This summer, Incyte Corp. hit a roadblock in the company’s quest to have its drug retifanlimab become the first FDA-approved treatment of its kind for patients with the most common type of anal cancer.
Retifanlimab is an immune checkpoint inhibitor (also known as immunotherapy) that aims to treat adult patients with locally advanced or metastatic squamous cell carcinoma of the anal canal (SCAC) whose disease has progressed after receiving platinum-based chemotherapy or who were intolerant of that type of chemotherapy. Currently, there are no approved treatment options available to patients who meet these criteria, according to Incyte.
But in a 13-4 decision on June 24, the FDA’s Oncologic Drugs Advisory Committee (ODAC) voted to defer a regulatory decision on retifanlimab until more data emerges from an ongoing confirmatory trial called POD1UM-303. Information gleaned from a previous trial — POD1UM-202 — is far from sufficient to support the drug’s approval, the committee said, highlighting questions about the drug’s effectiveness and issues such as the trial enrolling too few HIV-positive patients and racial minorities.
Incyte Says It Will Address FDA Feedback
The FDA itself followed that report with a Complete Response Letter issued in late July, stating that the agency cannot approve Incyte’s Biologics License Application for retifanlimab until more data is available to demonstrate its clinical effectiveness. Incyte, for its part, said that while it is “not surprised with the FDA decision given the ODAC recommendation, we are disappointed. We remain committed to advancing science to find solutions for patients with unmet medical needs, and we will ensure close coordination with the FDA in order to address feedback and determine next steps for the review of retifanlimab.”
Anal cancer is considered rare, accounting for just 0.5% of estimated new cancer cases and just 0.2% of all deaths in 2021, according to the FDA. But its survival rates vary considerably based on whether patients’ disease is localized (66-82%) or whether they have distant metastases (35%). Common risk factors include human papillomavirus virus (HPV) infections and HIV infections.
While a variety of treatments already exist for anal cancer patients, there are opportunities for more innovation, according to Robert Kinyua, Pharm.D., clinical program development director at Prime Therapeutics.
“Prognosis in anal cancer is variable, especially in the metastatic setting,” he tells AIS Health, a division of MMIT. “An unmet need in the management of anal cancer includes identification of relevant biomarkers that can guide clinical decisions and serve as targets for new therapeutics.”
To learn more about the landscape of therapies available to treat this rare type of cancer, AIS Health asked Mesfin Tegenu, chairman and CEO of RxParadigm, to share some additional insights.
Editor’s note: The following interview has been edited for length and clarity.
✦ AIS Health: Which drugs are currently used to treat anal cancer?
✦ Tegenu: Historically, primary treatment for anal cancer was abdominoperineal resection; but local recurrence rates were high, five-year survival was only 40-70%, and morbidity with a permanent colostomy was considerable. Currently, the standard of care for locoregional anal cancer is chemoRT with mitomycin plus 5-FU, resulting in complete tumor regression. Capecitabine, an oral chemotherapy agent, is considered as an acceptable substitute for 5-FU as it is well tolerated with minimal toxicity. Cisplatin plus 5-FU is an alternative regimen for the patients who cannot tolerate mitomycin.
For advanced cases of the disease, platinum-based chemotherapy is utilized as a first-line treatment. Currently in NCCN [National Comprehensive Cancer Network] guidelines, paclitaxel plus carboplatin is preferred over cisplatin plus 5-FU for having a better median overall survival and a more favorable toxicity profile. Combinations of docetaxel, cisplatin, and 5-FU (DCF) are active but can be toxic. Other recommended treatment options include 5-FU, leucovorin, and cisplatin (FOLCIS) and 5-FU, leucovorin, oxaliplatin (FOLFOX).
For the second-line treatment of metastatic anal cancer, immunotherapy is recommended. Immunotherapy (also known as immune checkpoint inhibitors or ICIs) differs from traditional chemotherapy, which primarily targets rapidly dividing cells, and from targeted therapies, which interfere with key molecular events in tumor cells that drive tumor growth and invasion. Immunotherapeutic approaches to cancer treatment are based on the premise that the immune system plays a key role in the surveillance and eradication of malignancy, and that tumors evolve ways to elude the immune system. The two immunotherapy agents currently used for anal cancer are nivolumab and pembrolizumab.
