Dostarlimab in Colorectal Cancer: Latest Evidence

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

• The National Comprehensive Cancer Network (NCCN) recommends dostarlimab as a guideline-recommended treatment option for locally advanced rectal cancer, achieving 100% clinical complete response rates in locally advanced rectal cancer 1, 2
• All 12 patients (100%) in the initial phase II trial achieved clinical complete response (cCR) with dostarlimab monotherapy alone, with no surgery, no chemotherapy, and 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, 2
• No grade 3 or higher adverse events were reported in this population, according to the Journal of Clinical Oncology 3, 4
• Both NCCN and ASCO 2024 guidelines now formally recommend immunotherapy as the initial treatment approach for MSI-H/dMMR locally advanced rectal cancer 3, 4, 5
• The NCCN panel has incorporated nonoperative management (NOM) with immunotherapy into the main treatment algorithm for dMMR/MSI-H disease 1, 2
• Rigorous monitoring is mandatory for patients pursuing NOM after immunotherapy-induced cCR, including digital rectal examination and flexible sigmoidoscopy every 4 months for 2 years, then every 6 months for 3 additional years 1, 2, 5
• 94-99% of tumor regrowth occurs within the first 2-3 years, making this surveillance window critical 1, 2

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

• Dostarlimab is FDA-approved and guideline-recommended as first-line therapy for metastatic dMMR/MSI-H colorectal cancer, with an objective response rate of 43.5% (95% CI, 34.3-53.0%) 6, 7, 8, 9
• NCCN recommends dostarlimab, pembrolizumab, nivolumab (alone or with ipilimumab) as interchangeable first-line options for dMMR/MSI-H metastatic disease 6
• In the phase I GARNET study of 115 colorectal cancer patients with dMMR who had received prior systemic therapy, the median progression-free survival was 8.4 months, and the median duration of response and overall survival were not yet reached at the time of analysis 7, 8, 9
• Grade ≥3 treatment-related adverse events occurred in 16.3% of the GARNET safety population 7, 8, 9

Clinical Decision Algorithm

• For patients with newly diagnosed colorectal cancer, the NCCN recommends testing all colorectal cancers for MMR/MSI status (IHC for MMR proteins or PCR for MSI) 3, 4, 5
• If dMMR/MSI-H locally advanced rectal cancer (stage II/III), offer dostarlimab or other PD-1 inhibitor as initial therapy, and assess for cCR at 6 months using MRI, PET/CT, endoscopy, DRE, and biopsy 1, 2, 5
• If dMMR/MSI-H metastatic colorectal cancer, first-line treatment options include dostarlimab, pembrolizumab, or nivolumab ± ipilimumab 6, 7, 8, 9

Immunotherapy for Stage IV Rectal Cancer

Introduction to dMMR/MSI-H Stage IV Rectal Cancer

• Only 3.5-6.5% of stage IV colorectal cancers are MSI-H/dMMR, which determines the role of immunotherapy in treatment 10
• The NCCN and ASCO guidelines recommend PD-1 inhibitors as first-line therapy for metastatic dMMR/MSI-H colorectal cancer, with options including pembrolizumab, which has an immune-related objective response rate of 40% in dMMR CRC 10
• dMMR tumors contain thousands of mutations that encode mutant proteins recognizable by the immune system, and upregulate PD-L1, allowing immune evasion that PD-1 inhibitors can reverse 10

Treatment of dMMR/MSI-H Stage IV Rectal Cancer

• Historically, fluoropyrimidine-based chemotherapy has been less effective in dMMR tumors, making immunotherapy the superior choice 11
• Pembrolizumab has a 20-week PFS rate of 78% in dMMR tumors, compared to 11% in pMMR/MSS tumors 10

Introduction to pMMR/MSS Stage IV Rectal Cancer

• Immunotherapy as a single agent or in combination with other immune checkpoint inhibitors, targeted therapy, chemotherapy, or radiotherapy has proven inefficient in pMMR/MSS colorectal cancer, with an immune-related objective response rate for pembrolizumab of 0% (95% CI, 0%-20%) 10
• Standard chemotherapy-based regimens remain the treatment of choice for pMMR/MSS stage IV rectal cancer 10

Biomarker-Guided Treatment Approach for Rectal Cancer

Critical Biomarker Testing Requirements

• The European Society for Medical Oncology (ESMO) recommends testing for MMR status (which determines MSI) and KRAS/NRAS mutations in all patients at the time of metastatic or locally advanced rectal cancer diagnosis, with a Level I, Grade A recommendation 12
• The American Society of Clinical Oncology (ASCO) guidelines state that immunotherapy is strongly recommended for MSI-H/dMMR rectal cancers, with low evidence quality and strong strength of recommendation 13

Practical Testing Approach

• Testing for MSI can be assessed by PCR-based microsatellite analysis or immunohistochemistry for MMR proteins (MLH1, MSH2, MSH6, PMS2) 12
• KRAS/NRAS testing should include exons 2, 3, and 4, and BRAF mutation status should be assessed simultaneously for prognostic assessment 12
• Next-generation sequencing panels are preferred over individual gene testing, as they can detect rare actionable mutations (NTRK, RET fusions, HER2 amplifications) 14

