Should dermatologic examinations become routine standard of care in patients with polycythemia vera? Observations from the phase 3 VERIFY study prior to rusfertide exposure Free

Background: Patients with polycythemia vera (PV) are at increased risk of developing other non-PV malignancies, including skin cancers (Landtblom AR, et al. Leukemia. 2018;32:2203-10; Loscocco GG, et al. Blood. 2024;144(Supplement 1):4552). Given the propensity of patients with PV to develop cutaneous malignancies, we performed dermatologic screening examinations prior to patient randomization and at Week 32 as part of the primary efficacy and safety analysis in the phase 3 VERIFY study (NCT05210790) to ensure patients received appropriate care and treatment. The primary objective of this abstract is to report results from dermatologic screening examinations that were conducted prior to randomization in the rusfertide and placebo groups and in the placebo group at the end of VERIFY Part 1a (Week 32, ie, prior to when patients cross over to rusfertide at the beginning of Part 1b).

Methods: The ongoing phase 3 VERIFY study enrolled patients with PV who required frequent phlebotomies (defined as ≥3 phlebotomies in 28 weeks or ≥5 phlebotomies in 52 weeks prior to randomization) to control and maintain hematocrit <45%. Patients were randomized (1:1) to either rusfertide or placebo in addition to current standard-of-care (SOC) therapy for PV. After patients provided informed consent, they underwent mandatory dermatologic examinations during a 4-week screening period, at Week 32 following completion of Part 1a, and at other periods throughout the study. Examinations by dermatologists were preferred but not required. If a dermatologist was not available, a trained investigator or medical professional performed the skin examination. If a patient had in situ or stage 1 squamous cell carcinoma (SCC) of the skin, in situ or stage 1 basal cell carcinoma (BCC) of the skin, or in situ melanoma of the skin identified during the dermatologic examination at screening, the patient was not eligible to participate in VERIFY unless the cancer was adequately treated (ie, curative treatment such as Mohs surgery). Patients diagnosed with skin cancer at Week 32 received appropriate therapy and were allowed to proceed onto Part 1b, the open-label portion of the study (Weeks 32-52).

Results: We screened 399 patients for study eligibility; of these patients, 106 failed screening, and 293 patients were randomized to rusfertide (n=147) or placebo (n=146). Of the 293 patients who were randomized in VERIFY, 47 (16.0%) had medical history of other non-PV cancers, and 40 (13.7%) had history of skin cancer. During screening, skin malignancies were identified in 11 patients, including 7 who had BCC, 1 who had malignant melanoma, 1 who had melanoma in situ, and 1 who had scrotal SCC in situ. Of the 11 patients who had skin malignancies identified during screening, 2 patients failed screening, and 9 patients were randomized to the rusfertide (n=4) or placebo (n=5) groups. Of these 11 patients, 9 (81.8%) received hydroxyurea (HU), 2 (18.2%) received interferon, and 1 (9.1%) received ruxolitinib prior to being screened for their potential participation in VERIFY (3/11 patients received more than one prior cytoreductive therapy [CRT]). During screening, 2 patients were found to have non-malignant dysplastic nevi, and an additional patient had non-malignant atypical nevus. In addition, 1 patient had two separate actinic keratosis lesions and a dermatofibroma lesion that was identified during screening. Another patient received treatment with liquid nitrogen for a suspicious lesion of uncertain behavior with a differential diagnosis of actinic keratosis vs SCC. After randomization to the placebo group, 6 patients (4.1%) were diagnosed with new skin cancers, including 3 BCCs (2.1%), 2 SCCs (1.4%), and 1 malignant melanoma (0.7%). Four of these 6 patients (66.7%) also received CRT prior to study entry (HU, n=3; ruxolitinib, n=2; 1 patient received both HU and ruxolitinib).

Conclusions: To our knowledge, this is the first phase 3 study in the setting of PV to prospectively screen patients for skin cancers prior to being exposed to the investigational agent under study. Identification of non-malignant and malignant skin lesions in VERIFY prior to rusfertide exposure illustrates the importance of screening patients with PV for these lesions. Routine dermatologic screening deserves further investigation in other clinical studies and as a potential SOC for optimal treatment and management of patients with PV.Supported by: Protagonist Therapeutics, Inc.