pegilodecakin (LY3500518) / Eli Lilly - LARVOL DELTA

A Phase 1 Study of Pegilodecakin (LY3500518) in Participants With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=350 | Active, not recruiting | Sponsor: Eli Lilly and Company | Trial completion date: Nov 2023 ➔ Aug 2024

Metastases • Trial completion date • Breast Cancer • Colorectal Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Hepatology • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Pancreatic Cancer • Prostate Cancer • Renal Cell Carcinoma • Solid Tumor

Interleukin-10 in cancer immunotherapy: from bench to bedside. (PubMed, Trends Cancer) - "Emerging data from published early-Phase trials have shown mixed results in different tumor types. In this review, we summarize the biological effects of IL-10 and highlight the clinical experience using pegilodecakin."

Journal • Review • Infectious Disease • Oncology • CD8 • IL10

Efficacy and Safety of Checkpoint Inhibitors in Clear Cell Renal Cell Carcinoma: A Systematic Review of Clinical Trials. (PubMed, Hematol Oncol Stem Cell Ther) - "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."

Checkpoint inhibition • Clinical • IO biomarker • Journal • Review • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • PD-L1

PEGylated human IL-10 (AM0010) in combination with an anti-PD-1 in advanced NSCLC (ESMO-IO 2017) - P1; "34 NSCLC pts received AM0010 (10-20ug/kg QD, SC) with pembrolizumab (2mg/kg, q3wk IV; n = 5) or nivolumab (3mg/kg, q2wk IV; n = 29). Conclusions AM0010 in combination with an anti-PD-1 is well-tolerated in advanced NSCLC pts. The improved efficacy regardless of PD-L1 status and the observed CD8 T cell activation is promising and encourages the continued study of AM0010 in combination with an anti-PD-1."

Combination therapy • Tumor mutational burden • Non Small Cell Lung Cancer

Efficacy of PEGylated human IL-10 (AM0010) in combination with anti-PD-1 blockade in patients (pts) with metastatic renal cell carcinoma (mRCC): A phase 1b trial (ESMO-IO 2017) - P1; "38 pts with metastatic RCC were enrolled from 2/20/2015 to 11/18/16 on AM0010 (10 or 20 ug/kg daily SC) and nivolumab (n = 29; 3mg/kg, q2wk IV) or pembrolizumab (n = 9; 2mg/kg, q3wk IV). Conclusions The combination of AM0010 with nivo or pembro is well-tolerated in mRCC pts; the recommended phase 2 dose is 10ug/kg. The observed efficacy is very promising and further studies of AM0010 and nivo or pembro in mRCC are in preparation."

Clinical • Combination therapy • P1 data • Renal Cell Carcinoma

Immunologic and objective tumor responses to PEGylated human IL-10 (AM0010) with 5-FU/LV and oxaliplatin (FOLFOX) in metastatic pancreatic adenocarcinoma (PDAC) (ESMO-GI 2017) - P1,P3; "In 2nd line therapy 5-FU/LV plus Oxaliplatin or nal-irinotecan are used with a mOS of 5-6 months. AM0010 in combination with FOLFOX is well tolerated in patients with metastatic PDAC. The immune activation included cytokine activation, and clonal T cell expansion. The immune activation, the objective tumor responses and the observed mOS are encouraging in this advanced PDAC population."

Gastrointestinal Cancer • Oncology • Pancreatic Cancer

Responses and Durability of Clinical Benefit in Non-Small Cell Lung Cancer Treated with Pegilodecakin in Combination With Anti-PD-1 Inhibitors (ESMO 2018) - P1; "Pegilodecakin when added to anti-PD-1 therapy in advanced NSCLC patients was associated with response rates and durability of benefit greater than has been seen with anti-PD-1 alone. Responses were seen in settings in which anti-PD-1 therapy has demonstrated limited benefit, such as absent PD-L1 expression, low TMB and/or the presence of liver metastasis. These preliminary findings support further studies of pegilodecakin with anti-PD-1 therapies.Table: 1144P110-20µg/kg QD SC;22mg/kg, q3wk IV;33mg/kg, q2wk IV;4pembrolizumab and nivolumab cohorts combined;5PD-L1 >50%;6PD-L1 1%-49%;7PD-L1 243 mut/exome;9TMB Low (tumor mutational burden low) 1 post-baseline assessments, and no major protocol deviations); ITT (intent to treat);11irAE - Immune-Related Adverse Events (e.g."

