Memorial Sloan Kettering Cancer Center researchers have demonstrated that the PD-1 inhibitor dostarlimab (Jemperli) can eliminate the need for surgery in patients with various locally advanced mismatch repair-deficient (dMMR) tumors, according to updated data presented at the American Association for Cancer Research (AACR) annual meeting in Chicago and simultaneously published in the New England Journal of Medicine.
The phase 2 study (NCT04165772) showed remarkable results across multiple cancer types, with all 49 patients with rectal cancer achieving complete clinical responses, along with 35 of 54 patients (65%) with non-rectal cancers. Of the 84 patients who achieved complete clinical responses, 82 opted to forgo surgery.
"These findings are very important for patients with early-stage dMMR tumors because it's likely they do not need surgery or radiation if they are treated first with immunotherapy for a sufficient amount of time," said Dr. Andrea Cercek, attending and section head of colorectal cancer at Memorial Sloan Kettering Cancer Center, who presented the findings.
Study Design and Key Findings
The trial enrolled 103 patients with stage 2-3 resectable dMMR cancers who received dostarlimab for six months. The first cohort included 49 patients with rectal cancer, while the second cohort comprised 54 patients with non-rectal cancers, including gastroesophageal, hepatobiliary, genitourinary, and gynecologic malignancies.
Among the 117 total patients in the study, the results were impressive:
- Recurrence-free survival at 2 years was 92% (95% CI, 86-99)
- Median follow-up for recurrence reached 20.0 months, with some patients followed for more than 5 years
- 60% of patients experienced reversible grade 1 or 2 adverse events, while 35% had no adverse events at all
The complete clinical response rate across all patients who completed treatment was 82% (95% CI, 72 to 88). Importantly, "The primary tumor did not progress or become unresectable during or after treatment in any of the patients," the investigators noted in their NEJM publication.
The Science Behind dMMR Tumors
Mismatch repair deficiency (dMMR) refers to a malfunction in the DNA repair mechanism that causes errors in DNA replication and increases mutation risk. This characteristic makes these tumors particularly responsive to immunotherapy. Approximately 5% to 15% of colorectal cancers have dMMR with high microsatellite instability (MSI-high).
The study utilized a "tumor-informed approach" with circulating tumor DNA (ctDNA) providing insights into the dynamic response to PD-1 blockade. The researchers employed a highly sensitive assay capable of evaluating up to 50 mutations in ctDNA while filtering out artifactual mutations from the sequencing process.
Lower ctDNA levels during therapy were linked to a higher likelihood of complete tumor clearance after treatment completion. Some patients showed excellent tumor downstaging but did not achieve complete response after six months, suggesting that extended treatment might have been beneficial.
Quality of Life Implications
The nonsurgical approach addresses significant quality of life concerns for patients. Surgical resection, particularly for organs like the stomach, pancreas, or rectum, can be complicated, risky, and debilitating.
This treatment strategy may be especially valuable for the rising number of young adult patients being diagnosed with colorectal cancer. According to the American Cancer Society, rates for advanced disease have climbed 3% annually in people younger than 50 years of age since around 2010.
"This is a huge problem for this earning population, 22 to 50 year olds," Dr. Cercek explained. "The majority of patients report financial problems dealing with cancer, from putting off major purchases, to debt, to worsening credit post cancer."
Beyond the financial burden, which can reach $35,000 for surgery alone according to a 2022 study, many patients fear the loss of sexual function and other complications that can result from surgical intervention.
Future Directions
The researchers are continuing to study the tumor microenvironment's potential role in patients whose tumors exhibited less robust responses to therapy, such as prostate and gastroesophageal tumors. They hope to uncover insights that could expand this approach beyond dMMR cancers.
"We believe that this study provides a basis for treatment approaches and clinical trials in the neoadjuvant setting, where effective therapy can lead to responses, preserve organs, and drastically improve survivorship," concluded Dr. Luis A. Diaz Jr., senior author and head of Solid Tumor Oncology at MSK.
The investigators called for additional work, including a possible randomized trial, to evaluate overall survival among patients eligible for surgery. The study was funded by the National Institutes of Health, the National Cancer Institute, Swim Across America, GlaxoSmithKline, Stand Up to Cancer, Haystack Oncology, the Simon and Eve Colin Foundation, and the Dalton Foundation.
