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Combining retifanlimab (Zynyz) with standard-of-care chemotherapy significantly improved progression-free survival (PFS) in treatment-naïve patients with locally advanced or metastatic squamous cell carcinoma of the anal canal (SCAC), according to phase III trial results.

PFS was 9.3 months for patients treated with the anti-PD-1 monoclonal antibody versus 7.4 months for those treated with placebo and chemotherapy (HR 0.63, 95% CI 0.47-0.84, P=0.0006), reported Sheela Rao, MBBS, MD, of the Royal Marsden Hospital NHS Foundation Trust in Sutton, England.

While overall survival (OS) data are not mature, "the curves are separating, and continue to separate, and are certainly showing a strong trend toward improved overall survival," with a current difference of 6 months between the placebo arm and the retifanlimab arm, she said in a presentation at the European Society for Medical Oncology (ESMO) annual congress in Barcelona.

At a median follow-up of 14.8 months in the retifanlimab arm and 12.9 in the placebo arm, median OS was 29.2 months and 23.0 months, respectively (HR 0.70, 95% CI 0.49-101, P=0.0273).

The trial "is the first and largest known phase III trial of a checkpoint inhibitor in squamous cell anal cancer -- a disease with high unmet medical need," Rao stated. "Retifanlimab plus carboplatin and paclitaxel represents a new standard of care for patients with advanced squamous cell anal cancer."

ESMO invited discussant Dominik P. Modest, MD, of the Charité University of Medicine in Berlin, said that in looking at the PFS and OS curves, "what I like especially about these curves is that they split early, much earlier than I would have expected."

"I think that based on these curves, it is safe to conclude that the benefit of added retifanlimab appears rather early in the progression-free survival curve while more than 80% of patients are at risk," he added. "The overall survival, although not mature, is absolutely consistent with this observation."

Rao called advanced SCAC a "neglected orphan disease" that is increasing in incidence annually, mainly due to endemic human papillomavirus (HPV). She pointed out that HIV is also strongly correlated with the development of SCAC.

Primary SCAC treatment is usually chemoradiotherapy (CRT), but "up to 30% of patients will progress following this treatment, and another 10% to 12% will present with metastatic disease," Rao said. "And really for these patients, quality of life and prognosis still remains poor."

She noted that HPV-driven malignancy is an "attractive target for immunotherapy" and retifanlimab has shown anti-tumor activity in platinum-refractory SCAC in the phase II .

The current study enrolled untreated adults with inoperable, locally recurrent/metastatic SCAC. Patients were excluded if they had prior chemotherapy, with the exception of CRT if it was given at least 6 months before study entry. Patients with well-controlled HIV also were included, and Rao and colleagues reported that there was no loss of HIV control in these patients during the study.

Patients were randomized to 6 cycles of standard-dose carboplatin-paclitaxel plus either placebo or retifanlimab (500 mg IV every 4 weeks) for up to 1 year, with the possibility of crossover.

The median ages in the retifanlimab and placebo arms were 61 and 62, respectively. Most patients overall were female, white, and had received prior RT. Over 80% had metastatic disease and about 90% in both arms were PD-L1 positive.

Median OS adjusted for crossover was 19.1 months in the placebo arm, and 29.2 months in the retifanlimab arm (HR 0.63, 95% CI 0.44-0.90, P=o.0055).

The overall response rate was 56% in the retifanlimab arm and 44% in the placebo arm, with a median duration of response in the retifanlimab arm that just about doubled that in the placebo arm (14.0 months vs 7.2 months). The disease control rate was 80% in the placebo arm and 87% in the retifanlimab arm.

Regarding safety, 83.1% of patients in the retifanlimab arm had grade ≥3 treatment-emergent adverse events (TEAEs) compared with 75.0% in the placebo arm, while twice as many patients in the retifanlimab arm had immune-related AEs (46.1% vs 23.7%). Common grade ≥3 TEAEs included neutropenia and anemia; common grade ≥2 immune-related AEs included peripheral sensory neuropathy and hypothyroidism.

At data cutoff, 58.4% of patients in the retifanlimab arm remained on study.

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