The novel immunomodulatory therapy Bempegaldesleukin developed by Nektar Therapeutics (NKTR) has demonstrated clear and durable improvement in patient response in frontline metastatic melanoma in combination with nivolumab.
18 January, 2021
1/18/2021 10:03 AM
The novel immunomodulatory therapy Bempegaldesleukin developed by Nektar Therapeutics (NKTR) has demonstrated clear and durable improvement in patient response in frontline metastatic melanoma in combination with nivolumab [1]. Despite challenges in drug formulation in the very beginning of the PIVOT-02 trial that resulted in some patients receiving suboptimal doses, the recently updated results support that the properly manufactured product produces a strong improvement in the duration of tumor response.
Bempegaldesleukin (NKTR-214) is an immunomodulatory agent designed to augment the tumor killing effect of immunotherapy. Bempegaldesleukin is a PEGylated form of interleukin-2 (IL-2) that functions as an IL-2 pathway agonist primarily via CD122. By stimulating CD122 function, this cytokine preferentially activates and promotes proliferation of CD8+ T-cells and NK cells and not regulatory T cells. In combination with immune checkpoint blockade from nivolumab, the increase in CD8+ T-cells and NK cells should enhance tumor targeting. In addition, bempegaldesleukin was observed to promote tumor transition from PD-L1-negative to PD-L1-positive [2].
Bempegaldesleukin in combination with nivolumab was granted Breakthrough Therapy designation by the FDA in August 2019 for treatment of previously untreated unresectable or metastatic melanoma based on the tumor response rates observed in the PIVOT-02 trial. In PIVOT-02, untreated stage IV melanoma patients have shown an overall response rate was 53% with 34% achieving complete response, regardless of PD-L1 status. Additionally, it was reported at the 2020 Annual Meeting of the Society for Immunotherapy of Cancer that a median progression-free survival of 30.9 months was observed for the entire cohort.
Nivolumab was first approved as a monotherapy for metastatic melanoma after failure of ipilimumab in December 2014 due to demonstration of a 32% overall response rate (3.3% complete response) that was sustained for over six months in many patients, with medial progression-free survival of 3.1 months and median overall survival of 15.7 months.
In October 2015, nivolumab received approval for treatment of BRAF V600 wild-type metastatic melanoma in combination with ipilimumab based on significant increase in overall response rate to 60% with 11% achieving complete response. Median progression-free survival was 8.9 months. This approval was expanded in January 2016 to include BRAF V600 mutant metastatic melanoma based on updated trial results demonstrating median PFS of 11.5 months and 50% objective response rate with 8.9% achieving complete response.
If the results observed so far for bempegaldesleukin plus nivolumab in frontline treatment of metastatic melanoma remain consistent through the remainder of the trial, then it is a clear improvement over immunotherapy alone. In parallel, bempegaldesleukin is in a Phase 3 trial for adjuvant use in melanoma after surgical resection in combination with nivolumab (PIVOT-12).
The safety profile for the combination of bempegaldesleukin plus nivolumab appears manageable with seven patients (17.1%) having grade 3 or 4 treatment-related adverse events, only two of which were immune-related. Five patients discontinued treatment due to toxicity and there have been no treatment-related deaths.
Bempegaldesleukin is being evaluated in parallel in a variety of tumor types in trials for advanced solid tumors in combination with immunotherapies such as nivolumab and pembrolizumab. While still in the early stages of clinical evaluation, immunomodulatory agents like bempegaldesleukin show promise for enhancement of current immunotherapy efficacy with tolerable toxicity and possibly re-sensitization of refractory tumors.
Nektar Therapeutics has not yet filed a New Drug Application for Bempegaldesleukin with the FDA. The primary completion date for PIVOT-02 is scheduled for November 2021.
If the efficacy and safety outcomes data from the PIVOT-02 trial are maintained or improved through the primary complete date, Biopharma Insights Group predicts an 82% probability of FDA approval for treatment of patients with untreated advanced melanoma in combination with nivolumab.
This probability score is based on a quantitative statistical model built on clinical outcomes data from hundreds of clinical trials.
References
1. Diab, A., Tykodi, S., Daniels, G., et al. Progression-free survival and biomarker correlates of response with bempeg plus nivo in previously untreated patients with metastatic melanoma: Results from the PIVOT-02 study. 2020 Society for Immunotherapy of Cancer Annual Meeting. Abstract 420. Presented November 11, 2020.
2. Helwick, Caroline. Novel Combination Under Study in First-Line Treatment of Metastatic Melanoma. The ASCO Post. December 25, 2020. https://ascopost.com/issues/december-25-2020/novel-combination-under-study-in-first-line-treatment-of-metastatic-melanoma/
About Biopharma Insights Group
Biopharma Insights Group is an investment research company providing insights on clinical trial approval probability using advanced statistical methods.
For more information: contact@biopharmainsights.com
Disclosure
Biopharma Insights Group has no affiliation with or involvement in any organization or entity with any financial interest, or non-financial interest with any business or individual involved in development of therapeutic agents being evaluated.
This analysis is not an offer or solicitation for the purchase or sale of a security or financial instrument. The factual statements herein have been taken from sources we believe to be reliable, but such statements are made without any representation as to accuracy or completeness or otherwise. Opinions expressed are our own unless otherwise stated and are subject to change without notice.