Bempegaldesleukin Ups Melanoma Responses

Preliminary findings of a phase I/II trial suggest that adding bempegaldesleukin (NKTR-214; Nektar Therapeutics) to the PD-1 checkpoint inhibitor nivolumab (Opdivo; Bristol-Myers Squibb) may lead to high overall and complete response rates, with relatively few side effects.

The data were presented by Adi Diab, MD, of The University of Texas MD Anderson Cancer Center in Houston, at the Society for Immunotherapy of Cancer (SITC) 2019 Annual Meeting in National Harbor, MD, in November.

Bempegaldesleukin is a CD122-preferential IL2-pathway agonist. In preclinical studies, it increased tumor-infiltrating lymphocytes, T-cell clonality, and PD-1 expression—and expanded and activated CD8+ T cells and natural killer (NK) cells—leading researchers to hypothesize that it might improve responses to a PD-1 inhibitor. “It is likely a synergistic mechanism” in which bempegaldesleukin and nivolumab “activate the T cells in somewhat distinct but complementary ways,” says Douglas Johnson, MD, of Vanderbilt-Ingram Cancer Center in Nashville, TN, who was not involved in the trial.

The PIVOT-02 trial is testing bempegaldesleukin plus nivolumab in solid tumors. At SITC, researchers reported on 38 evaluable patients with newly diagnosed metastatic melanoma. After 18.6 months of follow-up, the combination had elicited responses in 20 patients, including 13 complete responses; median progression-free survival had not been reached. In total, 17.1% of patients experienced grade 3 or 4 adverse events, most commonly acute kidney injury or atrial fibrillation; 12.2% of patients discontinued one of the drugs due to side effects.

“It is very promising activity in terms of high response rates, high complete response rates, early signs of durable responses, and excellent progression-free survival,” Johnson says. However, he adds that the results should be interpreted with caution given the study's small size.

Moreover, he emphasizes that immune checkpoint inhibitor monotherapy is associated with response rates of up to 40% to 45% in metastatic melanoma, so it is not clear how much bempegaldesleukin improves responses. “The gold standard is going to be randomized data comparing to nivolumab alone. That's really the only way to truly determine whether the combination is adding something over nivolumab monotherapy,” he says.

Ryan Sullivan, MD, of Massachusetts General Hospital in Boston, who was also not involved in the trial, agrees. “I do think it's encouraging; I just think it's not game changing” without results from a larger, randomized trial, he says. He notes, however, that the combination is well tolerated compared with historical data on nivolumab monotherapy. “We're seeing clearly that there doesn't appear to be worse toxicity, and there may be some attenuation of the toxicity.”

A phase III trial is now comparing the combination with nivolumab in melanoma; other trials will test bempegaldesleukin in other combinations and tumor types. In particular, Johnson and Sullivan want to know whether bempegaldesleukin, either alone or in combination with nivolumab, is active in patients who develop resistance to immune checkpoint inhibitors. The agent may be effective in these patients, Sullivan explains, because it increases NK cells, which selectively attack cells that have lost MHC class I—a common state in resistant cells.

If the combination demonstrates effectiveness, clinicians would have another therapeutic option, one that may lead to more individualized treatment. Eventually, Johnson says, he hopes that researchers can identify biomarkers, and use them to match patients with treatment regimens. “We're certainly not to that point yet,” he says, “but you can envision if you have another therapy like this, you can start to refine which patient populations need which therapies.” –Catherine Caruso

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