Renewed Hope in Advanced Anal Cancer With ICI-Chemo Combo

BARCELONA, Spain — Adding retifanlimab, an anti–programmed cell death 1 (PD-1) monoclonal antibody, to carboplatin plus paclitaxel in inoperable locally recurrent or metastatic squamous cell carcinoma (SCC) of the anal canal markedly improves survival outcomes, findings from the POD1UM-303 trial showed.

The research, presented at the European Society for Medical Oncology (ESMO) Annual Meeting 2024, is the first randomized phase 3 trial of an immune checkpoint in this disease, said lead researcher Sheela Rao, MD, Gastrointestinal and Lymphoma Units, The Royal Marsden NHS Foundation Trust, London, England.

The trial demonstrated the benefit of adding retifanlimab to standard-of-care chemotherapy in this population, Rao continued, with a significant 37% increase in progression-free survival and a trend for a significant 30% overall survival benefit.

With the treatment “generally well tolerated,” and the safety profile consistent with other chemotherapy plus checkpoint inhibitor regimens, Rao believes that the combination of retifanlimab and carboplatin-paclitaxel “represents a potential new reference treatment and standard of care” for these patients.

This is “a disease with a high unmet medical need,” she said. It’s considered an “orphan disease,” even though the incidence is increasing by approximately 3% a year due to the endemic presence of human papillomavirus, the primary cause of SCC of the anal canal. HIV infection amplifies the risk and is linked to a 25- to 35-fold increase in incidence, she reported.

Current Standard of Care

Andrés Cervantes, MD, PhD, president of ESMO and professor of medicine at the University of Valencia, Valencia, Spain, who was not involved in the study, told a press conference that the study is “very important” because anal cancer is a notable cause of disease.

The current standard-of-care curative treatment for SCC of the anal canal is chemoradiotherapy, Cervantes told Medscape Medical News. For many years, patients underwent radiation therapy concurrently with mitomycin, which was developed in the 1970s, plus fluorouracil.

More recently, the InterAACT trial, also led by Rao, demonstrated that carboplatin plus paclitaxel was associated with less toxicity and longer survival than cisplatin plus fluorouracil in chemotherapy-naive patients with advanced anal cancer.

This regimen is now the preferred first-line therapy for stage IV anal cancer in the current ESMO Clinical Practice Guidelines for the disease, Cervantes explained.

Nevertheless, “more than one third of patients will eventually relapse — local, regionally, or with distant disease — and there are a lot of patients presenting in a noncurative status with disseminated disease,” he noted.

“So far, chemotherapy is only providing palliative symptom control,” he continued, “so the addition of immunotherapy [here] is improving outcomes.”

The New Data

Following the InterAACT trial, the phase 2 POD1UM-202 trial, also led by Rao, established that retifanlimab had antitumor activity in platinum-refractory patients. Rao and her colleagues combined the two approaches in the current phase 3 study.

In the latest study, patients with locally recurrent or metastatic SCC of the anal canal, who had received no prior chemotherapy, apart from as radiosensitizing or (neo)adjuvant therapy for at least 6 months, were randomized to retifanlimab (n = 154) or placebo (n = 154) for 12 months. Both the groups received standard-dose carboplatin-paclitaxel for 6 months.

After 12 months, 69 patients in the placebo arm who had progressive disease crossed over to the retifanlimab arm.

The two study groups were well matched. The median age was approximately 61 years, and around 67% were women. Approximately 70% patients had received prior radiotherapy, and about 90% had PD-L1 tumor expression. Just over 80% had metastatic disease.

Retifanlimab plus standard chemotherapy was associated with a progression-free survival of 9.3 months vs 7.4 months with placebo plus chemotherapy (hazard ratio [HR], 0.63; P = .0006).

The interim overall survival analysis indicated that patients in the experimental vs placebo arm had a median overall survival of 29.2 vs 23 months, respectively (HR, 0.70; P = .0273). When adjusting for crossover, the benefit was slightly lower (HR, 0.63; P = .0055). The overall survival findings, however, are immature.

In addition, the overall response rate was higher with retifanlimab and carboplatin-paclitaxel at 56% vs 44% with placebo and carboplatin-paclitaxel (P = .0129), and the median duration of response was 14.0 vs 7.2 months, respectively.

Grade 3 or higher treatment-emergent adverse events were more common with the novel combination, occurring in 83.1% vs 75.0% (placebo). There were four deaths in the retifanlimab arm vs one death in the placebo arm.

As expected, immune-related adverse events were seen more often in the immunotherapy-treated patients, at 46.1% vs 23.7% in the chemotherapy only–treated patients, and adverse events leading to discontinuation occurred in 11.0% vs 2.6% patients, respectively.

The most common grade 3 or higher adverse events across the two groups were neutropenia (32.4%), anemia (19.9%), and a reduced neutrophil count (12.7%).

‘A Very Significant Finding’

“This is not only the first immunotherapy randomized trial, it’s the first phase three randomized trial in this disease…so I think it’s is a very significant finding,” said Cervantes.

Dominik P. Modest, MD, from the Department of Hematology, Oncology and Cancer Immunology, Charité – Universitätsmedizin Berlin, Berlin, Germany, who was not involved in the study, believes that based on the current findings, carboplatin-paclitaxel and retifanlimab should be considered a new standard of care in advanced/metastatic SCC of the anal canal.

The benefit is underlined by the “consistent efficacy data in secondary endpoints,” and that the gain is “greater than expected based on monotherapy with checkpoint inhibitors in pretreated patients,” added Modest.

Modest highlighted that there was a 45% crossover from the placebo arm to the retifanlimab arm during the follow-up.

This did not, however, have an impact on overall survival, and he speculated this may be because the late introduction of checkpoint inhibition in SCC in anal cancer may not offer a substantial benefit, which may have implications for treatment sequencing.

Modest said he would like to see more information on the efficacy of the triplet combination in clinical subgroups and when stratified by PD-L1 expression, as well as mature overall survival results.

Data from trials such as EA2176, which is looking at carboplatin plus paclitaxel with nivolumab (Opdivo) or placebo, could also have a bearing on how the current study results are viewed, said Modest.

The study was funded by Incyte Corporation. Rao declared advisory roles with Bayer, Hookipa, BeiGene, AstraZeneca, Merck Serono, Seagen, Servier, and Boehringer. Modest declared relationships with Servier, Amgen, Merck, Sanofi, BMS, MSD, AstraZeneca, Pierre Fabre, GSK, Seagen, G1, IKF GmbH, Onkowissen, COR2ED, Taiho, Takeda, Incyte, Cureteq, 21up, MedscapeMedical News, Aptitude Health, and Regeneron. Cervantes declared relationships with AbbVie, Amgen, AnHeart Therapeutics, Foundation Medicine, GSK, Merck Serono, Roche, Transgene, Actuate Therapeutic, Adaptimmune, Affimed, Amcure, Astellas Pharma, AstraZeneca, Bayer, BeiGene, BMS, F-star Therapeutics, FibroGen, Genentech, Gilead, Janssen, Lilly, MedImmune, Natera, Novartis, Ribon Therapeutics, Seamless, Servier, Sierra Oncology, and Takeda.