Phase 3 study (PIVOTAL) of neoadjuvant intralesional daromun vs. immediate surgery in fully resectable melanoma with regional skin and/or nodal metastases.
Authors: Hauschild Axel , Hassel Jessica Cecile , Ziemer Mirjana , Rutkowski Piotr , Meier Friedegund Elke , Flatz Lukas , Gaudy-Marqueste Caroline , Santinami Mario , Russano Francesco , von Wasielewski Imke , Eigentler Thomas , Maio Michele , Zalaudek Iris , Haferkamp Sebastian , Quaglino Pietro , Ascierto Paolo Antonio , Garbe Claus , Robert Caroline , Schadendorf Dirk , Kähler Katharina C. 
Published: June 2024

LBA9501 Background: PIVOTAL (NCT02938299) is an open label, randomized, multicenter, phase 3 trial evaluating Daromun as a neoadjuvant intralesional therapy for resectable, locally advanced Stage III melanoma. Daromun, a combination of two antibody-cytokine fusions (L19IL2 and L19TNF) showed efficacy in a phase 2 study (NCT02076633) in unresectable melanoma patients (pts). Methods: PIVOTAL was run at 22 sites in 4 EU countries. Pts were 1:1 randomly assigned to receive up to 4 weekly intratumoral injections of Daromun followed by surgery (week 5 to 8; treatment arm) or surgery alone within 4 weeks from randomization (control arm). Each weekly administration of Daromun (13 Mio IU of L19IL2 and 400 μg of L19TNF) was distributed among all injectable tumor lesions. Cutaneous melanoma pts with skin and/or LN metastases amenable to complete surgical resection were eligible. Prior anti-tumor treatments including surgery, radiation therapy (RT) and systemic therapies were allowed. Any approved adjuvant treatment post-surgery during follow-up was equally allowed. Pts with uveal or mucosal melanoma, metastatic melanoma with unknown primary, or distant metastases at screening (ruled out by PET/CT) were not eligible. Results: From 07/2016 to 08/2023, 127 pts were randomized to the treatment and 129 to the control arm. Most pts had received previous treatments, including surgery, systemic therapy or RT (Table). The study’s primary endpoint was relapse-free survival (RFS), assessed by investigators and confirmed by retrospective Blinded Independent Central Review (BICR) of PET/CT scans. The primary outcome analysis shows an HR between the RFS of the treatment and control arm of 0.59 [95% CI 0.41-0.86; log-rank p=0.005] as per BICR assessment and 0.61 [0.41-0.92; p=0.018] as per investigator assessment (power = 85%; two-sided α = 0.05). Median RFS was 16.7 mo. in the treatment and 6.9 mo. in the control arm as per BICR. Moreover, distant metastasis-free survival (DMFS) was significantly improved by the neoadjuvant treatment, with an HR of 0.60 [0.37-0.95; p=0.029]. Complete pathological responses (pCR) after surgery were recorded in 21% of treatment arm pts. The safety profile of Daromun was characterized mostly by low-grade, local adverse events (14% grade 3 TEAEs). Systemic AEs were limited and of low grade (no autoimmune TEAEs and no drug-related death recorded). Conclusions: The analysis of the primary efficacy endpoint RFS and of secondary endpoints DMFS, pCR and safety show that neoadjuvant Daromun is an effective and safe therapeutic option for resectable, locally advanced melanoma pts. Clinical trial information: NCT02938299 . [Table: see text]