Filling Unmet Needs in SCAC Is Key as Incidence Rates Are Rising

Incidence rates of squamous cell anal carcinoma (SCAC) are rising each year, and further research is needed to examine treatments for the fairly rare disease.1,2 The December 16, 2024, release of a new ASCO systemic therapy guideline for stage I to III anal cancer sought to provide evidence-based guidance through a systematic review of 3 randomized controlled trials and 3 nonrandomized studies of relevant interventions.3

ASCO highlighted that concurrent chemoradiation remains the standard systemic therapy for patients with localized anal cancer; mitomycin-C with 5-fluorouracil or capecitabine is recommended as the radiosensitizing component.2 Notable recent updates regarding care in the past year also surrounded systemic therapies. The latest version of the NCCN guidelines for anal carcinoma, version 1.2025—which was the most recent update published since version 1.2024—included revisions to the first-line section as well as second-line and subsequent therapy section of the Principles of Systemic Therapy- Metastatic Cancer portion of the guidelines.4

In the first-line setting, carboplatin plus paclitaxel and retifanlimab-dlwr (Zynyz) was added as a category 2B recommendation, and in the second-line and subsequent therapy section, cemiplimab-rwlc (Libtayo), dostarlimab-gxly (Jemperli), tislelizumab-jsgr (Tevimbra), and toripalimab-tpzi (Loqtorzi) were added as preferred regimens if patients did not receive prior immunotherapy.

A Potential New SOC Could Emerge With Retifanlimab

Retifanlimab represents a promising potential new standard of care (SOC) therapy, according to data from the phase 3 POD1UM-303/InterAACT 2 study (NCT04472429) which was conducted in patients with locally recurrent or metastatic SCAC who had not received prior chemotherapy except as radiosensitizing treatment or (neo)adjuvant therapy at least 6 months prior to study entry.1 Findings from the trial presented at the 2024 ESMO Congress were particularly notable as relapse after primary treatment with chemoradiotherapy is common and the SOC therapy has not changed since the early 1980s, according to investigators. They added that the phase 2 InterAACT study (NCT02051868) established carboplatin/paclitaxel as frontline treatment as responses were meaningful and durable, but patients still experienced short progression-free survival (PFS) and overall survival (OS).

POD1UM-303 was the first and largest known phase 3 trial of a checkpoint inhibitor in SCAC, and the primary end point of PFS was met. By blinded independent central review, the median PFS was 9.3 months (95% CI, 7.5-11.3) in the retifanlimab plus carboplatin/paclitaxel arm (n = 154) vs 7.4 months (95% CI, 7.1-7.7) in the placebo plus carboplatin/paclitaxel arm (n = 154; HR, 0.63; 95% CI, 0.47-0.84; P = .0006).

Data from the interim analysis of OS showed that the humanized anti–PD-1 monoclonal antibody and chemotherapy combination led to an improvement in OS (HR, 0.70; 95% CI, 0.49-1.01; P = .0273). When adjusted for crossover, patients treated with the retifanlimab combination experienced a median OS of 29.2 months (95% CI, 24.2-not estimable) compared with 19.1 months (95% CI, 13.4-27.9) among those who received placebo plus chemotherapy (HR, 0.63; 95% CI, 0.44-0.90; P = .0055). Improvements were also seen with the investigative regimen vs control regimen in overall response rate, duration of response, and disease control rate.

Data from POD1UM-303 are supporting the planned filing of a supplemental biologics license application (sBLA) for retifanlimab in SCAC by the end of 2024, according to retifanlimab’s manufacturer, Incyte.5 In 2021, the FDA issued a complete response letter to the BLA for retifanlimab for the treatment of adult patients with locally advanced or metastatic SCAC who progressed on or were intolerant to platinum-based chemotherapy; the BLA was based on data from the phase 2 POD1UM-202 trial (NCT03597295).6 The letter noted that the FDA could not approve the application in its current form and that additional data were needed to demonstrate the clinical benefit of retifanlimab. This was consistent with the 13 to 4 vote cast by the FDA’s Oncologic Drugs Advisory Committee in June 2021 that the regulatory decision should be deferred.7

