Invited discussant James Larkin, PhD, a clinical researcher at the Royal Marsden Hospital, London, commented on the findings from NICHE-2.1 “These striking data are consistent with the recent report in locally advanced mismatch repair–deficient [dMMR] rectal cancer from Memorial Sloan Kettering.2 You don’t see many waterfall plots like this [Kaplan-Meier disease-free survival curve]. It’s obviously a major effect for a very brief treatment.... Only one dose of ipilimumab at 1 mg/kg was used, and with really very good tolerance. However, the duration of follow-up is relatively short, so we’ll need to see those 3-year disease-free survival data in due course.”
James Larkin, PhD
Andrea Cercek, MD
The ASCO Post asked for additional comment from Andrea Cercek, MD, Head of the Colorectal Cancer Section and Co-Director of the Center for Young Onset Colorectal and Gastrointestinal Cancers at Memorial Sloan Kettering Cancer Center, New York. Dr. Cercek led the study of neoadjuvant dostarlimab-gxly in locally advanced dMMR rectal cancer.2
“NICHE-2 is a remarkable study with incredible responses and confirms pathologically what we saw in the rectal cancer study: dMMR, MSI-high [microsatellite instability] tumors that are early-stage have phenomenal responses to immune checkpoint blockade—whether it’s with a single agent, as we saw in the rectal study, or dual blockade, as in NICHE-2,” she said.
The 100% response rate and 67% pathologic complete response rate were achieved with 1 month of neoadjuvant therapy. The question is whether a longer duration of treatment might have boosted the pathologic complete response to 100% as well. “That’s certainly possible,” Dr. Cercek said. “But the point is that when these tumors are treated early in their innate environment, they are very, very sensitive to immunotherapy. This was clearly supported with these data, where the patients underwent surgery.”
Whether the tumor response will translate into improvement in disease-free survival remains to be seen. This may be more difficult to prove, since resected early dMMR/MSI-high tumors already have a favorable prognosis, Dr. Cercek added. Does this unusually high response rate mean these patients with stage III disease will not require adjuvant therapy? “We don’t know because the duration of neoadjuvant treatment was short,” although based on the significant tumor response, it’s possible, she said.
Dr. Cercek noted that patients with dMMR/MSI-high disease do not respond particularly well to chemotherapy anyway. “In patients with dMMR disease who undergo surgery, we are questioning whether adjuvant chemotherapy is the right treatment, or whether it should be adjuvant immunotherapy or, even better, neoadjuvant immunotherapy…. My thought is we are going to move away from chemotherapy in this patient population.”
Organ Preservation
Both Dr. Cercek and Dr. Larkin emphasized that organ preservation is a primary reason for pursuing neoadjuvant treatment, certainly in rectal cancer. In colon cancer, the benefits are less clear, as this has not yet been demonstrated by NICHE-2.
“With rectal cancer, pelvic radiotherapy and surgery have significant lifelong consequences in terms of morbidity and function. It may be, with colon cancer, that having a hemicolectomy plus or minus a temporary stoma is less morbid,” Dr. Larkin suggested. “For colon cancer, organ preservation would require subsequent surveillance with colonoscopy, even biopsies, so this needs to be defined. The organ preservation paradigm in rectal cancer was driven by patients, and as such, the data on the patient view on organ preservation in colon cancer are critical.”
DISCLOSURE: Dr. Larkin reported financial relationships with Eisai, Novartis, Merck, Pfizer, BMS, iOnctura, Debiopharm, Incyte, MSD, Pierre Fabre, Ipsen, Roche, EUSA Pharma, AstraZeneca, GSK, Calithera, Ultimovacs, Seagen, and Nektar Therapeutics. Dr. Cercek has served as a consultant or advisor to Bayer, GlaxoSmithKline, Incyte, Janssen, Merck, G1 Therapeutics, Pfizer, and Seattle Genetics and has received research funding from GlaxoSmithKline, Seattle Genetics, and Inspirna.
REFERENCES
1. Chalabi M, Verschoor Y, Van den Berg J, et al: Neoadjuvant immune checkpoint inhibition in locally advanced MMR-deficient colon cancer: The NICHE-2 study. ESMO Congress 2022. Abstract LBA7. Presented September 11, 2022.
2. Cercek A, Lumish MA, Sinopoli JC, et al: Single agent PD-1 blockade as curative-intent treatment in mismatch repair deficient locally advanced rectal cancer. 2022 ASCO Annual Meeting. Abstract LBA5. Presented June 5, 2022.
