POD1UM-303/InterAACT 2 brings retifanlimab to the fore of anal cancer treatment

Retifanlimab takes the stage in POD1UM-303/InterAACT 2, a trial showing encouraging efficacy and favourable risk-benefit ratio when the anti-PD-1 monoclonal antibody is added to standard-of-care (SoC) chemotherapy as first-line (1L) treatment for previously untreated, inoperable, locally recurrent/metastatic squamous cell carcinoma of the anal canal (SCAC).

“This [is the] first and largest known phase III trial of a checkpoint inhibitor in SCAC – a disease with a high unmet medical need … The study met its primary endpoint of progression-free survival (PFS),” said Dr Sheela Rao from Royal Marsden Hospital National Health Services Foundation Trust, Sutton, Surrey, UK, at ESMO 2024.

After a median follow-up time of about 7 months, PFS was significantly longer in the retifanlimab vs placebo arm (median 9.3 vs 7.39 months; hazard ratio [HR], 0.63; p=0.0006).

Albeit immature, there was a strong trend towards improved overall survival (OS), both in the interim analysis (median 29.2 vs 23 months; HR, 0.70; p=0.0273) and after adjusting for crossover (median 29.2 vs 19.1 months; HR, 0.63; p_nominal=0.0055). [ESMO 2024, abstract LBA2]

Retifanlimab also fared better than chemo in terms of overall response rate (56 percent vs 44 percent; p_nominal=0.0129), disease control rate (87 percent vs 80 percent), and median duration of response (14 vs 7.2 months).

The retifanlimab arm had more serious adverse events (SAEs; 47.4 percent vs 38.8 percent), treatment-related SAEs (16.2 percent vs 6.6 percent), immune-related AEs (46.1 percent vs 23.7 percent), and AEs leading to discontinuation (11 percent vs 2.6 percent) than the comparator arm.

“[Nonetheless,] the safety of retifanlimab plus chemo was consistent with prior phase II data and known checkpoint inhibitor in SCAC,” noted Rao, adding that there were no new safety signals to compromise or disrupt chemo administration.

A rare disease with a poor prognosis

“Advanced SCAC is a neglected orphan disease,” Rao stressed. The rising incidence of SCAC may have been primarily driven by HPV, the causative agent for most anogenital cancers. [Curr Oncol 2023;30:3232-3250; Int J Cancer 2015;136:2752-2760; J Gastrointest Oncol 2016;7:721-726] HIV is also strongly correlated with and an important amplifier of SCAC. [Oncol Clin N Am 2017;26:17-31]

The SoC for SCAC has not changed since the early 1980s, and relapse after chemoradiotherapy is common. [Ann Med Surg (Lond) 2020;55:36-46] “For these patients, prognosis and quality of life still remain poor,” said Rao.

The InterAACT study has established carboplatin-paclitaxel (CP) as 1L treatment for SCAC, but PFS and OS were modest despite meaningful and durable responses. Retifanlimab has demonstrated antitumour activity in individuals with advanced SCAC who have progressed on platinum-based chemo. [J Clin Oncol 2020;38:2510-2518; ESMO Open 2022;7:100529]

In the current analysis, Rao and her team explored the potential of combining SoC with retifanlimab in this setting. They enrolled 308 treatment-naïve participants (median age 62 years, 72 percent women), including individuals with well-controlled HIV. Participants were randomized 1:1 to six cycles of standard-dose CP plus IV retifanlimab 500 mg Q4W or placebo for up to a year. Crossover was allowed for placebo patients upon confirmed disease progression.

“[Overall, our study shows that] retifanlimab plus CP represents a potential new reference treatment and SoC for patients with advanced SCAC,” Rao said.

A new SoC for SCAC?

“[This] is a positive phase III trial in a rare cancer entity demonstrating superior efficacy in an acceptable primary endpoint [and] consistent efficacy data in secondary endpoints … [Retifanlimab plus CP] should be considered a new SoC in advanced/metastatic SCAC,” said discussant Professor Dominik Modest from the Charité-Universitätsmedizin Berlin, Germany, at ESMO 2024.

“However, I will argue that with a PFS of 7.4 months and an OS of 23 months in the control arm, more information on the use of further-line therapy might be helpful to understand the role of sequential therapy in this disease,” he said.

Mature OS and subgroup analysis (particularly the PD-L1 expression subgroup) data are awaited, as well as future developments and challenges of this new regimen, with more immunologic components or other chemo backbones (eg, triplet regimen), he added.