The study’s invited discussant was Kimmie Ng, MD, MPH, Associate Professor of Medicine at Harvard Medical School and Co-Director of the Colon and Rectal Cancer Center at Dana-Farber Cancer Institute, Boston. “Neoadjuvant dostarlimab-gxly for 6 months represents a promising new treatment for patients with stage II to III mismatch repair–deficient [dMMR] rectal cancer,” Dr. Ng commented. Although she considers the findings “clinically meaningful and scientifically plausible,” more data are needed before they become “practice-changing,” she stated.
The standard of care for T3–4 node-positive rectal cancer has long involved trimodality therapy, with a recent move toward total neoadjuvant therapy (TNT), whereby chemotherapy and chemoradiotherapy are moved upfront, prior to surgery. Any of these components of care may lead to significant morbidity, so there have been attempts to eliminate or deintensify these components while still maintaining treatment efficacy, she added.
“Dr. Cercek and colleagues are attempting to replace these components in favor of a biomarker-driven approach involving anti–PD-1 therapy alone for patients with dMMR rectal cancer. Although this may seem bold at first, especially in a potentially curative setting, the study is supported by strong data showing high efficacy of checkpoint blockade for dMMR metastatic colorectal cancer,” Dr. Ng noted.
Kimmie Ng, MD, MPH
Anti–PD-1 monotherapy results in response rates of approximately 30% in the refractory setting, with higher rates possible with combined blockade (ie, nivolumab plus ipilimumab). In the neoadjuvant setting, this approach appears even more promising. In the NICHE trial of neoadjuvant ipilimumab/nivolumab, 95% of patients with dMMR tumors achieved a major pathologic response, and 60% had a pathologic complete response rate.1
“Now, we have data showing the potential efficacy of preoperative immunotherapy, with a 100% clinical complete response rate among 14 patients. No radiation has had to be given, and no surgery has had to be done. The responses appear to be durable as well, although median follow-up is currently still only 6.8 months,” Dr. Ng noted.
In comparison to “benchmark data” on clinical complete responses and organ-preservation rates to TNT in the OPRA study, the current study’s clinical complete response rate of 100% “certainly does compare favorably” with the 74% rate reported with TNT in the OPRA study,2 she said.
“The potential to decrease morbidity by eliminating pelvic radiation and surgery for our patients is huge…. The potential impact is particularly relevant as rates of rectal cancer rise steadily in individuals younger than age 50,” Dr. Ng noted.
The results are also scientifically plausible. A growing body of evidence is showing that in early-stage disease, checkpoint blockade may yield durable responses and improve the control of micrometastatic disease.
“Is the study practice-changing today? My answer is ‘not yet,’” Dr. Ng said. “The sample size is small (14 patients), and median follow-up is still extremely short (6.8 moths); we know that 88% of tumor regrowths can happen up to 2 years after completion of TNT. All patients were enrolled at a single institution, with arguably the most extensive expertise in the nonoperative management of rectal cancer. And, finally, the only endpoint available right now is overall response, with no data on survival or other clinically relevant outcomes,” she explained.
For single-agent neoadjuvant checkpoint blockade to become the standard of care in early rectal cancer, several questions still need to be answered, and, ideally, a randomized trial (eg, a comparison of dostarlimab and TNT) should be performed. “However, I suspect it’s not feasible to conduct such a trial in this extremely rare population of patients with dMMR tumors. I also suspect that off-protocol use of neoadjuvant immunotherapy is likely to occur with the publication of these results. Finally, the willingness of patients to be randomly assigned to such a study is also questionable,” noted Dr. Ng.
Meanwhile, Dr. Ng said she looks forward to seeing 3-year disease-free survival, organ-preservation rates, and ideally biomarker findings from this study. She also hopes there will be multi-institutional participation in evaluating this promising approach. “We need to confirm that the high clinical complete response rates and the complex nonoperative management of rectal cancer can be replicated in all cancer care settings,” she added.
DISCLOSURE: Dr. Ng has served as a consultant or advisor for Bayer, Bicara Therapeutics, BiomX, GlaxoSmithKline, Redesign Health, Seattle Genetics, and X-Biotix Therapeutics.
1. Chalabi M, Fanchi LF, Dijkstra KK, et al: Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers. Nat Med 2020 26:566-576, 2020.
2. Garcia-Aguilar J, Patil S, Kim JK, et al: Preliminary results of the organ preservation of rectal adenocarcinoma (OPRA) trial. 2020 ASCO Annual Meeting. Abstract 4008.
In a study of 18 patients with locally advanced mismatch repair–deficient (dMMR) rectal cancer, 6 months of neoadjuvant treatment with the anti–PD-1 agent dostarlimab-gxly alone led to clinical complete responses in 100% of the study’s first 14 patients.1 These results were presented at the 2022...