Treatment Algorithm Based on Biomarker Results

• If MSI-H/dMMR is detected, first-line treatment is immunotherapy (pembrolizumab, nivolumab, or dostarlimab), with potential for organ preservation without surgery and superior progression-free and overall survival compared to chemotherapy 13
• If MSS/pMMR and KRAS wild-type, standard neoadjuvant therapy options include total neoadjuvant therapy (TNT) with chemotherapy and radiation, and anti-EGFR therapy (cetuximab/panitumumab) is an option in metastatic disease 12
• If MSS/pMMR and KRAS mutant, anti-EGFR therapy is contraindicated, and standard chemotherapy regimens (FOLFOX, CAPOX) with or without bevacizumab are appropriate 12

Common Pitfalls to Avoid

• Do not start fluoropyrimidine-based therapy without DPD deficiency testing, as this can cause severe, potentially fatal toxicity, with a Level III, Grade A recommendation 12
• For endoscopically treated patients with limited tissue, prioritize immunohistochemistry over PCR-based MSI testing, as IHC requires less tissue 15

Molecular Testing for Metastatic Rectal Cancer

Mandatory Molecular Tests

• The American Society of Clinical Oncology and FDA mandate that patients with KRAS codon 12 or 13 mutations should NOT receive anti-EGFR antibody therapy, as KRAS mutations occur in approximately 49% of metastatic colorectal cancers and predict complete non-responsiveness to cetuximab and panitumumab 16, 17, 18
• Test KRAS mutations in codons 12, 13, 61, 117, and 146 (exons 2, 3, and 4) in all metastatic rectal cancer patients who are candidates for anti-EGFR antibody therapy, and testing must be performed in a CLIA-accredited laboratory on tumor tissue from either the primary tumor or metastasis 16, 19, 17
• The National Comprehensive Cancer Network guidelines include BRAF genotyping as an option for KRAS wild-type stage IV disease, and BRAF V600E mutations occur in approximately 5-10% of metastatic colorectal cancers and confer poor prognosis with median overall survival of only 9.2 months 16, 19

Testing Algorithm

• Perform all molecular testing (KRAS, NRAS, BRAF, MMR/MSI) at the time of stage IV diagnosis, not in a time-sensitive manner before starting treatment, as recommended by the American Society of Clinical Oncology 16, 19
• If MSS/pMMR and RAS wild-type (KRAS and NRAS), patient is eligible for anti-EGFR therapy (cetuximab or panitumumab) in combination with chemotherapy, which represents approximately 50% of metastatic colorectal cancer patients 16, 17

Additional Considerations

• Evidence for PIK3CA, PTEN, and AKT testing remains insufficient to make definitive recommendations for or against their use in guiding anti-EGFR therapy, according to the American Society of Clinical Oncology 16, 19, 20
• Do not assume KRAS wild-type status guarantees response to anti-EGFR therapy; 40-60% of KRAS wild-type patients still fail to respond, as noted by the FDA 17, 21

Molecular Testing in Metastatic Rectal Cancer

Guideline-Based Rationale for Simultaneous Testing

• The European Society for Medical Oncology (ESMO) recommends testing for MMR status and KRAS, NRAS exon 2, 3 and 4 and BRAF mutations in all patients at the time of metastatic colorectal cancer (mCRC) diagnosis with Level I, Grade A evidence 22, 23, 24
• ESMO recommends HER2 amplification testing by IHC or FISH in RAS wild-type patients with Level III, Grade B evidence, and suggests doing this test with the initial molecular tests 22, 23, 24, 25, 26
• The suggested turnaround time for molecular testing is 10 days, which supports batching all tests together rather than sequential testing that would delay treatment decisions 24, 26

Economic and Practical Advantages

• Ordering all tests simultaneously is more economical and practical than sequential testing because it allows for single tissue sample utilization, avoiding multiple biopsies and reducing tissue consumption 22, 23
• Simultaneous testing prevents treatment delays that would occur with sequential testing, allowing for comprehensive treatment planning and avoiding delays in therapy 24, 26
• Comprehensive treatment planning is enabled by knowing all biomarker results upfront, allowing clinicians to plan the entire treatment continuum, not just first-line therapy 27

Clinical Impact of Each Biomarker

• MMR/MSI status determines first-line treatment eligibility for immunotherapy, which achieves superior outcomes compared to chemotherapy in dMMR/MSI-H disease, and assists in genetic counseling for Lynch syndrome 22, 23, 28
• KRAS/NRAS mutations are mandatory before anti-EGFR therapy, as mutations predict complete non-responsiveness to these agents, and RAS wild-type patients are eligible for anti-EGFR therapy 22, 23, 27
• BRAF V600E mutation is a strong negative prognostic factor requiring assessment for treatment planning, and enables targeted therapy with cetuximab-encorafenib in second/third-line treatment 22, 23, 24, 26
• HER2 amplification identifies patients eligible for HER2-directed therapy in second-line and beyond, and testing upfront avoids delays when patients progress on first-line therapy 22, 24, 25

Practical Implementation Algorithm

• At diagnosis of metastatic rectal cancer, obtain adequate tumor tissue and order comprehensive molecular panel including MMR protein IHC or MSI testing, KRAS/NRAS mutations, BRAF V600E mutation, and HER2 amplification by IHC or FISH 22, 23, 24
• Select first-line therapy based on results, considering dMMR/MSI-H status, RAS mutation status, and HER2 amplification status 22, 27

Common Pitfalls to Avoid

• Do not delay testing until progression on first-line therapy, as this creates time pressure and may result in suboptimal treatment selection when patients are clinically deteriorating 27
• Ensure testing is performed in CLIA-certified laboratories that participate in external quality assessment schemes for molecular pathology 22, 27
• Do not forget DPD deficiency testing before initiating fluoropyrimidine-based chemotherapy, as this is a separate mandatory test with Level III, Grade A recommendation 22, 23