Frontline Bempegaldesleukin/Nivolumab Continues to Elicit Durable Responses in Metastatic Melanoma


The combination of bempegaldesleukin plus nivolumab continued to produce promising antitumor activity with favorable tolerability when used in the frontline treatment of patients with metastatic melanoma, according to findings from a phase 2 cohort of the phase 1/2 PIVOT-2 trial.

Adi Diab, MD

Adi Diab, MD

The combination of bempegaldesleukin (NKTR-214) plus nivolumab (Opdivo) continued to produce promising antitumor activity with favorable tolerability when used in the frontline treatment of patients with metastatic melanoma, according to findings from a phase 2 cohort of the phase 1/2 PIVOT-2 trial (NCT02983045) published in the Journal of Clinical Oncology.1

At 29.0 months of follow-up, the doublet induced a confirmed objective response rate (ORR) of 52.6% (95% CI, 35.8%-69.0%; n = 20/38) per blinded independent central review (BICR) assessment, with a complete response (CR) rate of 34.2% (n = 13) in this patient population. Notably, the combination also resulted in a -78.5% change in the size of target lesions from baseline, with 47.4% (n = 18) of patients achieving complete clearance of target lesions.

The median progression-free survival (PFS) experienced with the immunotherapy combination was 30.9 months (95% CI, 5.3–not estimable), and the median overall survival (OS) had not yet been reached.

Moreover, data from an exploratory biomarker analysis revealed that early on-treatment blood biomarkers correlated with response to the combination and suggest that the regimen may not only boost T-cell numbers but may also result in improved T-cell function.2

“Immune checkpoint inhibitors have become standard of care for [patients with] advanced melanoma, yet there is still an urgent, unmet need for patients whose disease does not respond to these therapies,” Adi Diab, MD, associate professor of Melanoma Medical Oncology, stated in a press release.2 “We sought to overcome some of the limitations of checkpoint inhibitors by adding an agent that leverages the IL-2 pathway to modulate the tumor microenvironment, without adding significant toxicity.”

Bempegaldesleukin is a first-in-class, CD122-preferential interleukin-2 pathway agonist that was designed to leverage the pathway to stimulate an antitumor immune response. The agent has previously been shown to increase the proliferation and infiltration of CD8+ T cells and natural killer cells into the tumor microenvironment, without resulting in the expansion of regulatory T cells.

Additionally, the agonist also has been known to increase PD-1 expression on lymphocytes within the microenvironment as well as expression on the tumor cells themselves; this supported the rationale to explore the agent in combination with an immune checkpoint inhibitor.

In the international phase 1/2 PIVOT-02 trial, investigators set out to evaluate bempegaldesleukin plus nivolumab in patients with advanced solid tumors. Data from the phase 2 cohort of the trial were published in the journal and focused on the use of the regimen in the first-line treatment of patients with metastatic melanoma.

To be eligible for inclusion, patients needed to be at least 18 years of age, have histologically confirmed stage III or IV melanoma that was measurable per RECIST v1.1 criteria, an ECOG performance status of 0 or 1, and available tumor tissue for biomarker testing. Moreover, patients needed to have known BRAF mutational status and PD-L1 immunohistochemistry status, as well as acceptable organ function.

If patients received previous treatment for their disease in the neoadjuvant, adjuvant, locally advanced, or metastatic settings, they were excluded from the trial. Patients who had previously received IL-2 therapy, who had uveal melanoma, or who had active brain metastases, were also excluded from the analysis.

Participants included in the phase 2 cohort were given intravenous bempegaldesleukin at a dose of 0.006 mg/kg in combination with nivolumab at 360 mg once every 3 weeks. Treatment was administered until progressive disease, death, intolerable toxicity, symptomatic deterioration, achievement of maximal response, investigator decision prompting discontinuation, withdrawn consent by the patient, pregnancy, loss to follow-up, or study termination via the sponsor. Responders received treatment with the doublet for a maximum of 2 years.

The co-primary end points of the trial included safety and ORR per RECIST v1.1 criteria, and key secondary end points included duration of response (DOR), clinical benefit rate or disease control rate (DCR), PFS, and OS. An important exploratory end point consisted of a biomarker analyses in the blood and tumor to identify associations with response to treatment.

A total of 41 patients with unresectable or metastatic melanoma were enrolled to a total of 12 sites across 3 countries between March 27, 2017, and March 28, 2018. At baseline, 29.3% of patients were noted to have elevated serum lactate dehydrogenase, 26.8% had liver metastases, and 34.1% had PD-L1 negativity.

All patients received at least 1 dose of the combination and were thus evaluable for safety. Thirty-eight patients underwent at least 1 baseline scan, so they were evaluable for response. A total of 3 patients discontinued before they had their first scan; 2 were because of patient decision and 1 was because of an unrelated treatment-emergent toxicity.

