3 Things You Should Know About Squamous Cell Anal Carcinoma

LEARNING OBJECTIVES

Upon successful completion of this activity, you should be better prepared to:

• Review the epidemiology, risk factors, pathophysiology, and diagnostic principles essential to early recognition of squamous cell anal carcinoma (SCAC)

• Interpret recent clinical trial data and guideline recommendation updates to inform individualized care planning and optimize therapeutic sequencing in SCAC

• Evaluate the safety and efficacy data of emerging immune checkpoint inhibitors in SCAC

RELEASE DATE: March 1, 2026

EXPIRATION DATE: March 1, 2027

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Acknowledgement of Commercial Support

This activity is supported by an educational grant from Incyte Corporation.

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This activity may or may not discuss investigational, unapproved, or off-label use of drugs. Learners are advised to consult prescribing information for any products discussed. The information provided in this activity is for accredited continuing education purposes only and is not meant to substitute for the independent clinical judgment of a health care professional relative to diagnostic, treatment, or management options for a specific patient’s medical condition. The opinions expressed in the content are solely those of the individual faculty members, and do not reflect those of PER^® or any company that provided commercial support for this activity.

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1. Read this activity in its entirety.

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Squamous cell anal carcinoma (SCAC) accounts for almost 90% of anal cancer cases in the United States.¹ Well-established risk factors for developing SCAC are important screening tools, as both the incidence and mortality of this disease are rising.^2,3 Retifanlimab plus carboplatin-paclitaxel is the preferred first-line treatment for advanced SCAC, whereas subsequent-line treatment remains an important area of unmet need.

1. The incidence and associated mortality of SCAC are rising among older adults.

Several risk factors are strongly linked to SCAC. More than 90% of SCAC cases are attributable to human papillomavirus (HPV) infection.⁴ The HPV-16 high-risk subtype is linked to the development of SCAC in men and women engaging in receptive anal intercourse, and HPV-16/18 vaccines are effective for preventing the disease.^5-11 Persons living with HIV are also at increased risk for SCAC, particularly when their CD4 count has a prolonged nadir below 200 cells/µL.^12,13 Additional risk factors include multifocal female genital intraepithelial neoplasia, smoking, and receipt of a solid organ transplant.^6,7,14

In 2025, SCAC accounted for an estimated 0.5% of incident cancer cases and 0.3% of cancer-related deaths in the United States.¹⁵ The incidence and burden of SCAC are rising disproportionately in people aged 65 years and older, particularly in women.² From 2001 to 2015, SCAC incidence rose in the United States by 2.7% per year.³ The incidence of distant-stage disease tripled, and there was a 1.9% annual SCAC incidence-based mortality increase from 2001 to 2016.

Despite the rise in advanced cases of SCAC, this disease is still most commonly diagnosed at a locoregional stage, with 40% of cases localized, 37% with regional spread, 14% with metastatic disease, and 8% with unknown stage at presentation (Figure).¹⁶ Anal cancer had a 71.3% 5-year relative survival rate from 2015 to 2021, with stage-specific 5-year relative survival rates of 85.0%, 70.4%, 36.3%, and 66.5% for localized, regional, metastatic, and unknown stage, respectively.

2. Chemoimmunotherapy is the new standard-of-care frontline treatment for patients with advanced SCAC.

In treatment-naive advanced SCAC, the randomized phase 2 InterAACT study (NCT02051868) demonstrated equivalent response rates, improved safety, and a trend toward improved survival for carboplatin-paclitaxel vs cisplatin-fluorouracil.¹⁷ Although this study established carboplatin-paclitaxel as the standard of care for advanced, treatment-naive SCAC, the median progression-free survival (PFS) and overall survival (OS) were just 8.1 months and 20 months, respectively.

Investigators for the double-blind, phase 3 POD1UM-303/InterAACT-2 study (NCT04472429) randomly assigned 308 patients with treatment-naive, inoperable, locally recurrent, or metastatic SCAC to receive carboplatin-paclitaxel plus either the PD-1 inhibitor retifanlimab or placebo.¹⁸ The median PFS significantly favored the retifanlimab vs placebo group (9.3 vs 7.4 months, respectively; HR, 0.63; 95% CI, 0.47-0.84; 1-sided P = .0006). The PFS was superior in the retifanlimab group for all prespecified subgroups containing enough study participants for comparison. The study was unable to demonstrate a clear PFS benefit, however, for the addition of retifanlimab in the smaller subgroups, such as those with PD-L1 less than 1% disease (n = 28) and HIV-positive (n = 11) participants. The objective response rate (ORR) also favored the retifanlimab vs placebo group (55.8% vs 44.2%), with patients receiving retifanlimab plus carboplatin-paclitaxel achieving a 22% and 87.0% complete response and disease control rate, respectively. The median duration of response was improved for patients receiving retifanlimab vs placebo (14.0 vs 7.2 months), as was the median OS (32.8 vs 22.2 months; HR, 0.75; 95% CI, 0.55-1.01; P = .03; adjusted for crossover to retifanlimab monotherapy, HR, 0.63; 95% CI, 0.47-0.86; P = .002).^18,19 The most commonly reported grade 3 or worse adverse events (AEs) were neutropenia and anemia, with AE data summarized in Table 1.¹⁸ Retifanlimab plus carboplatin plus paclitaxel was FDA approved for frontline treatment of patients with inoperable locally recurrent or metastatic SCAC, and this regimen is the National Comprehensive Cancer Network–preferred first-line treatment for patients with metastatic SCAC.^20,21 Investigators for the phase 3 EA2176 trial (NCT04444921) are evaluating the addition of another PD-1 inhibitor, nivolumab, to carboplatin-paclitaxel for patients with advanced SCAC.²²

