What is the role of Dostarlimab (antibody) in treating colorectal cancer, particularly in patients with deficient mismatch repair (dMMR) or microsatellite instability-high (MSI-H) tumors?

Dostarlimab in Colorectal Cancer: Latest Evidence

Dostarlimab demonstrates remarkable efficacy in dMMR/MSI-H colorectal cancer, achieving 100% clinical complete response rates in locally advanced rectal cancer and 43.5% objective response rates in metastatic disease, establishing it as a guideline-recommended treatment option across multiple clinical settings. 1

Locally Advanced Rectal Cancer (Stage II/III dMMR/MSI-H)

Groundbreaking Complete Response Data

• All 12 patients (100%) in the initial phase II trial achieved clinical complete response (cCR) with dostarlimab monotherapy alone—no surgery, no chemotherapy, no radiation required. 1, 2

• Updated 2024 ASCO data expanded enrollment to 48 patients, with all 42 patients who completed treatment maintaining cCR with zero cases of progression or recurrence. 1

• Follow-up ranges from 6 to 25 months in the original cohort, with no patients requiring chemoradiotherapy or surgery. 2

• No grade 3 or higher adverse events were reported in this population. 1, 2

Guideline Recognition and Implementation

• Both NCCN and ASCO 2024 guidelines now formally recommend immunotherapy as the initial treatment approach for MSI-H/dMMR locally advanced rectal cancer. 1

• The NCCN panel has incorporated nonoperative management (NOM) with immunotherapy into the main treatment algorithm (not just footnotes) for dMMR/MSI-H disease. 1

• This represents a paradigm shift: immunotherapy replaces the traditional sequence of chemoradiation followed by total mesorectal excision (TME) in this molecular subset. 1

Critical Surveillance Requirements

Rigorous monitoring is mandatory for patients pursuing NOM after immunotherapy-induced cCR: 1

• Digital rectal examination and flexible sigmoidoscopy every 4 months for 2 years, then every 6 months for 3 additional years
• MRI every 6 months for 2 years, then yearly for 3 years
• CEA monitoring at the same intervals
• 94-99% of tumor regrowth occurs within the first 2-3 years, making this surveillance window critical 1

Important Caveats

• NOM with immunotherapy should only be offered at centers with experienced multidisciplinary teams capable of intensive surveillance and timely surgical salvage if needed. 1

• Patients must understand their risk tolerance and commit to the demanding surveillance schedule. 1

• dMMR/MSI-H status occurs in only 3% of rectal cancers (versus 10-12% in colon cancers), making molecular testing essential. 3

Metastatic/Advanced Colorectal Cancer (dMMR/MSI-H)

First-Line Treatment Setting

Dostarlimab is FDA-approved and guideline-recommended as first-line therapy for metastatic dMMR/MSI-H colorectal cancer, despite limited prospective first-line data. 1

• NCCN recommends dostarlimab, pembrolizumab, nivolumab (alone or with ipilimumab) as interchangeable first-line options for dMMR/MSI-H metastatic disease. 1

• The panel justifies dostarlimab's first-line use based on its efficacy in both untreated locally advanced disease and previously treated metastatic disease, combined with the class effect of PD-1 inhibitors in this molecular subset. 1

Previously Treated Metastatic Disease (GARNET Trial Data)

In the phase I GARNET study of 115 colorectal cancer patients with dMMR who had received prior systemic therapy: 1

• Objective response rate: 43.5% (95% CI, 34.3-53.0%) 1
• Complete response rate: 12.2% 1
• Median progression-free survival: 8.4 months 1
• Median duration of response and overall survival: not yet reached at time of analysis 1

Durability of Response Across All dMMR Solid Tumors

In the broader GARNET efficacy population of 327 patients with various dMMR solid tumors (including 105 with colorectal cancer): 4

• Overall objective response rate: 44.0% (95% CI, 38.6-49.6%) 4
• Median duration of response: not reached (range ≥1.18 to ≥47.21 months) 4
• 72.2% of responders (104/144) maintained response for ≥12 months 4
• Median progression-free survival: 6.9 months; 24-month PFS probability: 40.6% 4
• Median overall survival: not reached 4

Safety Profile

Dostarlimab demonstrates a favorable safety profile in colorectal cancer: 1, 4

• Grade ≥3 treatment-related adverse events: 16.3% in the GARNET safety population 1
• Most common immune-related adverse events: hypothyroidism (6.9%), ALT elevation (5.8%), arthralgia (4.7%) 4
• Dostarlimab was discontinued due to treatment-related adverse events in 25 of 363 patients (6.9%) 1
• No new safety signals identified with extended follow-up 4

Comparative Context with Other Checkpoint Inhibitors

While dostarlimab shows excellent efficacy, other PD-1 inhibitors have more extensive colorectal cancer data:

• Nivolumab plus ipilimumab in first-line metastatic dMMR/MSI-H CRC showed 79% reduction in progression risk versus chemotherapy (HR 0.21), with 24-month PFS not yet reached in CheckMate 8HW. 1

• Pembrolizumab in previously treated MSI-H/dMMR CRC demonstrated median OS of 31.4-47.0 months with 5-year follow-up in KEYNOTE-164. 5

• However, NCCN considers these agents interchangeable for dMMR/MSI-H disease based on mechanism of action and consistent class effects. 1

Ongoing Research: AZUR-1 Trial

A multicenter phase 2 study (NCT05723562) is currently enrolling approximately 150 patients with untreated stage II/III dMMR/MSI-H locally advanced rectal cancer to receive dostarlimab monotherapy. 6

• Primary endpoint: cCR by independent central review at 12 months 6
• Key secondary endpoints: cCR at 24 and 36 months, 3-year event-free survival, organ preservation rate at 3 years 6
• All patients will be followed for 5 years, providing crucial long-term outcome data 6
• This study will standardize clinical response assessment and provide international multicentric validation of the immunotherapy approach 6

Clinical Decision Algorithm

For patients with newly diagnosed colorectal cancer:

1. Test ALL colorectal cancers for MMR/MSI status (IHC for MMR proteins or PCR for MSI) 1

2. If dMMR/MSI-H locally advanced rectal cancer (stage II/III):

   • Offer dostarlimab or other PD-1 inhibitor as initial therapy 1
   • Assess for cCR at 6 months using MRI, PET/CT, endoscopy, DRE, and biopsy 2
   • If cCR achieved: pursue NOM with intensive surveillance (only at experienced centers) 1
   • If contraindication to immunotherapy: offer standard chemoradiation (dMMR tumors remain sensitive to CRT) 1

3. If dMMR/MSI-H metastatic colorectal cancer:

   • First-line: dostarlimab, pembrolizumab, or nivolumab ± ipilimumab 1
   • Subsequent-line (if not previously treated with checkpoint inhibitor): same options 1

4. If proficient MMR/microsatellite stable (pMMR/MSS):

   • Checkpoint inhibitors are NOT effective 3
   • Proceed with standard chemotherapy-based regimens 1