PD-1 inhibitors may improve surgical outcomes or eliminate the need for surgery in patients with localized, mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) colorectal cancer (CRC), according to researchers.
The team found that some patients who received PD-1 inhibitors achieved a complete response (CR) and were able to forgo surgery. These responders and patients who went on to surgery were all still alive and disease-free at a median follow-up of 17.2 months.
These findings were published in the Journal of the National Comprehensive Cancer Network.
“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,” study author Pei-Rong Ding, MD, of Sun Yat-sen University Cancer Center in Guangzhou, China, said in a statement.
“With such a powerful option at hand [PD-1 inhibitors], 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.”
This study included 73 patients with nonmetastatic dMMR/MSI-H CRC who received PD-1 inhibitors between 2017 and 2021 at 3 centers in China. The patients’ median age was 48 years (range, 19-78 years), and 60.3% of patients were men.
Patients had T2 (4.1%), T3 (30.1%), T4a (26.0%), or T4b (39.7%) disease. Most patients (90.4%) had positive nodal status, 34.2% had RAS mutations, 37.0% had Lynch syndrome, and 32.9% had received prior chemotherapy.
Most patients (79.5%) received PD-1 inhibitors alone, but some received ipilimumab (4.1%) or cytotoxic chemotherapy (16.4%, 2 with concurrent radiation) as well.
The objective radiologic response rate was 84.9%. CRs occurred in 23.3% of patients, and partial responses were seen in 61.6%. The median time to response was 9.6 weeks (range, 3.7-17.3 weeks).
“Responses were observed irrespective of tumor location, RAS mutation status, the presence of Lynch syndrome, and whether there were combinatory therapies,” the researchers wrote.
Response rates were similar regardless of disease stage. The objective response rate was 85.4% for patients with cT4a/4b disease and 84.0% for patients with cT2-3 disease. However, patients with cT4a/4b disease were less likely to achieve a CR than those with cT2-3 disease — 8.3% and 52%, respectively (P <.001).
Ultimately, 50 patients went on to surgery, and 57.1% achieved a pathologic CR. The 17 patients who had achieved a CR on PD-1 inhibitors did not undergo surgery.
At a median follow-up of 17.2 months, none of the patients who underwent surgery had disease recurrence, and there were no relapses among patients who achieved a CR on PD-1 inhibitor therapy. The 2-year disease-free survival and overall survival rates were both 100% in this group.
Eight grade 3-4 treatment-related adverse events were reported during PD-1 inhibitor therapy. The most common event was bowel obstruction requiring intervention (n=3). Ten patients reported immune-related toxicities, including hypothyroidism (n=6), hypoadrenocorticism (n=2), pneumonitis (n=2), and encephalitis (n=1).
Severe surgical complications included adhesive intestinal obstruction (n=1), abdominal infection (n=1), anastomotic leak (n=1), and abdominal bleeding (n=1). Three of these patients required a second surgery.
Based on these results, the researchers concluded that neoadjuvant PD-1 inhibitor therapy is “highly effective” and has an “acceptable safety profile” in localized dMMR/MSI-H CRC.
“Although longer follow-up is need[ed] to validate its survival benefits, neoadjuvant immunotherapy has shown great promise as the new standard of care for locally advanced dMMR/MSI-H CRC,” the researchers wrote.
They noted, however, that the results of this study may be limited by the fact that PD-1 inhibitor therapy was not uniform. A variety of PD-1 inhibitors were used, some patients were prescribed off-label treatment, and 20% of patients received concurrent therapies.
Xiao B-Y, Zhang X, Cao T-Y, et al. Neoadjuvant immunotherapy leads to major response and low recurrence in localized mismatch repair–deficient colorectal cancer. J Natl Compr Canc Netw. Published online January 2023. doi:10.6004/jnccn.2022.7060
Surgery first for colon cancer? Not so fast, according to new study in JNCCN. NCCN. News release. Published January 11, 2023.