FDA Grants Bempegaldesleukin Plus Nivolumab Breakthrough Designation in Melanoma

The FDA granted a breakthrough therapy designation to the combination of bempegaldesleukin (NKTR-214) and nivolumab (Opdivo) for the treatment of patients with previously untreated unresectable or metastatic melanoma.

Stephen Doberstein, PhD, SVP

The FDA granted a breakthrough therapy designation to the combination of bempegaldesleukin (NKTR-214) and nivolumab (Opdivo) for the treatment of patients with previously untreated unresectable or metastatic melanoma.

The designation is based on results from a cohort of the ongoing phase I/II PIVOT-02 trial, in which the combination of bempegaldesleukin and nivolumab led to an overall response rate (ORR) of 53% by independent radiology review, which included a 34% complete response (CR) rate, in this patient population.

“In collaboration with our partner Bristol-Myers Squibb, we plan to work closely with FDA as we continue to advance our development program of bempegaldesleukin in combination with nivolumab in advanced melanoma patients,” Stephen Doberstein, PhD, SVP, Research and Development and Chief R&D Officer of Nektar Therapeutics, stated in a press release. “Our teams are encouraged by the deepening of responses we observed in patients with previously untreated advanced melanoma who received the doublet therapy in our PIVOT-02 study. We look forward to continuing to provide updated results at a future medical meeting as the data mature further from this ongoing cohort of melanoma patients.”

In February 2018, Bristol-Myers Squibb, the developer of nivolumab, and Nektar executed a global strategic development and commercialization collaboration for bempegaldesleukin.

Bempegaldesleukin is an investigational CD122-preferential interleukin-2 pathway agonist that is developed to activate and proliferate CD8+ effector T cells and natural killer cells.

In melanoma, nivolumab is currently FDA approved as a single agent for the treatment of patients with unresectable or metastatic disease, and also in combination with ipilimumab (Yervoy) for the treatment of patients with unresectable or metastatic disease.

In the multicenter PIVOT-02 trial, there was a dose escalation phase across a range of solid tumors in which bempegaldesleukin and nivolumab were given at varying doses. A 0.006 mg/kg every-3-week dose of bempegaldesleukin plus nivolumab at 360 mg every 3 weeks was determined as the recommended phase II dose in patients with melanoma and metastatic urothelial cancer, both in the first-line setting. Other tumor types are being evaluated in ongoing expansion arms.

In the melanoma cohort, patients had a known BRAF status, measurable disease per RECIST v1.1 criteria, and an ECOG performance status of 0 or 1. Forty-one patients with melanoma were enrolled and received ≥1 dose of bempegaldesleukin/nivolumab. As of the data cutoff date, which was March 29, 2019, 38 patients were evaluable for efficacy; 3 patients had discontinued prior to the first scan due to an unrelated treatment-emergent adverse event (TEAE; n = 1) and patient decision (n = 2).

Updated findings, which were presented at the 2019 ASCO Annual Meeting, included data on baseline tumor immune signatures associated with response to the frontline combination in patients with stage IV melanoma. Results showed that, by independent radiology review, the ORR was 53%, which included a 34% CR rate. The disease control rate was 74%.

In PD-L1—positive, PD-L1–negative, and PD-L1–unknown tumors, the ORRs were 62%, 43%, and 33%, respectively. There was a 100% reduction in target lesions in 42% of patients.

At a median 12.7 months of follow-up, 80% of patients had an ongoing response. The median duration of response was not reached (NR; 95% CI, 11.0—NR). The median time to response was 2.0 months, and the median maximum reduction from baseline was –55%.

Exploratory biomarker analyses showed that in baseline tumor biopsies, immune signatures that enrich for response were identified in treatment-naïve patients with melanoma. The highest ORRs correlated with these baseline marker scores: IFNg (81.8%), CD8+ tumor-infiltrating lymphocytes (TILs; 80.0%), CD3+ TILs (78.6%), and PD1+CD8+TILs (76.9%).

Overall, response rates were observed regardless of PD-L1 expression or unfavorable tumor microenvironments.

Regarding safety, all of the grade 3/4 treatment-related adverse events (TRAEs) were reported in 6 (14.6%) patients, and included atrial fibrillation (4.9%); hyperglycemia (2.4%); and acute kidney injury, blood creatinine increase, dyspnea, hypernatremia, and hypoxia (n = 1 each). Grade 1/2 TRAEs included flu-like symptoms (80.5%), rash (70.7%), fatigue (65.9%), pruritus (48.8%), nausea (41.5%), arthralgia (36.6%), and myalgia (31.7%). A total 9.8% of patients discontinued therapy due to a TRAE.

The ongoing phase III PIVOT 1O 001 trial is evaluating bempegaldesleukin in combination with nivolumab versus nivolumab alone as frontline therapy for patients with advanced melanoma (NCT03635983).


  1. Nektar Therapeutics and Bristol-Myers Squibb Announce U.S. FDA Breakthrough Therapy Designation for Bempegaldesleukin (NKTR-214) in Combination with OPDIVO (nivolumab) for the Treatment of Patients with Untreated Advanced Melanoma. Nektar. Published August 1, 2019. https://bit.ly/2ZnIeKw. Accessed August 1, 2019.
  2. Hurwitz ME, Cho DC, Balar AV, et al. Baseline tumor-immune signatures associated with response to bempegaldesleukin (NKTR-214) and nivolumab. J Clin Oncol. 2019;37(suppl; abstr 2623). doi: 10.1200/JCO.2019.37.15_suppl.2623.