between Oct. 1, 2017, and Dec. 31, 2021, prior to standard-of-care surgical resection.
Most patients (79.5%) received anti-PD-1 monotherapy and had locally advanced tumors.
Median follow-up was 17.2 months (range, 3.4-45.1).
Results
Radiologic assessment showed an objective response to neoadjuvant anti-PD-1 therapy in 62 patients (84.9%), including 17 (23.3%) who had a complete response and 45 (61%) with a partial response to therapy. Patients with more advanced T4a/4b disease showed similar response rates after therapy as those with less advanced T2-T3 disease (84% vs. 85.4%).
Seventeen patients are following a “watch-and-wait” strategy and have not undergone surgery. After more than 17 months of follow-up, median OS and recurrence-free survival had not yet been reached among these patients.
Fifty patients underwent surgical resection after neoadjuvant immunotherapy, resulting in a pathologic complete response rate of 57.1%. Thirty-eight patients with more advanced T4a/4b tumors had slightly higher (59.5%) complete response rates.
Patients who underwent surgery after neoadjuvant anti-PD-1 therapy had 2-year tumor-specific DFS and OS rates of 100%.
Eight patients experienced grade 3 or grade 4 treatment-related adverse events during the neoadjuvant treatment period. Four patients required acute intervention to resolve symptoms.
Four patients had severe postoperative complications, but no deaths occurred within 1 month of surgery.
Clinical implications
The results suggest neoadjuvant therapy with anti-PD-1 therapy is “highly effective” for adults with localized dMMR/MSI-H colorectal cancer, Ding and colleagues noted.
“Although longer follow-up is needed to validate its survival benefits, neoadjuvant immunotherapy has shown great promise as the new standard of care for locally advanced dMMR/MSI-H [colorectal cancer],” they wrote.
“We need to keep in mind that our final goal is to cure patients long term, not just remove the tumor at the moment,” Ding said in a National Comprehensive Cancer Network press release .
“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,” he added. “With such a powerful option at hand, we have the duty to offer a safer surgery with better outcomes or a nonsurgical-yet-equally effective approach for this group of patients, especially for those who might suffer from function damage or organ sacrifice after surgery.”
References:
- National Comprehensive Cancer Network. Surgery first for colon cancer? Not so fast, according to new study in JNCCN (press release). Jan. 11, 2023. Available at: www.nccn.org/home/news/newsdetails?NewsId=3596. Published Jan. 11, 2023. Accessed Jan. 12, 2023.
- Xiao BY, et al. J Natl Compr Canc Netw. 2023;doi:10.6004/jnccn.2022.7060.
Perspective
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This study asked a very important question about the efficacy of neoadjuvant PD-1 blockade monotherapy for patients with localized colorectal cancers that are dMMR/MSI-H, which represents approximately 15% of colorectal cancers.
However, it is severely limited in the application of the results because it is a retrospective analysis without a well-defined intervention. The choice of drug for PD-1 blockade and the number of doses varied between patients, and some patients (20%) received combination therapy with chemotherapy, targeted therapy or radiation. Additionally, one-third of patients had received prior chemotherapy.
Most patients in this study had locally advanced disease with clinical lymph node involvement or clinical T4 disease. The results are remarkable with a high response rate (84.9%). Patients who had a complete radiographic response (23.3%) — including four with clinical T4 disease — did not undergo surgery, and at time of follow-up, there was no evidence of recurrence, but median follow-up was less than 18 months.
Of the 50 patients who underwent surgery, 57% had a complete pathologic response and 95% had negative lymph node on pathology. This raises the question if these lymph nodes were truly involved with malignant disease or inflammatory? In future trials, it will be important to determine which patients will be able to avoid surgery, a main component of curative treatment for localized colorectal cancers, as there was poor correlation between post-treatment imaging and pathology.
The results need to be substantiated in a large randomized clinical trial with long-term follow-up to determine durability of response to immunotherapy, risk for recurrence and whether treatment can be de-intensified to forgo surgery and/or chemotherapy.
Most importantly, this study highlights the importance of testing MMR/MSI status for all patients with colorectal cancer, regardless of stage. In this study, 37% of patients had Lynch syndrome.
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