Evolving SCAC Care: Clinical Perspectives on Innovation and Implementation | Written Recap

Marwan Fakih, M.D., is associate director of clinical sciences and medical director of the Judy and Bernard Briskin Center for Clinical Research at City of Hope, a hospital and research center in Duarte, California. In this Managed Healthcare Executive K-Cast video series, Fakih discussed the epidemiology and treatment of squamous cell anal carcinoma.

Increasing incidence and HPV vaccination

The incidence of squamous cell anal carcinoma (SCAC) has almost doubled over the past 30 years, Fakih said. The most important risk factor is HPV infection, he said, and immunosuppression in combination with HPV infection “will drive the carcinogenesis process even further.” People who have HIV in addition to HPV have more than a 30-fold increased risk of getting SCAC, according to Fakih. People taking immunosuppressant medications for rheumatoid arthritis, inflammatory bowel disease and organ transplants are also at increased risk for the disease, according to Fakih. And, as with many cancers, older age and smoking are risk factors.

Vaccination against HPV started in 2006, Fakih said, but he said it is going to take decades to see the effect of HPV vaccination on the rates of SCAC.

Unmet needs

Patients with SCAC predominantly have local regional disease, Fakih explained. The recurrence rate continues to be quite high in patients with high-risk SCAC, particularly people with large, bulky tumors, classified as T3 and T4 tumors, and those with significant pelvic nodal involvement. The recurrence rates can be as high as 40% in those patients. “We really need more effective therapies than the typical chemoradiation regimens for that patient population,” Fakih said.The five-year overall survival of patients with recurrent SCAC following chemoradiation is about a third, and the median overall survival is less than 20 months, he said.

Fakih said there’s also a need to “deintensify” the treatment of patients with T1 and T2 tumors. “Perhaps those patients can receive a lower dose of radiation, but that has to be really studied prospectively and proven to be as effective before that can be implemented,” Fakih said.

Shifting standards of care

Historically, SCAC was treated with cisplatin and 5-fluorouracil. Based on the results of the phase 2 InterAAct trial, the standard of care has switched more recently toward carboplatin and paclitaxel, a combination that is sometimes referred to as CarboTaxol. The InterAAct trial showed that the carboplatin and paclitaxel combination is a “better backbone” than cisplatin and 5-fluorouracil based on progression-free survival results and a trend toward improvement in overall survival, Fakih said. Other regimens for patients with metastatic SCAC have been investigated, including FOLFOX (folinic acid, 5-fluorouracil and oxaliplatin) and a modified version of the docetaxel, cisplatin and 5-fluorouracil regimen, Fakih said. But he said that the carboplatin and paclitaxel combination has been the established treatment for metastatic SCAC squamous cellor recurrent unresectable squamous cell cancer of the anal canal until the results of the POD1UM-303 trial came out. “Now the standard of care has changed,” Fakih said.

The POD1UM-303 trial results

The industry-funded POD1UM-303 was a phase 3 clinical trial designed to assess whether retifanlimab [sold under the brand name Zynyz], a PD-1 inhibitor, added to carboplatin and paclitaxel as a first-line treatment of metastatic SCAC would improve outcomes compared with carboplatin and paclitaxel. The researchers randomly assigned 308 patients on a 1:1 basis to the experimental and standard of care arms of the study. The patients receiving carboplatin and paclitaxel received a placebo instead of retifanlimab and were allowed to cross over to retifanlimab if their cancer progressed. Progression-free survival was the primary end point. Thetrial results showed that the median progression-free survival was 9.3 months for the patients randomly assigned to the investigational arm compared with 7.4 months for the patients assigned to the standard-of-care arm, according to Fakih. There was also what Fakih described as a “very strong trend” toward improvement in overall survival: 29.2 months in the experimental arm compared with 23 months in the standard-of-care arm, despite 45% of the patients in the standard-of-care arm crossing over to the experimental arm, a switch that would tend to dilute the improved survival signals for the experimental treatment, Fakih said. “In my opinion, the study is conclusive here: Adding a PD-1 inhibitor, namely retifanlimab, to carboplatin and paclitaxel will delay the time to progression in these patients and will result in a strong trend toward overall survival improvement,” he said. Fakih said the trial also showed better results for patients treated with carboplatin and paclitaxel plus retifanlimab on several secondary end points, including overall response rate, complete response and duration of response.

Side effects

Patients in the carboplatin and paclitaxel plus retifanlimab arm of the trial tended to receive a bit more chemotherapy than those who received just carboplatin and paclitaxel because the treatment was more effective, according to Fakih. As a result, they experienced more bone marrow suppression and grade 3 neutropenia, he said. A greater percentage of patients who were treated with retifanlimab experienced side effects seen with checkpoint inhibition, such as adrenal insufficiency, diarrhea and hypothyroidism. Fakih said they are class effects and manageable.

Fakih saidanalysis of the POD1UM-303 resultsdid not reveal any subpopulations that failed to benefit from the addition of retifanlimab to carboplatin and paclitaxel. Some of the subgroups were small, he noted, limiting the statistical power of the results. About 10% of the patients enrolled in the study were PD-L1 negative, Fakih noted, and although they benefited when it came to progression-free survival, the “signal” of overall survival was not as strong as it was for other patients in the trial. “I don’t think the PD-L1 is a validated biomarker that excludes patients from receiving retifanlimab, but it also highlights that we need to understand more as to what the benefit in this particular patient population is,” he said.

Fakih said patients who shouldn’t be treated with retifanlimab include those with a history of autoimmune disease and organ transplantation because the risks of checkpoint inhibition outweigh the benefits for them.

A milestone and future treatments

Fakih described the FDA approval of retifanlimab in combination with carboplatin and paclitaxel and the National Comprehensive Cancer Network endorsement of the regimen as milestones that will “certainly put significant focus on the importance of adding a PD-1 inhibitor, namely retifanlimab,” to the management of advanced squamous cell cancer of the anal canal. He stressed the importance of disseminating information about the favorable data from the POD1UM-303 trial. Fakih added that he hoped that payers will not be an obstacle to access to the treatment. “I think we have level 1 evidence now, and with the level 1 evidence, we cannot deny our patients this important treatment,” he said.

Other immunotherapy agents have been tested as treatments for advanced SCAC, said Fakih, adding that he sees “some room for additional checkpoint inhibitors to be assessed.” Fakih also mentioned the possibility of future treatment of advanced SCAC with bispecific antibodies, cellular therapies, CAR-T and antibody-drug conjugates.