Adding Zynyz to carboplatin and paclitaxel prolonged survival without progression in chemotherapy-naive recurrent or metastatic squamous cell carcinoma of the anal canal.
There was a significant progression-free survival (PFS; how long a person lives without their disease getting worse) benefit when Zynyz (retifanlimab-dlwr) was added to carboplatin and paclitaxel compared with 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.
Findings from the phase 3 POD1UM-303/InterAACT 2 trial presented at the 2024 ESMO Congress showed that patients who received Zynyz in addition to carboplatin and paclitaxel (154 patients) experienced a median PFS of 9.3 months compared with 7.4 months among those who received placebo plus carboplatin and paclitaxel (154 patients). The median follow-up times for PFS were 7.6 months and 7.1 months, respectively.
Study Highlights:
“[Zynyz] plus carboplatin [and] paclitaxel represents a potential new reference treatment and standard of care [SOC] for patients with advanced SCAC,” Dr. Sheela Rao, a consultant medical oncologist in the Gastrointestinal Unit at the Royal Marsden Hospital NHS Foundation Trust in London, said during the presentation of findings.
Moreover, data revealed that patients who received Zynyz achieved an overall response rate (ORR; the percentage of people whose disease shrinks or disappears after treatment) of 56% with a complete response (CR; when a person's disease cannot be detected by any tests or examinations) rate of 22%, versus 44% with a 14% CR rate among those who received placebo. The median duration of response (DOR; the length of time a person's disease shrinks or remains stable after treatment) was 14 months versus 7.2 months, respectively, and the respective disease control rates were 87% versus 80%.
Data from the overall survival (OS; the time from the start of treatment when a patient with cancer is still alive) analysis showed that patients in the Zynyz arm achieved a median OS of 29.2 months versus 23 months in the placebo arm. The median OS adjusted for patient crossover (meaning that a person was originally in one treatment arm then moved to the other) was 29.2 months versus 19.1 months, respectively.
Taking a Closer Look at POD1UM-303 Enrollment
“[Zynyz] 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 [Zynyz] in combination with SOC chemotherapy in patients with locally advanced, inoperable or metastatic SCAC.”
POD1UM-303/InterAACT 2 was a 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 0 or 1 (either fully active or restricted in physically strenuous activity) and could not have received prior chemotherapy unless it was radio-sensitizing treatment or (neo)adjuvant therapy (post-surgery) for at least six months prior to enrollment. Those with HIV and well-controlled infections were permitted to enter the study.
“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 to receive either intravenous (through the vein) Zynyz every four weeks for 12 months or placebo, both in combination with standard dosing of carboplatin and paclitaxel for six months. Patients in the placebo arm were permitted to crossover to the Zynyz arm following disease progression.
OS was the key secondary focus of the study, with others including ORR, DOR, safety and pharmacokinetics (how a body processes drugs). Investigators also evaluated PFS after first subsequent therapy, patient-reported outcomes, HIV control and immunogenicity (ability of a therapy to trigger an immune response in the body) as exploratory endpoints.
The baseline characteristics were well balanced between the two arms; the median age was 62 years versus 61 years in the Zynyz arm compared with the placebo arm, respectively. Most patients in both arms were female (68% versus 77%), White (86% versus 89%), received prior radiotherapy (68% versus 73%), had an ECOG performance status of 0 (53% versus 56%), and had a PD-L1 expression of at least 1% (90% versus 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.
Zynyz Is Safe in Combination With Chemotherapy
In terms of safety, any-grade treatment-emergent side effects occurred in all patients in the Zynyz and placebo arms. Patients in both arms experienced grade 3 (severe) or higher treatment-emergent side effects (83.1% versus 75%), grade 5 treatment-emergent side effects (2.6% versus 0.7%), serious side effects (47.4% versus 38.8%), treatment-related serious side effects (16.2% versus 6.6%), immune-related side effects (46.1% versus 23.7%), and side effects leading to treatment discontinuation (11% versus 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 treatment-emergent side effects in both arms included neutropenia (low number of neutrophils, a type of white blood cell that helps combat infections; 35.1% versus 29.6%), anemia (19.5% versus 20.4%), and decreased neutrophil count (fewer infection-fighting cells in blood) (16.9% versus 8.6%). The most common any-grade immune-related treatment-emergent side effects consisted of peripheral sensory neuropathy (a condition affecting the nerves outside of the brain and spinal cord that may affect temperature, touch and pain; 11% versus 9.9%), hypothyroidism (insufficient thyroid hormone; 14.3% versus 3.3%), and hyperthyroidism (when the thyroid gland produces too much thyroid hormone; 8.4% versus 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 Zynyz to SOC chemotherapy, and [the trial] met our primary end point. Zynyz plus carboplatin and paclitaxel represents a new SOC for patients with advanced SCAC.”
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