✦ AIS Health: How do payers typically cover these drugs (preferred/non-preferred, utilization management restrictions, etc.)?
✦ Tegenu: Most payers will typically cover the conventional chemotherapy (e.g., mitomycin, 5-FU, cisplatin, etc.) as preferred, but immunotherapy (e.g., nivolumab and pembrolizumab) agents are generally non-formulary. Of note, these covered agents do not have UM restrictions; except the oral chemotherapy that is used for anal cancer (capecitabine) generally requires PA.
✦ AIS Health: Would these drugs usually be covered under the medical or pharmacy benefit?
✦ Tegenu: Most of the chemotherapy agents used for anal cancer would be covered under the medical benefit, since they require medical supplies and devices used during the infusion process. However, if the criteria are met for the patient to be treated at home, then these chemotherapy agents can be dispensed by home-infusion pharmacy, which would be covered under the pharmacy benefit.
✦ AIS Health: Are drugs used to treat anal cancer typically in the high-cost category?
✦ Tegenu: The cost of cancer treatment can vary since the dose of chemotherapy is based on a patient’s weight or body surface area, and different regimens may have different frequency or duration of chemo infusion per cycle of therapy. However, in general, most of the conventional chemotherapy agents used to treat anal cancer are not in the high-cost category, while immunotherapy is in the higher cost category. Some exceptions that may be more costly include mitomycin and capecitabine.
✦ AIS Health: Are these drugs effective in treating the disease or is there an unmet need for novel therapies?
✦ Tegenu: In the most updated NCCN Anal Carcinoma Guideline, chemoRT with mitomycin and 5-FU or capecitabine is recommended as the first-line therapy for the localized anal carcinoma, as trials showed good complete remission rates with decreased risk of having a colostomy. Although metastatic anal cancer is rare, there are several platinum-based chemotherapy regimens that have a moderate response rate (e.g., carboplatin plus paclitaxel or cisplatin plus 5-FU) with variabilities in toxicities. Because of the rarity of the disease, there is limited data on treatment for metastatic anal cancer and no prospective data is available.
✦ AIS Health: Are there any treatments in the pipeline for this condition that payers/PBMS are watching?
✦ Tegenu: Immunotherapies are showing great promise. Several ongoing clinical trials are investigating whether the immunotherapy could have a role in the first-line treatment of metastatic anal cancer. NCT04444921 is a randomized, Phase III trial comparing chemotherapy along (carboplatin and paclitaxel) to chemotherapy plus nivolumab for treatment-naïve metastatic anal cancer. POD1UM303/InterAACT2 is a similar, Phase III global study (NCT04472429) investigating the addition of the immune checkpoint inhibitor (ICI), retifanlimab, to carboplatin/paclitaxel chemotherapy and comparing to chemotherapy alone. These two studies are expected to complete in 2023 and 2024, respectively. Another one that is currently under investigation is the combination of two ICIs [immune checkpoint inhibitors], nivolumab with ipilimumab. ICIs have improved outcomes in a variety of solid tumors, most notably melanoma and non-small cell lung cancer.
✦ AIS Health: Is there anything else about this disease you’d like to mention that I failed to ask?
✦ Tegenu: Although considered to be a rare type of cancer, the incidence rate of anal carcinoma in the U.S. has continued to increase, rising 2.7% each year between 2001 to 2015. Anal cancer mortality rates (2001-2016) also rose, with an average increase of 3.1% per year. As over 80% of SCAC cases are attributable to high-risk HPV infection, it is important that we also focus on the preventive strategies with immunization. HPV vaccines prevent infection and disease related to the viral strains that causes anal cancer with 96.7% efficacy.
This story was reprinted from AIS Health’s biweekly publication RADAR on Drug Benefits.