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

Squamous cell anal carcinoma | Image

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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

“I’m involved in those guidelines [and] we [created them] to provide updates for individuals because there’s a rising incidence of anal carcinoma—as of 2024, it is over 10,000 cases per year—so it’s been rising a little less than 2% annually,” Cathy Eng, MD, FACP, FASCO, said in an interview with OncLive®. “It’s important to make sure that providers, both in the community and academic setting, are familiar with any new developments in a disease that was previously considered rare. Now that we’re exceeding 10,000 cases per year, we want individuals to become more familiar with recent updates.”

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.

“The most important thing for [patients with] earlier stage disease, meaning stages I through III non-metastatic [disease], is being diagnosed in a timely fashion because it’s well documented that the tumor size—a tumor greater than 4 centimeters—and having any lymph node involvement reduces a patient’s chance of benefiting from combined chemotherapy and radiation therapy, which can be curative," Eng explained.

"For early-stage disease, we try our best to avoid any surgical intervention because if a patient has to undergo surgery, they end up losing their sphincter and [have] a permanent colostomy. Therefore, it is critical to be diagnosed early on. A common finding that I hear repeatedly is patients presume it’s a hemorrhoid or the physician has misdiagnosed them and has presumed it’s a hemorrhoid. If a patient has something there that is unresolving for several weeks [they should] see another physician or go to their gastroenterologist or a colorectal surgeon for an evaluation. That’s the best way we can cure our patients with earlier stage disease,” Eng added.

Eng is the David H. Johnson Endowed Chair in Surgical and Medical Oncology; a professor of medicine; director for Strategic Relations, VICC; co-director, GI Oncology and Co-Leader, of the GI Cancer Research Program; and director of the Young Adult Cancers Program at Vanderbilt-Ingram Cancer Center in Nashville Tennessee.

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.

"The most important thing about the current landscape is that POD1UM-303 fulfilled its primary end point of PFS; it may be too early regarding OS [as] the follow-up is rather short at the initial presentation, [but] we’ll get further data as time goes by," Eng said. "It’s important for patients to understand that there are options out there where chemotherapy alone may not be sufficient, and there may be a role for immunotherapy based upon the results of this trial. We hope that the NCI sponsored phase 3 study EA2176 [NCT0444492] will further validate these findings, and then that would indicate that there is a definitive role moving forward for chemotherapy combined with immunotherapy. I would love to see OS data from POD1UM-303 after a longer period."

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

“Given that approximately 90% of all anal carcinomas are HPV-positive, vaccination rates need to improve for preventative purposes,” Eng said. “[If] we make a breakthrough in any HPV-associated cancer research, it could be applied to cervical cancer, head and neck cancer, [and] penile cancer, etc. Any breakthroughs in HPV-associated research in any of these malignancies can benefit some of the other malignancies as well.”

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 approximately 2,190 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

“This is also a great opportunity for other pharmaceutical companies to understand that we need additional treatment options for patients in the second- and third-line settings because if we’re going to use immunotherapy in the frontline setting, and immunotherapy used to historically be used in the previously treated setting, that means we have no known treatment options as a SOC now in the second-line setting," Eng said. "That is also a concern because now we have no backup plan. I would appeal to pharmaceutical companies, as well as the NCI for that matter, to please put effort in research for us to identify some new pathways and new drugs that are focused on anal carcinoma or squamous cell carcinoma.”

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