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Frontline Bempegaldesleukin Nivolumab Combo Misses Primary End Points in Unresectable or Metastatic Melanoma


The addition of bempegaldesleukin to nivolumab did not significantly improve progression-free survival, objective response rate, or overall survival vs nivolumab alone in the frontline treatment of patients with unresectable or metastatic melanoma, missing the primary end points of the phase 3 PIVOT IO-001 trial.

The addition of bempegaldesleukin (NKTR-214) to nivolumab (Opdivo) did not significantly improve progression-free survival (PFS), objective response rate (ORR), or overall survival (OS) vs nivolumab alone in the frontline treatment of patients with unresectable or metastatic melanoma, missing the primary end points of the phase 3 PIVOT IO-001 trial (NCT03635983).1

Bristol Myers Squibb (BMS) and Nektar Therapeutics were informed that a review of safety and efficacy data from the trial, which was conducted by the independent Data Monitoring Committee (DMC), revealed that these end points had not been met per blinded independent central review assessment. Moreover, the DMC also told the companies that the third primary end point of OS did not meet statistical significance at the first interim analysis of the trial.

In light of this information, the companies decided to unblind the trial and to not perform any additional OS analyses. They also decided to discontinue enrollment to, and unblind, the ongoing phase 3 PIVOT-12 study (NCT04410445), which was designed to examine the doublet vs single-agent nivolumab in the adjuvant treatment of patients who are at high risk for recurrence following complete resection of melanoma.

“We are disappointed with the results of this trial, which we had hoped would lead to a new therapeutic option to treat metastatic melanoma,” Johnathan Cheng, senior vice president and head of oncology development, at Bristol Myers Squibb, stated in a press release. “We express our gratitude to the patients, caregivers, and investigators who chose to participate in these trials.”

PIVOT IO-001 enrolled those with histologically confirmed stage III or stage IV melanoma who were treatment naïve, with the exception of previous adjuvant and/or neoadjuvant treatment for their disease with approved agents.2 To be eligible for enrollment, patients needed to be at least 18 years of age, have an ECOG performance status of 0 or 1, and a Lansky performance score of 80% or higher. If patients had active brain metastases or leptomeningeal metastases, uveal melanoma, or active, known, or suspected autoimmune disease, they were excluded.

A total of 783 patients were randomized 1:1 to receive bempegaldesleukin at a dose of 0.006 mg/kg in combination with nivolumab at 360 mg or nivolumab at the same dose given every 3 weeks in an outpatient setting. Treatment was continued until disease recurrence, intolerable toxicity, withdrawn consent, or for up to 24 months.

The companies shared that they plan to review the findings from PIVOT IO-001 and to share more information with the scientific community at a later date.

Previously, the multicenter phase 1/2 PIVOT-02 trial (NCT02983045) evaluated the doublet in patients with advanced solid tumors.3 To be eligible for inclusion, patients needed to be 18 years of age or older, have histologically confirmed stage III or IV melanoma, measurable disease per RECIST v1.1 criteria, an ECOG performance status of 0 or 1, acceptable organ function, and tumor tissue available for biomarker evaluation. BRAF mutational status and PD-L1 status needed to be known.

Patients could not have received treatment in the neoadjuvant, adjuvant, locally advanced, or metastatic settings. Those who received prior interleukin-2 therapy, who had uveal melanoma, or anyone with active brain metastases, were excluded.

Participants in the phase 2 cohort received bempegaldesleukin at 0.006 mg/kg plus nivolumab at 360 mg once every 3 weeks until disease progression, death, unacceptable toxicity, symptomatic deterioration, maximal response was achieved, discontinuation per investigator decision, withdrawn consent by patient, loss to follow-up, or the sponsor terminated the study. Patients could receive the combination for up to 24 months.

The co-primary end points of the trial were safety and ORR per RECIST v1.1 criteria. Secondary end points included duration of response, clinical benefit rate or disease control rate, PFS, and OS. Biomarker analyses were conducted and served as an exploratory end point.

A total of 41 patients were enrolled to the trial, and the median duration of treatment was 6.2 months (range, 3.1-17.3) with a median of 9.0 cycles (range, 4-22) received. Data showed that the doublet produced encouraging antitumor activity with acceptable tolerability when used as frontline treatment in patients with metastatic melanoma.

At 29.0 months of follow-up, bempegaldesleukin plus nivolumab elicited a confirmed ORR of 52.6% (95% CI, 35.8%-69.0%; n = 20/38) per blinded independent central review assessment in this population, and this included a complete response (CR) rate of 34.2% (n = 13). The median PFS with the doublet was 30.9 months (95% CI, 5.3–not estimable) and the median OS had not yet been reached.

Additional data showed that the median time to onset of first response was 2.0 months (range, 1.5-4.1), and the median time to CR was 7.9 months (range, 1.5-15.2). Responses to treatment were noted to deepen over time.

Secondary analyses of PFS and OS were conducted in the intent-to-treat population. The 12-month PFS rate with the doublet was 56.2% (95% CI, 38.4%-70.6%); the 24- and 36-month rates were 53.1% (95% CI, 35.4%-67.9%) and 45.5% (95% CI, 25.5%-63.5%), respectively. The OS rates at 12 months, 24 months, and 36 months with the combination 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.

PIVOT IO-001 was launched to confirm the data observed in this trial.

“While we are surprised and deeply disappointed in these results for the melanoma study, we will continue to await initial results from our first 2 ongoing studies in renal cell carcinoma and urothelial cancer, which are currently expected in the first half of 2022,” Jonathan Zalevsky, chief research and development officer of Nektar Therapeutics, added in the press release. “We look forward to collaborating with BMS to evaluate the data from these other studies to guide the future development of bempegaldesleukin.”


  1. Bristol Myers Squibb and Nektar announce update on phase 3 PIVOT IO-001 trial evaluating bempegaldesleukin (BEMPEG) in combination with Opdivo (nivolumab) in previously untreated unresectable or metastatic melanoma. News release. Bristol Myers Squibb and Nektar Therapeutics; March 14, 2022. Accessed March 14, 2022. https://bit.ly/3taq14x
  2. A study of NKTR-214 combined with nivolumab vs nivolumab alone in participants with previously untreated inoperable or metastatic melanoma. ClinicalTrials.gov. Updated January 20, 2022. Accessed March 14, 2022. https://clinicaltrials.gov/ct2/show/NCT03635983
  3. Diab A, Tykodi SS, Daniels GA, et al. Bempegaldesleukin plus nivolumab in first-line metastatic melanoma. J Clin Oncol. 2021;39(26):2914-2925. doi:10.1200/JCO.21.00675

This was originally posted by our sister publication OncLive.

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