Clinical • Combination therapy • IO biomarker • PD(L)-1 Biomarker • Tumor mutational burden • Hepatocellular Cancer • Non Small Cell Lung Cancer

Responses and Durability of Clinical Benefit in Renal Cell Carcinoma Treated with Pegilodecakin in Combination With Anti-PD-1 Inhibitors (ESMO 2018) - P1; "Pegilodecakin when combined with anti-PD-1 therapy in advanced RCC patients was associated with response rates and durability of benefit greater than has been seen with anti-PD-1 alone. These preliminary findings support further studies of pegilodecakin with anti-PD-1 therapies."

Clinical • Combination therapy • IO biomarker • PD(L)-1 Biomarker • Tumor mutational burden • Renal Cell Carcinoma

Immune correlates for the efficacy of PEGylated Human IL-10 (AM0010) with nivolumab in renal cell cancer (ESMO 2017) - P1; "In dose escalation, 4 of 8 RCC patients receiving AM0010 plus pembrolizumab in 3rd line, had a PR. AM0010 in combination with anti-PD-1 is well-tolerated in RCC pts, the recommended phase 2 dose is 10ug/kg. The efficacy and the observed CD8 T cell activation is promising and encourages the continued study of AM0010 in combination with nivolumab."

Biomarker • Clinical • Renal Cell Carcinoma

Efficacy and immune activation with PEGylated human IL-10 (AM0010) in combination with an anti-PD1 in advanced NSCLC: Update (ESMO 2017) - P1; "received AM0010 (10-20mg/kg QD, SC) with pembrolizumab (2mg/kg, q3wk IV; n = 5) or nivolumab (3mg/kg, q2wk IV; n = 29). AM0010 in combination with anti-PD-1 is well-tolerated in advanced NSCLC pts. AM0010 improved on the expected response rates of nivolumab regardless of PD-L1 status. The observed CD8 T cell activation is promising and encourages the continued study of AM0010 in combination with an anti-PD-1."

Combination therapy • Non Small Cell Lung Cancer

Pegilodecakin as monotherapy or in combination with anti-PD-1 or tyrosine kinase inhibitor in heavily pretreated patients with advanced renal cell carcinoma (RCC): Updated results from phase I/Ib IVY study. (ASCO-GU 2020) - P1; "As part of the multi-arm (arm A to J) phase 1 IVY study, PEG alone (Part A) or in combination with pazopanib (Part G) or anti-PD-1 (pembrolizumab or nivolumab; Parts H+I) were investigated in heavily pretreated RCC patients (pts). PEG alone or in combination with anti-PD-1 or pazopanib suggested some clinical activity with manageable toxicity in advanced RCC pts. These findings support further ongoing studies of PEG combinations in RCC pts. Clinical trial information: NCT02009449."

Clinical • Combination therapy • Monotherapy • P1 data • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • IL10

Responses and durability in NSCLC treated with pegilodecakin and anti-PD-1. (ASCO 2018) - P1; "... Pretreated NSCLC subjects (n = 34), received pegilodecakin (10-20g/kg QD, SC) with pembrolizumab (2mg/kg, q3wk IV; n = 5) or nivolumab (3mg/kg, q2wk IV; n = 29)... Pegilodecakin when added to anti-PD-1 therapy in advanced NSCLC patients was associated with response rates and durability of benefit greater than has been seen with anti-PD-1 alone. Responses were seen in settings in which anti-PD-1 therapy has demonstrated limited benefit, such as absent PD-L1 expression, low TMB and/or the presence of liver metastasis. These preliminary findings support further studies of pegilodecakin with anti-PD-1 therapies."