At the time of the data cutoff, no patients were still receiving treatment with the doublet. Bempegaldesleukin was discontinued because of progressive disease per RECIST criteria (n = 9), patient decision (n = 9), achievement of maximal response (n = 8), or clinical progression (n = 1). A total of 10 patients died while on the study, all because of progressive disease.

The median duration of treatment was 6.2 months (range, 3.1-17.3) and the median number of cycles received was 9.0 (range, 4-22). Additional data from the trial indicated that the median time to onset of first response to the doublet was 2.0 months (range, 1.5-4.1) and the median time to CR was 7.9 months (range, 1.5-15.2). Of 13 patients, 8 achieved a CR either on or after the third post-baseline scan was done, which was approximately after at least 8 treatment cycles; this was determined to be suggestive of a deepening of response over time.

Secondary analyses of response were also conducted for the trial. At data cutoff, 80.0% of 20 patients were noted to have an ongoing objective response with the combination. Responses persisted for 6 months or longer in 90.0% of these patients; 80.0% of patients experienced a response that lasted for 12 months or longer. The median DOR had not been reached (range, 29.0–not reached). Additionally, the DCR per BICR assessment was 73.7% with the doublet (n = 28/38).

Notably, the BICR-assessed ORRs in patients who had characteristics considered to be associated with poor prognosis, like the presence of liver metastases (n = 10) or an elevated lactate dehydrogenase greater than the upper limit of normal (n = 11), were 50.0% and 45.5%, respectively.

Secondary analyses of PFS and OS in the intent-to-treat population showed that at 12 months, 24 months, and 36 months, the PFS rates were 56.2% (95% CI, 38.4%-70.6%), 53.1% (95% CI, 35.4%-67.9%), and 45.5% (95% CI, 25.5%-63.5%), respectively. OS rates at these time points were 82.3% (95% CI, 66.4%-91.1%), 77.0% (95% CI, 60.4%-87.3%), and 70.9% (95% CI, 53.5%-82.8%), respectively.

Results from baseline tumor biomarker analyses demonstrated that PD-L1 expression and tumor mutational burden were not linked with objective response. However, other markers like high interferon-γ GEP, high CD8+ TIL, high CD74, and high HLA-E in baseline tumor biopsies were associated with a higher ORR with the doublet and a longer PFS.

After evaluating blood-based biomarkers for ability to predict response to treatment with the combination, investigators reported robust upregulation of polyfunctional CD8+ T cells in the blood of patients who achieved an objective response. A robust upregulation of CD4+ T cells was also observed in patients with and without an objective response following treatment. In contrast, investigators also reported a decrease in polyfunctionality of natural killer cells following treatment with the doublet.

Patients who had a high CD8+ polyfunctional strength difference (PSD) were found to experience a higher ORR with the combination vs those with a low CD8+ PSD; high CD8+ PSD was also associated with a longer PFS (HR, 3.75; 95% CI, 1.1-12.3). Lastly, a high-fold change in eosinophils from baseline to day 8 was linked with a higher ORR.

“Our exploratory biomarker findings advance our working hypothesis on the mechanism by which [the regimen] could provide additional efficacy over PD-1 inhibition alone–not only by increasing the number of T cells but also by boosting their fitness and functional capacity,” the study authors noted.

Regarding safety, 95.1% of 41 patients experienced adverse effects (AEs) that were determined to be related to the study treatment. The most common any-grade toxicities included flu-like symptoms, rash, fatigue, pruritus, arthralgia, and nausea. Additionally, 17.1% of patients experienced treatment-related AEs that were grade 3 or 4 in severity.

Five patients discontinued treatment due to a treatment-related AE, and these included increased blood creatinine, cerebrovascular accident, malaise, peripheral edema, and pharyngitis (1 each).

Moreover, 31.7% of patients experienced immune-mediated AEs, and 4.9% of these were grade 3 or higher; they included nephritis and renal dysfunction (n = 1) and diabetes mellitus–related hyperglycemia (n = 1). Notably, the incidence of cytokine-related AEs was found to decrease with continued dosing of the doublet. No treatment-related deaths were reported.

“These data provide preliminary evidence to support the safety and efficacy of bempegaldesleukin plus nivolumab in patients with previously untreated metastatic melanoma,” the study authors concluded. “The responses appeared deep and durable, with 90% of responding patients achieving 100% reduction in their target lesions vs baseline, and rates of grade 3 or higher [effects] were within acceptable limits.”


  1. Diab A, Tykodi SS, Daniels GA, et al. Bempegaldesleukin plus nivolumab in first-line metastatic melanoma. J Clin Oncol. Published online July 13, 2021. doi:10.1200/JCO.21.00675
  2. Novel immunotherapy combination produces durable response in frontline metastatic melanoma. News release. The University of Texas MD Anderson Cancer Center. July 13, 2021. Accessed July 14, 2021.
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