By Lynda Williams, medwireNews Reporter
medwireNews: Patients with deficient mismatch repair (dMMR) cancers may not require surgery after 6 months of neoadjuvant treatment with the PD-1 inhibitor dostarlimab, suggests research published in The New England Journal of Medicine.
“This study provides a foundation for altering the traditional therapeutic paradigm for early-stage dMMR solid tumors and eliminating the need for surgery and other therapies in most patients”, write Andrea Cercek (Memorial Sloan Ketting Cancer Center, New York, USA), and co-authors.
Following clinical complete responses (CCRs) with this strategy for patients with locally advanced rectal cancer, the team conducted a phase 2 study in a second cohort of rectal cancer patients and in a group of patients with other types of solid dMMR tumours.
The team gave the combined 117 patients, who had stage I–III dMMR disease suitable for surgery with curative intent, dostarlimab 500 mg every 3 weeks for 6 months and assessed the participants’ responses for up to 8 weeks after completing all nine cycles.
Patients who developed residual disease were offered standard neoadjuvant therapy and resection, while those with a CCR on tumour-specific imaging and, where feasible, endoscopy could continue without surgery or further treatment, the researchers explain.
The study included 50 patients (56% women, median age 51.0 years) with locally advanced rectal cancer, most commonly at stage T3 (56%), 49 of whom, had completed dostarlimab therapy at the time of data cutoff. All patients achieved a CCR, and continued care without surgery, and at 12 months, 37 of the patients had sustained their CCR. Therefore, the study met the primary efficacy endpoint, the researchers say.
Among the 67 patients (57% men, median age 67 years) with non-rectal types of cancer, the most common types were colon cancer (49%), gastric cancer (22%), urothelial cancer (10%), oesophageal or gastro-oesophageal junction cancer (4% each) and prostate cancer (3%). There were also individual cases of patients with periampullary cancer, cholangiocarcinoma, small bowel cancer and endometrial cancer.
The non-rectal cancer group was split evenly by nodal status and the most common tumour stage was T3 (63%). Over half (55%) of the patients did not have an MMR gene germline variant, but 21% had MSH2 and 13% had MLH1.
Overall, 35 of 54 non-rectal cancer patients who had completed treatment at the time of reporting had a CCR and 33 continued with nonoperative care, Cercek and co-authors report.
All urothelial and hepatobiliary cancer patients achieved a CCR, as did 82% of the colon cancer patients, 57% of the gastric cancer patients and 33% of the gastro-oesophageal junction cancer patients. By contrast, none of the oesophageal cancer patients or those with other tumour types did so.
Sixteen patients underwent primary tumour resection; of these, 13 had evidence of neoadjuvant therapy response, and three had pathological CR in the primary tumour but residual tumour in the lymph nodes.
“The option for curative resection was not compromised during or after treatment in any of the patients”, the team emphasises.
After a median follow-up of 20.0 months, the overall 2-year recurrence-free survival rate was 92% for the full 117 patient group, 96% for the rectal cancer group after a median 30.2 months, and 85% for the non-rectal cancer group after a median of 14.9 months.
Across both cohorts, one patient had tumour recurrence at the primary site but did not require surgery, and four had lymph node recurrence, requiring resection of a node in one patient who remained disease-free. PD-1 therapy was reinitiated in four patients, three of whom have continued to be free from disease at the time of reporting.
Reversible grade 1–2 adverse events were reported for 60% of the study participants, most commonly fatigue, rash or pruritus. There was one grade 3 episode each of diabetes, lung infection, hypothyroidism, encephalitis and neutropenia, and one grade 4 case of febrile neutropenia.
“Although the data from this study are encouraging, larger studies are needed to confirm the long-term benefit of this treatment, especially among patients with nonrectal tumors, who had a shorter median follow-up for recurrence”, Cercek et al write.
“Whether these studies enroll patients with various tumor types or focus on those with a single tumor type will be an important consideration.”
The investigators believe that a randomised trial to measure overall survival “would be prudent” for tumour types, such as colon cancer, that can be resected without major complications or impact on quality of life. This may be “less feasible” for tumours in organs such as the pancreas or stomach where surgery has life-altering effects, they note, suggesting that for these patients “results from a single-group study may be sufficient to modify clinical practice, especially when there is a high likelihood of complete response.”
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N Engl J Med 2025; doi:10.1056/NEJMoa2404512