Retifanlimab Plus Carboplatin and Paclitaxel Offers PFS Benefit in Recurrent/Metastatic SCAC

The phase 3 POD1UM-303/InterAACT 2 study (NCT04472429) met its primary end point, with data demonstrating there was a significant progression-free survival (PFS) benefit with the addition of retifanlimab-dlwr (Zynyz) to carboplatin and paclitaxel vs placebo plus carboplatin and paclitaxel in patients with recurrent or metastatic squamous cell carcinoma of the anal canal (SCAC) who did not receive prior chemotherapy.¹

Findings from the trial presented at the 2024 ESMO Congress showed that patients who received retifanlimab in addition to carboplatin and paclitaxel (n = 154) experienced a median PFS by blinded independent central review (BICR) of 9.3 months (95% CI, 7.5-11.3) compared with 7.4 months (95% CI, 7.1-7.7) among those who received placebo plus carboplatin and paclitaxel (n = 154; HR, 0.63; 95% CI, 0.47-0.84; P = .0006). The median follow-up times for PFS were 7.6 months (range, 0.0-33.9) and 7.1 months (range, 0.0-27.4), respectively.

“Retifanlimab plus carboplatin [and] paclitaxel represents a potential new reference treatment and standard of care [SOC] for patients with advanced SCAC,” Sheela Rao, MD, MBBS, FRCP, a consultant medical oncologist in the Gastrointestinal Unit at the Royal Marsden Hospital NHS Foundation Trust in London, England, said during the presentation of findings.

Moreover, data revealed that patients who received retifanlimab achieved an overall response rate (ORR) of 56% (95% CI, 48%-64%), with a complete response (CR) rate of 22%, vs 44% (95% CI, 36%-52%) with a 14% CR rate among those who received placebo (P = .0129). The median duration of response (DOR) was 14.0 months (95% CI, 8.6-22.2) vs 7.2 months (95% CI, 5.6-9.3), respectively, and the respective disease control rates were 87% (95% CI, 81%-92%) vs 80% (95% CI, 73%-86%).

Data from the interim overall survival (OS) analysis showed that patients in the retifanlimab arm achieved a median OS of 29.2 months (95% CI, 24.2-not estimable [NE]) vs 23.0 months (95% CI, 15.1-27.9) in the placebo arm (HR, 0.70; 95% CI, 0.49-1.01; P = .0273). The median OS adjusted for patient crossover was 29.2 months (95% CI, 24.2-NE) vs 19.1 months (95% CI, 13.4-27.9), respectively (HR, 0.63; 95% CI, 0.44-0.90; P = .0055).

Taking a Closer Look at POD1UM-303 Enrollment

“Retifanlimab is a humanized anti–PD-1 monoclonal antibody [which] showed activity in anal cancer in the second-line setting in [patients with] platinum-refractory disease,” Rao said. “We conducted this study to evaluate the addition of retifanlimab in combination with SOC chemotherapy in patients with locally advanced, inoperable or metastatic SCAC.”

POD1UM-303/InterAACT 2 was global, double-blind trial that enrolled patients with inoperable locally recurrent or metastatic SCAC who did not receive prior systemic chemotherapy. Eligible patients needed to be at least 18 years of age, have an ECOG performance status of 1 or less, and could not have received prior chemotherapy unless it was radio-sensitizing treatment or (neo)adjuvant therapy for at least 6 months prior to enrollment. Those with HIV and well-controlled infections were permitted to enter the study.^1,2

“Advanced SCAC is a neglected orphan disease; incidence is increasing by approximately 3% per year mainly due to endemic HPV, the causative agent for most anogenital cancers. HIV is an important amplifier of SCAC; people with HIV are 25- to 35-fold more likely to develop SCAC,” Rao said. “Relapse after primary therapy is common [and the] SOC treatment has not changed since the early 1980s.”

In POD1UM-303, eligible patients were randomly assigned 1:1 to receive either intravenous retifanlimab at 500 mg every 4 weeks for 12 months or placebo, both in combination with standard dosing of carboplatin and paclitaxel for 6 months. Patients were stratified by PD-L1 expression (<1% vs ≥1%), region (Australia, European Union, North America, or the United Kingdom vs the rest of the world), and extent of disease (locally recurrent vs metastatic). Patients in the placebo arm were permitted to crossover to the retifanlimab arm following BICR-verified disease progression.¹

OS was the key secondary end point of the study, and other secondary end points included ORR, DOR, safety, and pharmacokinetics. Investigators also evaluated PFS2, patient-reported outcomes, HIV control, and immunogenicity as exploratory end points.

The baseline characteristics were well balanced between the 2 arms; the median age was 62 years vs 61 years in the retifanlimab arm compared with the placebo arm, respectively. Most patients in both arms were female (68% vs 77%), White (86% vs 89%), received prior radiotherapy (68% vs 73%), had an ECOG performance status of 0 (53% vs 56%), and had a PD-L1 expression of at least 1% (90% vs 91%). Eighty-two percent and 83% of patients in the respective arms had metastatic disease; 36% of patients in each arm had disease metastatic to the liver.

Retifanlimab Is Safe in Combination With Chemotherapy

In terms of safety, any-grade treatment-emergent adverse effects (TEAEs) occurred in all patients in the retifanlimab and placebo arms. Patients in both arms experienced grade 3 or higher TEAEs (83.1% vs 75.0%), grade 5 TEAEs (2.6% vs 0.7%), serious AEs (47.4% vs 38.8%), treatment-related serious AEs (16.2% vs 6.6%), immune-related adverse effects (46.1% vs 23.7%), and AEs leading to treatment discontinuation (11.0% vs 2.6%). At the data cutoff, 58.4% of patients in the investigation arm remained on the study.

The most common grade 3 or higher TEAEs in both arms included neutropenia (35.1% vs 29.6%), anemia (19.5% vs 20.4%), and decreased neutrophil count (16.9% vs 8.6%). The most common any-grade immune-related TEAEs consisted of peripheral sensory neuropathy (11.0% vs 9.9%), hypothyroidism (14.3% vs 3.3%), and hyperthyroidism (8.4% vs 0.7%).

“This is the first and largest known phase 3 trial of a checkpoint inhibitor in SCAC; this is a disease with a high unmet medical need,” Rao said in conclusion. “We have demonstrated a benefit by adding retifanlimab to SOC chemotherapy and [the trial] met our primary end point. Retifanlimab plus carboplatin and paclitaxel represents a new SOC for patients with advanced SCAC.”

Disclosures: Dr Rao has served as an advisory for AstraZeneca, Bayer, BeiGene, Hookipa, Merck Serono, Seagen, Takeda, and Servier; been an invited speaker for Bayer, Merck Serono, and Servier; received travel grants from Servier; and has provided expert testimony for Boehringer Ingelheim.

References

1. Rao S, Samalin-Scalzi E, Evesque L, et al. POD1UM-303/InterAACT 2: phase 3 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).Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. Abstract LBA2.
2. Rao S, Jones M, Bowman J, Tian C, Spano JP. POD1UM-303/InterAACT 2: A phase III, global, randomized, double-blind study of retifanlimab or placebo plus carboplatin-paclitaxel in patients with locally advanced or metastatic squamous cell anal carcinoma. Front Oncol. 2022;12:935383. doi:10.3389/fonc.2022.935383