Keeping an Eye on Unmet Needs in SCAC Remains a Priority

The potential approval of retifanlimab could represent a notable advancement for patients with SCAC as the number of new anal cancer cases rises, which is largely due to endemic HPV.5 SCAC is an HPV-driven malignancy that is commonly diagnosed in the local or locoregional setting and SCAC is the most common type of anal cancer, comprising approximately 90% of cases.8,9 Furthermore, as the prognosis is poor for patients who experience relapse, have de novo metastatic disease, or have metastatic disease, therapies are needed; there are currently no FDA-approved treatments for patients who have advanced disease.1,5

The American Cancer Society (ACS) estimated that in 2024 there would be approximately 10,540 new cases of anal cancer—3,360 in men and 7,180 in women—and approximately2,190 deaths—1,000 in men and 1,190 in women.10 Although anal cancer is less common than colon or rectal cancer, ACS noted that the chance of being diagnosed with anal cancer is approximately 1 in 500. Anal cancer rarely occurs in those younger than 35 years of age and the average patient is in their early 60s. Most commonly, White women and Black men will be diagnosed, and notably, HIV is an important amplifier of SCAC—people with HIV are 25 to 35 times more likely to develop SCAC.1,10

Next steps to address unmet needs in the anal cancer field also include the evaluation of nivolumab (Opdivo) after chemoradiation in patients with higher risk localized anal cancer in the phase 3 ECOG-ACRIN EA2165 trial (NCT03233711).2

References

1. Rao S, Samalin-Scalzi E, Evesque L, et al. POD1UM-303/InterAACT 2: phase III study of retifanlimab with carboplatin-paclitaxel (c-p) in patients (pts) with inoperable locally recurrent or metastatic squamous cell carcinoma of the anal canal (SCAC) not previously treated with systemic chemotherapy (chemo). Ann Oncol. 2024;35(suppl 2):S1217. doi:10.1016/j.annonc.2024.08.2262
2. ASCO issues systemic therapy guideline for stage I-III anal cancer. ASCO Daily News. December 16, 2024, Accessed December 19, 2024. https://dailynews.ascopubs.org/do/asco-issues-systemic-therapy-guideline-stage-i-iii-anal-cancer
3. Morris VK, Kennedy EB, Amin MA, et al. Systemic therapy for stage I-III anal squamous cell carcinoma: ASCO Guideline. J Clin Oncol. Published online December 16, 2024. doi:10.1200/JCO-24-02120
4. NCCN. Clinical Practice Guidelines in Oncology. Anal carcinoma, version 1.2025. Accessed December 19, 2024. https://www.nccn.org/professionals/physician_gls/pdf/anal.pdf
5. Incyte’s retifanlimab (Zynyz) extends progression-free survival in patients with squamous cell anal carcinoma (SCAC); data featured at ESMO 2024 presidential symposium. News release. Incyte. September 14, 2024. Accessed December 19, 2024. https://investor.incyte.com/news-releases/news-release-details/incytes-retifanlimab-zynyzr-extends-progression-free-survival
6. Incyte provides regulatory update on retifanlimab for the treatment of certain patients with squamous cell carcinoma of the anal canal (SCAC). News release. Incyte. July 23, 2021. Accessed December 19, 2024. https://investor.incyte.com/news-releases/news-release-details/incyte-provides-regulatory-update-retifanlimab-treatment-certain
7. Oncologic Drugs Advisory Committee (ODAC) Meeting. FDA. June 24, 2021. Accessed December 19, 2024. https://www.youtube.com/watch?v=zj1lRsDwWB0
8. Rogers JE, Leung M, Johnson B. Metastatic or locally recurrent anal squamous cell carcinoma (SCAC): current clinical trial landscape and novel approaches. Cancer Manag Res. 2022;14:2065-2077. doi:10.2147/CMAR.S331429
9. Types of anal cancer. Cancer Research UK. Accessed December 19, 2024. https://www.cancerresearchuk.org/about-cancer/anal-cancer/stages-types/types#:~:text=Squamous%20cell%20cancer,anal%20canal%20and%20anal%20margin
10. Key statistics for anal cancer. American Cancer Society. Updated January 17, 2024. Accessed December 19, 2024. https://www.cancer.org/cancer/types/anal-cancer/about/what-is-key-statistics.html#:~:text=On%20this%20page,risk%20factors%20for%20anal%20cancer