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A combination of the novel interleukin-2 (IL-2) pathway agonist bempegaldesleukin (BEMPEG) with the programmed death-1 (PD-1) inhibitor nivolumab shows promising clinical activity with tolerable toxicity in patients with advanced melanoma.

There is an unmet need for novel first-line combinations to extend the treatment benefit of immunotherapy to more patients with metastatic melanoma, without substantially adding toxicity, noted Adi Diab, MD, of the University of Texas MD Anderson Cancer Center in Houston, and colleagues.

As they reported in the , the phase II cohort from the international, single-arm PIVOT-02 study evaluated BEMPEG plus nivolumab as first-line therapy in patients with previously untreated, unresectable, or metastatic melanoma. The combination was tolerated, with relatively low rates of grade 3/4 treatment-related (17.1%) and immune-mediated (4.9%) adverse events, and showed encouraging antitumor activity, including an extended median progression-free survival (PFS).

In the following interview, one of the co-researchers, Igor Puzanov, MD, MSci, director of the Early Phase Clinical Trials Program in the Department of Medicine at Roswell Park Comprehensive Cancer Center in Buffalo, New York, discusses the highlights of the results.

What does the study add to the literature about the inclusion of an agent that modulates the tumor microenvironment to immune checkpoint inhibitors?

Puzanov: This is the most developed report on a novel IL-2 modified molecule plus immunotherapy in metastatic melanoma. We clearly show tolerable toxicity and that this combination can induce inflamed tumors to respond to anti-PD-1 therapy. This is a single-arm trial, with limited numbers of patients -- 38 patients evaluable for efficacy -- so we need to wait for data from a phase III trial, which is ongoing.

Patients achieved deep and durable clinical responses, as evidenced by the observed 52.6% overall response rate, 34.2% complete response (CR) rate, median 78.5% reduction in tumor burden from baseline, and median PFS of 30.9 months.

These preliminary findings indicate that BEMPEG plus nivolumab has the potential to provide additional efficacy over PD-1 inhibition alone. In comparison, the CR for single-agent nivolumab is 18% with longer follow-up.

We also found a difference in patients with liver metastases. Our responses with the combination were better than the historical experience with single-agent nivolumab. This is a clinically important and promising finding.

The current gold standard for advanced melanoma is a combination of ipilimumab plus nivolumab. The study showed a median 72.1 months overall survival (OS) with ipilimumab-nivolumab after a minimum of 6.5 years follow-up. But grade 3/4 treatment-related adverse events were reported in 59% of combination-treated patients. We would like to extend the benefits of checkpoint inhibitors with less toxicity. We hope this combination may do that.

By what mechanism does BEMPEG plus nivolumab provide additional efficacy over PD-1 inhibition alone?

Puzanov: BEMPEG increases the proliferation and infiltration of CD8-positive T cells and natural killer cells into the tumor microenvironment without expansion of regulatory T cells, both in preclinical and in human studies. BEMPEG also increases PD-1 expression on lymphocytes in the tumor microenvironment -- a marker of CD8-positive tumor-reactive T cells -- and PD-L1 expression on tumor cells.

BEMPEG may contribute to increased efficacy over nivolumab alone not only by increasing the number of T cells in the blood and tumor but also by enhancing their fitness and functional capacity. On the translational side, the combination turns "cold" tumors into "hot" ones. This suggests we are changing the microenvironment, increasing CD8-positive T cells and not increasing CD4-positive regulatory cells. Changing this ratio for the better helps support suppressor cells.

What's important for practicing oncologists to know about the results?

Puzanov: This promising combination shows preliminary activity with an unprecedented rate of CR, as well as activity in liver metastases, which raises the interest even higher. BEMPEG is tolerable for outpatient treatment and therefore can be given in a clinic, which is another benefit.

Primary analysis of a randomized phase III trial will be available within a year. It may take several years to show improvement in PFS and OS. With improved outcomes in the treatment of advanced melanoma, the benchmark becomes even higher, and we may have to wait longer for treatment and duration results.

The bottom line is this appears to be a good formulation.

Read the study here and expert commentary about the clinical implications here.