What is the role of Dostarlimab (antibody-drug) in treating rectal cancer?

Dostarlimab in Rectal Cancer

Dostarlimab is now a guideline-recommended first-line treatment for patients with dMMR/MSI-H locally advanced rectal cancer (stage II/III), achieving 100% clinical complete response rates without requiring surgery, chemotherapy, or radiation. 1, 2

When to Use Dostarlimab

Patient Selection Criteria

• Test all rectal cancers for MMR/MSI status using immunohistochemistry for MMR proteins or PCR for microsatellite instability 2, 3
• dMMR/MSI-H occurs in approximately 5-10% of rectal cancers 1
• Dostarlimab is specifically indicated for locally advanced (stage II or III) dMMR/MSI-H rectal adenocarcinoma as initial therapy 1, 2
• Patients must not have received prior PD-1, PD-L1, or CTLA-4 inhibitors 1

Treatment Protocol

• Administer dostarlimab 500 mg intravenously every 3 weeks for 6-9 months (typically 6-9 cycles) 4, 5
• This is monotherapy—no concurrent chemotherapy or radiation required 5, 2
• Both ASCO 2024 and NCCN guidelines formally recommend immunotherapy as the initial treatment approach for MSI-H/dMMR locally advanced rectal cancer, not as salvage therapy 1, 2

Clinical Outcomes

Efficacy Data

• All 12 patients (100%) in the landmark phase II trial achieved clinical complete response with dostarlimab monotherapy alone 5, 2
• Updated 2024 ASCO data expanded to 48 patients, with all 42 patients who completed treatment maintaining cCR with zero cases of progression or recurrence 2
• No grade 3 or higher adverse events were reported in the locally advanced rectal cancer population 1, 2
• Median follow-up ranges from 6 to 25 months with sustained responses 5

Real-World Evidence

• Italian multicenter study (STAR(t)-IT-REDUCE) confirmed 94.1% clinical complete response rate in 17 dMMR/MSI-H LARC patients treated with immune checkpoint inhibitors in routine practice 6
• Only 2 grade 3 adverse events and no grade 4 events occurred in real-world use 6

Assessment of Response

Response Evaluation Timeline

• Assess for clinical complete response at 6 months after initiating dostarlimab 2, 3
• Use multimodal assessment including:
  • High-quality pelvic MRI 2, 3
  • 18F-FDG PET/CT 5, 2
  • Endoscopic evaluation with biopsy 5, 2
  • Digital rectal examination 5, 2

Surveillance Protocol for Nonoperative Management

If clinical complete response is achieved, rigorous monitoring is mandatory 1, 2:

• Years 1-2: Digital rectal examination and flexible sigmoidoscopy every 4 months, plus MRI every 6 months 1, 2
• Years 3-5: Digital rectal examination and flexible sigmoidoscopy every 6 months, plus MRI yearly 1, 2
• 94-99% of tumor regrowth occurs within the first 2-3 years, making this surveillance window critical 2

Alternative Scenarios

When Immunotherapy is Contraindicated

• Patients may be offered standard total neoadjuvant therapy (TNT) with chemoradiotherapy followed by surgery 1
• dMMR tumors remain sensitive to chemoradiotherapy despite being less responsive to fluorouracil-based chemotherapy alone 1

For Metastatic/Advanced dMMR/MSI-H Rectal Cancer

• Dostarlimab is FDA-approved and guideline-recommended as first-line therapy for metastatic dMMR/MSI-H colorectal cancer 2, 3
• Objective response rate of 43.5% (95% CI, 34.3-53.0%) in the metastatic setting 2
• Alternative first-line options include pembrolizumab or nivolumab (with or without ipilimumab) 2, 3

For Patients with Difficulties in Anal Sphincter Preservation

• Chinese Society of Clinical Oncology guidelines suggest neoadjuvant immunotherapy (including dostarlimab) may be considered for dMMR/MSI-H patients with T4b stage or difficulties preserving the anal sphincter 1
• MDT evaluation should determine timing and approach of surgery after immunotherapy 1

Important Caveats

Potential Complications

• Rectal stenosis from scarring can occur during immunotherapy response, potentially causing intestinal obstruction requiring balloon dilation 7
• Unlike other oncological treatments, obstructions may paradoxically worsen during immunotherapy as the tumor responds and scars 7
• Patients must be counseled about this risk and monitored for obstructive symptoms 7

Limitations of Clinical Complete Response

• Concordance between clinical complete response and pathological complete response remains imperfect 1
• Risk of residual tumor in the rectal wall beyond the mucosa or in mesenteric lymph nodes exists 1
• Patients pursuing nonoperative management must understand the risk of local regrowth and potential distant metastasis 1

Ongoing Research

• The AZUR-1 trial (NCT05723562) is enrolling approximately 150 patients across 10 countries to further evaluate dostarlimab efficacy with standardized response assessment and 5-year follow-up 4
• This will provide definitive international multicentric data on long-term outcomes 4