IO biomarker • PD(L)-1 Biomarker • Tumor mutational burden • Hepatocellular Cancer • Non Small Cell Lung Cancer

Pegilodecakin with nivolumab (nivo) or pembrolizumab (pembro) in patients (pts) with metastatic renal cell carcinoma (RCC). (ASCO 2018) - P1; "Pegilodecakin with nivo or pembro is well-tolerated in mRCC pts; the recommended phase 2 dose is 10ug/kg. The efficacy and the observed CD8+ T cell activation are very encouraging."

Clinical • IO biomarker • PD(L)-1 Biomarker • Renal Cell Carcinoma

Overall survival and immunologic responses in metastatic pancreatic adenocarcinoma (PDAC) on PEGylated human IL-10 (AM0010) with 5-FU/LV and oxaliplatin (FOLFOX) (ESMO 2017) - P1; "Median overall survival on 2nd line therapy of PDAC with 5-FU/LV plus oxaliplatin or nal-irinotecan is ∼ 5-6 m. PDAC is refractory to immune therapies and mutational burden is relatively low and tumor infiltrating CD8+ T cells are rare. The combination of AM0010 with FOLFOX is well tolerated in patients with metastatic PDAC. This regimen induced sustained immune activation including the expansion of oligoclonal T cells. The prolonged tumor responses and OS are encouraging in this advanced population."

Pancreatic Cancer

PEGylated IL-10: Clinical Development in Cancer Immunotherapy, Where to Go? (PubMed, Curr Oncol Rep) - "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."

Journal • Review • Gastrointestinal Cancer • Genito-urinary Cancer • Hepatology • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Renal Cell Carcinoma • Solid Tumor • IL10

A Phase 1 Study of Pegilodecakin (LY3500518) in Participants With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=350 | Active, not recruiting | Sponsor: Eli Lilly and Company | Trial completion date: Nov 2022 ➔ Nov 2023

Trial completion date • Breast Cancer • Colorectal Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Hepatology • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Pancreatic Cancer • Prostate Cancer • Renal Cell Carcinoma • Solid Tumor

Efficacy, safety, and immune activation with pegylated human IL-10 (AM0010) in combination with an anti-PD1 in advanced NSCLC. (ASCO 2017) - P1; "...AM0010 is anticipated to activate antigen stimulated, intratumoral CD8 T cells while PD-1 inhibits them, providing the rationale for combining AM0010 and anti-PD-1 antibody. We treated a cohort of 34 NSCLC pts with AM0010 (10-20mg/kg QD, SC) and a PD-1 inhibitor [pembrolizumab (2mg/kg, q3wk IV; n=5) or nivolumab (3mg/kg, q2wk IV; n=29)]...AM0010 plus anti-PD1 increased serum Th1 cytokines (IL-18, IFNγ), the number and proliferation of PD1+ Lag3+ activated CD8+ T cells and a de-novo oligoclonal expansion of T cell clones in the blood while decreasing TGFβ. AM0010 in combination with anti-PD1 is well-tolerated in advanced NSCLC pts. The efficacy and the observed CD8+ T cell activation is promising."

Clinical • Combination therapy • Biosimilar • Dyslipidemia • Immunology • Non Small Cell Lung Cancer • Venous Thromboembolism

PEGylated human IL-10 (AM0010) in combination with pembrolizumab in anti-PD1 and CTLA-4 refractory melanoma. (ASCO 2017) - P1; "AM0010 plus pembrolizumab increased Th1 cytokines as well as the number and proliferation of PD1+ Lag3+ activated CD8 T cells in the blood while reducing inflammatory cytokines and TGFb. AM0010 in combination with anti-PD1 is well-tolerated in refractory melanoma pts. The clinical activity and the observed CD8+ T cell activation may suggest to study AM0010 in combination with an anti-PD-1 in melanoma patients with less prior treatments."

