Neoadjuvant Daromun Elicits RFS Benefit in Locally Advanced, Fully Resectable Melanoma

Neoadjuvant treatment with intratumoral daromun (Nidlegy) led to a statistically significant and clinically meaningful improvement in recurrence-free survival (RFS) compared with surgery alone in patients with locally advanced, fully resectable melanoma, meeting the primary end point of the phase 3 PIVOTAL trial (NCT02938299).¹

Finding showed that at a median follow-up of 27.6 months, neoadjuvant daromun reduced the risk of disease recurrence or death by 33% compared with surgery alone per blinded independent central review assessment (HR, 0.67). Per investigator assessment, daromun lowered the risk of recurrence or death by 37% (HR, 0.63).

Full results and data from a subgroup analysis will be presented at an upcoming medical meeting and shared with regulatory authorities.

“We are extremely pleased to announce positive topline data emerging from our PIVOTAL program in locally advanced resectable melanoma. The clinical data in melanoma and high-risk non-melanoma skin cancers bode well for the possible adoption of intralesional [daromun] in a series of dermato-oncology indications,” Dario Neri, PhD, cofounder, chief executive officer, and chief scientific officer of Philogen S.p.A., stated in a news release. “Philogen is currently executing 6 additional advanced clinical trials with registration potential featuring either [daromun] or fibromun, the company’s most advanced product candidates, as active ingredients.”

Daromun consists of 2 active ingredients: L19 interleukin 2 (IL-2) and L19 tumor necrosis factor (TNF). The 2 products are created independently before being combined prior to administration.

“Neoadjuvant cytokine therapy for the treatment of locally advanced skin cancers enables a robust expansion of tumor-infiltrating lymphocytes. By anchoring IL-2 and TNF within the tumor mass through the L19 antibody moiety, we minimize systemic [adverse] effects [AEs] while mounting a systemic robust anticancer immune response,” Alfredo Covelli, MD, chief medical officer of Philogen, added in the news release. “This phase 3 study merged the intralesional approach with IL-2, pioneered by [Claus Garbe, MD, PhD], more than 20 years ago, with the concepts of antibody-based tumor targeting, and with neoadjuvant therapy in locally advanced melanoma. The approach may find a broad applicability in different types of cancer.”

PIVOTAL was an international, multicenter, randomized, comparator-controlled study that enrolled patients at least 18 years of age with locally advanced, fully resectable stage IIIB/C melanoma with cutaneous, subcutaneous, or nodal metastases.² Prior treatment for the primary lesion was allowed, including surgery and approved adjuvant treatments such as radiotherapy, immune checkpoint inhibitors, and BRAF/MEK inhibitors. Other key inclusion criteria included an ECOG/World Health Organization performance status of 0 or 1, a life expectancy of at least 24 months, and adequate hematologic and hepatic function.

Patients were excluded if they had uveal melanoma, mucosal melanoma, or melanoma with unknown primary; evidence of distant metastases; active infections; a history of acute or subacute coronary syndromes within 1 year of enrollment; inadequately controlled cardiac arrhythmias; a left ventricular ejection fraction of 50% or less and/or echocardiogram abnormalities; and uncontrolled hypertension.

Investigators randomly assigned 257 patients enrolled across 22 centers in Germany, Italy, France, and Poland to receive daromun once per week for up to 4 weeks prior to surgery or surgery alone.1,2 Notably, those in the experimental arm did not receive the full 4 weeks of daromun if all injectable tumors disappeared, intolerance occurred, or if immediate surgical resection or another treatment for melanoma was warranted.1Approved adjuvant treatments were permitted for patients in both arms.1

RFS rate at 1 year served as the trial’s primary end point. Key secondary end points included local RFS, distant metastasis-free survival, 2- and 3-year RFS rates, overall survival, and safety.2

Regarding safety, findings from PIVOTAL were in line with previously reported data. Treatment-related AEs were considered benign and manageable.1 Grade 3 AEs were reported in 24.8% of patients, and no grade 4 toxicities or treatment-related deaths occurred. Notably, treatment with daromun was not associated with the onset of autoimmune conditions.

References

1. Nidlegy phase III PIVOTAL trial meets the study’s primary objective demonstrating statistically significant and clinically meaningful improvement in recurrence-free survival for patients with locally advanced fully resectable melanoma. News release. October 16, 2023. Accessed October 16, 2023. https://www.philogen.com/philogen/wp-content/uploads/2023/10/Press_release_PIVOTAL.pdf
2. Neoadjuvant L19IL2/​L19TNF- pivotal study (Pivotal). ClinicalTrials.gov. Updated October 10, 2023. Accessed October 16, 2023. https://clinicaltrials.gov/study/NCT02938299