pegilodecakin (LY3500518)

P1, N=353, Completed, Eli Lilly and Company | Active, not recruiting --> Completed

P1, N=350, Active, not recruiting, Eli Lilly and Company | Trial completion date: Nov 2023 --> Aug 2024

Overall response rates (ORR) were 9-25% with nivolumab (niv), 42% with niv + ipilimumab (ipi), 55.7% with niv + cabozantinib, 56% with niv + tivozanib vs. 5% with everolimus. ORR was 51.5-58% with avelumab + axitinib vs. 25.5% with sunitinib...ORR was 32-36% with atezolizumab + bevacizumab vs. 29-33% with sunitinib. In patients with PD-L1+ve and -ve ccRCC, niv, atezolizumab, ipi, and pembrolizumab were safe and effective alone and when combined with cabozantinib, tivozanib, axitinib, levantinib, and pegilodecakin...Pembrolizumab was safe and effective in preventing recurrence in ccRCC patients with nephrectomy. Additional randomized, double-blind, multicenter clinical trials are needed to confirm these results.

However, the phase II and III trials did not justify its application as potential immunotherapy in selected cancers. Further evaluation of pegilodecakin's efficacy in other cancers, either as monotherapy or in combination with the current treatments, is worth investigating clinically, which warrants to better understand its potential clinical utility.

The safety and the anti-tumor activity of newly engineered cytokines including PEGylated IL-2 (NKTR-214), PEGylated IL-10 (AM0010), and IL-15 super agonist (ALT-803) have been evaluated in clinical trials with encouraging clinical activity and acceptable safety profile, both as single agents and in combination with immuno-oncology agents. A greater understanding of the mechanisms of action and effective dosing of these newly engineered cytokine together with determination of optimum combination therapy regimens may yield greater clinical benefits in the future.

Pegilodecakin with pembrolizumab or nivolumab revealed clinical activity in aRCC (data cutoff 1 July 2018). Here, we report for the first time the results of pegilodecakin+ pazopanib, and final results for monotherapy and long-term follow-up with pegilodecakin+ anti-PD-1 inhibitors (data cutoff 19 February 2019)...In these heavily pretreated RCC cohorts of IVY, pegilodecakin+anti-PD-1 inhibitor showed promising clinical activity. Safety profile of pegilodecakin alone and with anti-PD-1 inhibitors was consistent as previously reported.

PEG added to FOLFOX did not improve efficacy in advanced gemcitabine-refractory PDAC. Safety findings were consistent as previously observed from PEG with chemotherapy; toxicity was manageable and tolerable. Exploratory pharmacodynamic results were consistent with immunostimulatory signals of the IL-10R pathway.

Despite evidence of biological effect in peripheral blood, adding pegilodecakin to CPI did not improve ORR, PFS, or OS, in 1L/2L NSCLC. Pegilodecakin+CPI demonstrated overall higher toxicity compared to CPI alone, leading to doubling of treatment discontinuation rate due to AEs.

Aim: We describe a case of an advanced disease non-small-cell lung cancer patient with low PD-L1 expression, but high tumor mutation burden (35 muts/Mb) who developed immune-related hypothyroidism and achieved subsequent partial response, while on clinical trial (NCT03382912) with nivolumab and PEGylated IL-10 (Pegilodecakin, ARMO BioSciences/Eli Lilly and Company, IN, USA). Results/ Results suggest positive antitumor activity to combination IL-10/nivolumab despite low PD-L1 expression but in likely relationship to high tumor mutation burden and in association with immune-mediated thyroid dysfunction in this case.

The increased half-life of pegilodecakin enabled compelling preclinical data for IL-10 which has now been confirmed by clinical activity in a variety of cancers. The ability of pegilodecakin to both exert anti-tumor immunity and inhibit tumor-associated inflammation characterizes the uniqueness of this cytokine therapy.

Exploratory pharmacodynamic results were consistent with immunostimulatory signals of the IL-10R pathway. Despite evidence of biological effect, adding PEG to N did not lead to improvement in ORR, PFS, or OS in post-platinum advanced NSCLC with no or low PD-L1 expression. PEG+N arm demonstrated expected safety profile but overall higher toxicity compared to nivolumab alone.

Adding PEG to P did not lead to improvement in ORR, PFS, or OS, in 1L advanced NSCLC with high PD-L1 expression. PEG+P arm demonstrated expected safety profile but overall higher toxicity compared to pembrolizumab alone. Research Funding: Eli Lilly and Company