Adverse events • Clinical • Combination therapy • Biosimilar • Cutaneous T-cell Lymphoma • Dyslipidemia • Immunology • Indolent Lymphoma • Lymphoma • Ocular Melanoma • Oncology • Venous Thromboembolism

Efficacy and safety of pegylated human IL-10 (AM0010) in combination with an anti-PD-1 in renal cell cancer. (ASCO 2017) - P1; "...In the dose escalation of AM0010 plus pembrolizumab, 4 of 8 patients had an objective response...AM0010 + anti-PD1 increased Th1 cytokines in the serum while decreasing TGFb, an expansion of proliferating PD1+ Lag3+ activated CD8 T cells and de-novo oligoclonal expansion of T cell clones in the blood. AM0010 in combination with nivolumab is well-tolerated in RCC pts. The efficacy and the observed CD8 T cell activation is promising and encourages the continued study of AM0010 in combination with nivolumab."

Clinical • Combination therapy • Biosimilar • Immunology • Renal Cell Carcinoma • Venous Thromboembolism

Phase I study with pegylated human IL-10 (AM0010) alone or in combination with anti-PD-1 or FOLFOX-immune biomarker update. (ASCO-SITC 2017) - P1; "In addition, PD1+ Lag-3+ KI-67+ CD8+ T cells expanded in the blood, remained Tim-3- CTLA-4-. AM0010 has predominantly immune stimulatory activity in cancer patients, alone and in combination with other immune oncology therapies."

P1 data • Biosimilar • Gastrointestinal Cancer • Immunology • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer

PEGylated human IL-10 (AM0010) monotherapy in refractory metastatic colorectal cancer. (ASCO 2017) - P1; "Patients with CRC who have progressed on SOC first and second line of therapy have a reported 7.1 months OS with TAS-102 (Meyer et al. AM0010 is well tolerated in patients with refractory CRC. Although objective tumor responses were not seen in this very advanced CRC population, the observed immune activation including clonal T cell expansion, prolonged stable disease, and the mOS of 11.7 months is encouraging in this advanced CRC population. Future study of AM0010 in combination with FOLFOX in a second – line of therapy colorectal cancer patients is being planned."

Clinical • Monotherapy • Biosimilar • Colorectal Cancer • Immunology

Efficacy, safety, and immune activation with pegylated human IL-10 (AM0010) plus FOLFOX in metastatic pancreatic adenocarcinoma (PDAC). (ASCO 2017) - P1; "Background: Oxaliplatin or nal-irinotecan plus 5-FU are used as 2nd-line PDAC therapy (mOS 5-6 months (m)). AM0010 plus FOLFOX is well tolerated in patients with PDAC. The observed immune activation including clonal T cell expansion and prolonged objective tumor responses are encouraging in this advanced PDAC population. This regimen is currently being studied in a phase 3 trial."

Biosimilar • Immunology • Pancreatic Cancer • Venous Thromboembolism

IL-10 in cancer: an essential thermostatic regulator between homeostatic immunity and inflammation - a comprehensive review. (PubMed, Future Oncol) - "Recently, there has been interest in the paradoxical role of IL-10 in cancer, its controversial prognostic utility and novel strategies to enhance its therapeutic profile. Here, the authors review the literature surrounding the role of IL-10 within the tumor microenvironment, its prognostic correlates to cancer patient outcomes and its pro- and antitumor effects, and they assess the legitimacy of potential therapeutic strategies harnessing IL-10 by outlining the notable preclinical and clinical evidence to date."

Journal • Review • Immunology • Inflammation • Oncology • IL10

Randomized Phase III Study of FOLFOX Alone or With Pegilodecakin as Second-Line Therapy in Patients With Metastatic Pancreatic Cancer That Progressed After Gemcitabine (SEQUOIA). (PubMed, J Clin Oncol) - "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."

Clinical • Journal • P3 data • Fatigue • Gastrointestinal Cancer • Hematological Disorders • Hepatology • Neutropenia • Oncology • Pain • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • Thrombocytopenia • GZMB • IL18

[VIRTUAL] Randomized phase II study of pembrolizumab (P) alone versus pegilodecakin (PEG) in combination with P as first-line (1L) therapy in patients (pts) with stage IV non-small cell lung cancer (NSCLC) with high PD-L1 expression (CYPRESS 1). (ASCO 2020) - P1, P2 | "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"

Clinical • Combination therapy • IO Biomarker • P2 data • Hematological Disorders • Immune Modulation • Inflammation • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thoracic Cancer • Thrombocytopenia • ALK • EGFR • PD-L1