Novel Immunotherapy Combination Produces Durable Response in Untreated Metastatic Melanoma

Researchers at The University of Texas MD Anderson Cancer Center have found that a rare resistance mutation first thought to appear in melanoma (pictured) following treatment with a targeted therapy has instead turned out to be hiding in the tumor all along. [Definiens]

An unmet need remains for novel immune checkpoint inhibitor combinations that achieve durable and deep responses in patients with metastatic melanoma, without adding substantial toxicity.

Results from the Phase II  PIVOT-02 study in untreated metastatic melanoma has shown the combination of interleukin-2 (IL-2) pathway agonist bempegaldesleukin (BEMPEG) plus the immunotherapy nivolumab may fit the bill. Findings from the trial, published in the Journal of Clinical Oncology, showed the treatment provided a 34.2% complete response rate.

A total of 41 previously untreated patients with stage III/IV melanoma received BEMPEG plus nivolumab every 3 weeks for ≤ 2 years; 38 patients were available for evaluation. Consistent with overall melanoma incidence, 92.7% of participants were white and 7.3% were other races.

At 29.0 months’ median follow-up, the objective response rate was 52.6%; the complete response rate was 34.2%.

Other findings:

  • Median change in size of target lesions from baseline was −78.5%
  • 4% experienced complete clearance of target lesions
  • Median progression-free survival was 30.9 months
  • The median overall response rate was not reached but was 77% at 24 months
  • Grade 3 and 4 treatment-related and immune-mediated adverse events occurred in 17.1% (7 of 41) and 4.9% (2 of 41) of patients, respectively. These rates were consistent with reported toxicity for PD-1 inhibitor monotherapy.

“Interleukin-2 plays an important role in promoting tumor cell death by enhancing the survival and expansion of CD4+ and CD8+ T cells and natural killer cells,” the authors write. High-dose IL-2 is approved for the treatment of metastatic melanoma, but its clinical use is limited by its short half-life, which necessitates a high dose leading to significant toxicities, such as vascular leak syndrome. As a result, high-dose IL-2 requires inpatient administration at specialized centers.

BEMPEG is a first-in-class IL-2 pathway agonist that leverages the clinically validated IL-2 pathway to stimulate an antitumor immune response.

“Immune checkpoint inhibitors [like nivolumab] have become standard of care for advanced melanoma patients, yet there is still an urgent, unmet need for patients whose disease does not respond to these therapies,” said lead author Adi Diab, MD, from the University of Texas MD Anderson Cancer Center.

Looking to overcome some of the limitations of checkpoint inhibitors, was engineered BEMPEG as an immunostimulatory IL-2 cytokine drug that leverages the IL-2 pathway. “The goal was to deliver a controlled and sustained IL-2 pathway signal and thereby minimize toxicity, allowing for outpatient administration.”

In addition, the trial indicated that early on-treatment exploratory biomarker analysis in CD8+ and CD4+ T cells correlate with response. Other baseline tumor biomarkers, including high IFN-y GEP, CD8+, tumor infiltrating lymphocytes (TIL), CD74 and HLA-E, were associated with a higher overall response rate and a longer progression-free survival.

Based on these and the blood-based biomarker findings, the researchers theorize that adding BEMPEG to nivolumab increases the number of T cells, while also boosting their fitness and functional capacity.

“Our study shows that the combination of BEMPEG and nivolumab is safe and effective,” Diab said. “We are encouraged by the potential of a new treatment option for newly diagnosed patients with advanced melanoma, and we look forward to the results from the Phase III study, which is enrolling now.”

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