The randomized, noncomparative phase 2 SCARCE C17-02/PRODIGE 60 study (NCT03519295) evaluated modified docetaxel, cisplatin, and fluorouracil with (group A, n = 64) or without (group B, n = 33) atezolizumab for patients with treatment-naive, advanced SCAC.²³ The 12-month PFS (primary end point) was 45% in group A vs 43% in group B; however, a subgroup analysis suggested a trend toward benefit for SCAC with a PD-L1 combined positive score of 5 or greater. Although more grade 3 or higher AEs were reported in group A (61%) vs group B (42%), rates of discontinuation due toserious AEs were similar for groups A (12%) and B (10%).

3. Anti–PD-1 monotherapy is the preferred treatment for immunotherapy-naive, previously treated advanced SCAC, while novel approaches are being evaluated to treat immunotherapy-resistant disease.

Multiple phase 1b and 2 studies have established anti–PD-1 monotherapy as the preferred treatment for immunotherapy-naive, previously treated advanced SCAC (Table 2).^24-28 The addition of bevacizumab or cetuximab to anti–PD-1/PD-L1 therapy in 2 separate phase 2 studies failed to improve outcomes for patients with advanced, refractory, immunotherapy-naive SCAC.^29,30

Activation of TGF-β has been implicated in loss of response to antibodies targeting PD-1/PD-L1 in solid tumors.^32-34 In a single-arm study (NCT04429542) of patients with advanced, chemotherapy-resistant, immune checkpoint inhibitor (ICI)–naive SCAC, addition of the dual TGF-β:EGFR antibody ficerafusp alfa to pembrolizumab yielded encouraging disease control and PFS.^26,35 The first-in-class fusion protein bintrafusp alfa fuses a TGF-β receptor type 2 extracellular domain (acting as a “TGF-β trap”) to an anti–PD-L1 monoclonal antibody.³⁶ In a phase 1/2 trial (NCT04287868) of patients with advanced, HPV-positive cancers, the combination of an HPV vaccine, a tumor-targeting IL-12 antibody-drug conjugate, and bintrafusp alfa showed an acceptable safety profile and initial activity in ICI-naive and -resistant disease.³⁷ 

Key References

16. Cancer Stat Facts: anal cancer. National Cancer Institute Surveillance, Epidemiology, and End Results Program. Accessed January 27, 2026. https://seer.cancer.gov/statfacts/html/anus.html

18. Rao S, Samalin-Scalzi E, Evesque L, et al; POD1UM-303/InterAACT-2 study investigators. Retifanlimab with carboplatin and paclitaxel for locally recurrent or metastatic squamous cell carcinoma of the anal canal (POD1UM-303/InterAACT-2): a global, phase 3 randomised controlled trial. Lancet. 2025;405(10495):2144-2152. doi:10.1016/S0140-6736(25)00631-2

37. Floudas CS, Goswami M, Donahue RN, et al. Novel combination immunotherapy and clinical activity in patients with HPV-associated cancers: a nonrandomized clinical trial. JAMA Oncol. 2025;11(4):394-399. doi:10.1001/jamaoncol.2024.6998

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CME Posttest Questions

1. Squamous cell anal carcinoma (SCAC) is most commonly diagnosed at which of the following stages?

A. Localized disease

B. Regional disease

C. Metastatic disease

2. A 64-year-old patient presents with recent bleeding and rectal pain after bowel movements. Examination under anathestic shows an anal canal mass, and further workup demonstrates multiple small liver and lung lesions. A biopsy confirms squamous cell carcinoma and p16 positivity. The patient’s ECOG performance status is 0. Based on recent evidence, which of the following would be the most appropriate treatment approach at this time?

A. Any anti–PD-1 antibody (eg, nivolumab, retifanlimab)

B. Carboplatin plus paclitaxel

C. Carboplatin plus paclitaxel plus retifanlimab

D. mFOLFOX6 plus retifanlimab

E. Any multiagent chemotherapy regimen plus retifanlimab

3. In the randomized, phase 2 SCARCE C17-02/PRODIGE 60 study, what was the apparent impact of adding atezolizumab to modified docetaxel, cisplatin, and fluorouracil vs modified docetaxel, cisplatin, and fluorouracil alone on 12-month progression-free survival (PFS) rates for patients with previously untreated, advanced SCAC?

A. Modest improvement (52% vs 45%)

B. Substantial improvement (65% vs 45%)

C. No difference (43% vs 45%)

D. Worse 12-month PFS rate (32% vs 45%)

4. In part B of the NCI9673 study, what was the apparent impact of adding
ipilimumab 1 mg/kg every 8 weeks to nivolumab compared with nivolumab
alone in patients with advanced SCAC and at least 1 prior line of therapy?

A. Improved PFS with ipi-nivo

B. Worse PFS with ipi-nivo

C. No significant difference in PFS

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