Is there a role for Immunotherapy (IO) in the treatment of adenocarcinoma of the anorectum with metastases?

Immunotherapy for Metastatic Adenocarcinoma of the Anorectum

Yes, immunotherapy has a definitive role in metastatic adenocarcinoma of the anorectum, but only for tumors that are MSI-H/dMMR—these patients should receive PD-1 inhibitors as first-line therapy with superior outcomes compared to chemotherapy alone. 1, 2

Critical First Step: Biomarker Testing

Before initiating any systemic therapy, test all anorectal adenocarcinomas for MSI/MMR status using immunohistochemistry or PCR, as this determines whether immunotherapy is appropriate. 2 This testing is mandatory because treatment pathways diverge completely based on MMR status.

MSI-H/dMMR Tumors (5-10% of cases)

For MSI-H or dMMR metastatic anorectal adenocarcinoma, immunotherapy is the preferred first-line treatment:

First-Line Options (Category 2A Preferred):

• Pembrolizumab monotherapy: ORR 43.5-45.8%, median PFS 11 months 2
• Dostarlimab monotherapy: Similar efficacy profile to pembrolizumab 2
• Nivolumab monotherapy: Established option with durable responses 2
• Nivolumab plus ipilimumab: Median OS not reached versus 10 months with chemotherapy 2

Rationale for Immunotherapy Preference:

The biological basis is compelling—dMMR tumors accumulate frameshift mutations creating neoantigens that make them highly immunogenic. 1 These tumors demonstrate 100% clinical complete response rates in locally advanced disease with dostarlimab, with zero progression at extended follow-up. 2 This extraordinary response translates to the metastatic setting.

When Immunotherapy is Contraindicated:

If the patient has active autoimmune disease requiring immunosuppression or corticosteroids >10mg prednisone equivalent, consider fluoropyrimidine-based chemotherapy, though historically this has been less effective in dMMR tumors. 1

Microsatellite Stable (MSS) Tumors (90-95% of cases)

For MSS metastatic anorectal adenocarcinoma, standard chemotherapy remains the backbone, with limited immunotherapy benefit:

First-Line Treatment:

• Carboplatin-paclitaxel is the standard of care based on the InterAACT trial showing median OS of 20 months versus 12.3 months with cisplatin-5FU (HR 2.00; 95% CI 1.15-3.47, P=0.014). 1

Second-Line Considerations:

• Cisplatin-5FU, carboplatin, doxorubicin, taxanes, irinotecan ± cetuximab or combinations 1
• PD-L1 inhibitors may be considered in patients who have progressed on first-line therapy, but only in clinical trial settings 1

Limited Immunotherapy Data in MSS Disease:

The KEYNOTE-028 study evaluated pembrolizumab in PD-L1-positive (≥1% staining) advanced anal cancer showing ORR 17%, stable disease 42%, median PFS 3.0 months, and median OS 9.3 months. 1 Similarly, nivolumab in NCI9673 showed 24% response rate (19% partial, 5% complete) with 47% stable disease, median PFS 4.1 months, and OS 11.5 months. 1

These modest response rates in heavily pre-treated MSS patients suggest immunotherapy should be reserved for second-line or later settings when chemotherapy options are exhausted.

Critical Distinction: Anorectal Location Matters

The anorectum represents a unique anatomic site where both rectal adenocarcinoma (arising from columnar epithelium) and anal canal adenocarcinoma can occur. The treatment paradigm follows rectal cancer guidelines for tumors above the dentate line and anal cancer guidelines for tumors at or below the dentate line. 1

For Rectal-Type Adenocarcinoma with Metastases:

• If MSI-H/dMMR: Immunotherapy first-line 1, 2
• If MSS: Consider systemic chemotherapy per colorectal cancer guidelines 3

For Anal Canal Adenocarcinoma with Metastases:

• If MSI-H/dMMR: Immunotherapy first-line 2
• If MSS: Carboplatin-paclitaxel first-line 1

Common Pitfalls to Avoid

Do not use pembrolizumab monotherapy in unselected (MSS) anorectal adenocarcinoma—the response rates are insufficient to justify foregoing effective chemotherapy. 4 Immunotherapy in MSS disease should only be considered after progression on standard chemotherapy or within clinical trials.

Do not skip MMR/MSI testing—this is the single most important predictive biomarker for immunotherapy response in gastrointestinal malignancies. 2, 3 Without this testing, you risk undertreating MSI-H patients who could achieve durable complete responses with immunotherapy alone.

Do not assume PD-L1 expression predicts response in colorectal/anorectal adenocarcinoma the way it does in other tumor types—MSI/MMR status is the dominant predictive biomarker, not PD-L1 CPS or TPS. 3

Practical Treatment Algorithm

1. Confirm pathology: Adenocarcinoma of anorectum with metastases
2. Test MMR/MSI status immediately (IHC or PCR) 2
3. If MSI-H/dMMR (5-10% of cases):
   • First-line: Pembrolizumab 200mg IV Q3W, dostarlimab, or nivolumab ± ipilimumab 2
   • Continue until progression, unacceptable toxicity, or maximum 24 months 5
   • Monitor for immune-related adverse events
4. If MSS (90-95% of cases):
   • First-line: Carboplatin-paclitaxel 1
   • Second-line: Alternative chemotherapy regimens 1
   • Consider immunotherapy only after chemotherapy failure or in clinical trials 1

Emerging Considerations

Combination strategies pairing immunotherapy with chemotherapy are under investigation in MSS colorectal cancer (COMMIT trial: NCT02997228), but results are not yet available to guide practice. 1 Until these data mature, the MSI/MMR status remains the gatekeeper for immunotherapy use in anorectal adenocarcinoma with metastases.