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CHICAGO -- Preoperative intralesional treatment with a dual antibody-cytokine fusion significantly improved relapse-free survival (RFS) in locally advanced melanoma versus surgery alone, a randomized trial showed.

Median RFS more than doubled when patients received daromun before surgery (16.7 vs 6.8 months). Landmark analyses showed similar advantages in favor of daromun out to 3 years. Results were similar for blinded review and investigator assessment.

The intralesional therapy also significantly improved distant metastasis-free survival (DMFS), suggesting the local therapy induced a systemic immune response, reported Axel Hauschild, MD, of University Hospital Schleswig-Holstein in Kiel, Germany, at the American Society of Clinical Oncology (ASCO) meeting.

"Treatment with daromun resulted in a clinically meaningful and statistically significant longer median relapse-free survival with a reduction of 41% in the risk of recurrence or death in pretreated, locally advanced melanoma," said Hauschild. "The statistically significant difference in distant metastasis-free survival suggests a systemic immune response induced by the local infiltration."

"The overall survival data remain immature and will be presented at a later conference," he added. "Daromun showed a manageable safety profile with mainly local adverse events."

The trial continued the long history of intralesional injections to treat melanoma, said ASCO invited discussant Paul Chapman, MD, of Memorial Sloan Kettering Cancer Center in New York City. In preparation for the talk, he found "a long list of stuff we've injected into melanoma" since at least 1893. The list included bacteria, viruses, cells, cytokines, chemicals, monoclonal antibodies, and other "things."

"Almost all of these things, when injected into a melanoma tumor, have a pretty high chance of causing regression of that tumor, but it's been very difficult to demonstrate significant systemic immunity and responses in non-injected tumors," said Chapman.

In the trial of T-VEC (Imlygic) versus granulocyte macrophage-colony stimulating factor, complete responses occurred in 22% of non-injected, non-visceral lesions and 9% of non-injected visceral lesions. In a , preoperative T-VEC led to improved relapse-free survival and a slight improvement in overall survival, he continued.

PIVOTAL produced a pathologic complete response (pCR) rate of 21%, "but the real question is whether treatment resulted in a systemic immune response."

A of daromun showed some complete responses in non-injected tumors and superior distant metastatic-free survival, implying a systemic immune response.

"Daromun, and T-VEC for that matter, may find a niche in patients who progress after checkpoint inhibitor therapy with limited and potentially resectable recurrences," said Chapman. "The data presented here, and previously with T-VEC, suggest outcomes in these patients will be better than with surgery alone."

The daromun construct comprises a fusion of the L19 antibody (which binds fibronectin) to interleukin-2 and tumor necrosis factor. Preclinical studies showed the antibody fusion elicits a potent immunostimulatory effect in the tumor microenvironment. showed that a single injection of daromun eradicated tumors in all of the animals, said Hauschild.

PIVOTAL was a phase III randomized trial involving 256 patients with resectable locally advanced melanoma. Patients went directly to surgery or received a single injection of daromun into target lesions followed by surgery. Patients could receive injections in multiple lesions. About 80% of the study population had stage IIIB-C disease, 30-40% had BRAF mutation, and 50-60% had a single metastatic lesion. Almost all lesions were in the skin (60%) or lymph nodes (38-39%).

The patients had a median surgical history of two prior operations, and a third of the patients had prior systemic therapy, primarily immunotherapy.

The primary endpoint was RFS by blinded independent central review. With a median follow-up of 21.2 months, the data showed that daromun reduced the hazard ratio by 41% versus surgery alone (95% CI 0.41-0.86, P=0.005). More patients in the daromun arm were relapse free at 12 months (57.5% vs 39.5%), 24 months (41.6% vs 23.6%), and 36 months (25.5% vs 10.3%). By investigator assessment, daromun reduced the RFS hazard 39% (95% CI 0.41-0.92, P=0.018).

The secondary endpoint of DMFS was 40% lower in the daromun arm (95% CI 0.37-0.95, P=0.029). Median values were 28.0 months with daromun and 17.8 months with surgery alone.

More patients in the upfront surgery group received post-surgery adjuvant therapy (40.5% vs 29.8%). After adjustment for the potential impact of post-surgical adjuvant therapy, the superiority of daromun for RFS remained unchanged (HR 0.60, P=0.009).

Preoperative daromun achieved pCR in 21% of patients, defined as "absence of residual vital tumor cells in all material examined." The pilot study that preceded PIVOTAL showed that Daromun induced tumor necrosis and promoted T-cell infiltration into the remaining vital tumor areas, data that will be presented at a future date, said Hauschild.

Local and systemic treatment-related adverse events (TRAEs) occurred in 83.9% and 87.3% of patients, respectively, in the daromun group, but severe TRAEs were uncommon, 12.7% grade 3 local events and 15% grade 3/4 (only one grade 4) systemic events. Overall, 14% of daromun-treated patients discontinued treatment because of TRAEs.

Hauschild said patients in the daromun arm received a median of four injections and a mean of three.

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