Immune checkpoint inhibitor (ICI) treatment in advanced melanoma (aMel) patients (pts) with renal or hepatic dysfunction (dysf): Real-world patient characteristics and outcomes.

2018 ◽  
Vol 36 (15_suppl) ◽  
pp. 9569-9569
Author(s):  
Susan Spillane ◽  
Amy Pickar Abernethy ◽  
Nicholas R Brown ◽  
Andrew N Freedman ◽  
David Lenis ◽  
...  
Keyword(s):  
Real World ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Hepatic Dysfunction ◽  
Checkpoint Inhibitor ◽  
Patient Characteristics ◽  
Advanced Melanoma

scholarly journals 673 Precision microbiome mapping identifies a microbiome signature predictive of Immune checkpoint inhibitor response across multiple research study cohorts

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A711-A711
Author(s):  
Matthew Robinson ◽  
Kevin Vervier ◽  
Simon Harris ◽  
David Adams ◽  
Doreen Milne ◽  
...  
Keyword(s):  
Gut Microbiome ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Advanced Melanoma ◽  
List Type ◽  
Metagenomic Sequencing ◽  
Genome Database ◽  
Sequencing Platform ◽  
Melanoma Patients

BackgroundThe gut microbiome of cancer patients appears to be associated with response to Immune Checkpoint Inhibitor (ICIs) treatment.1–4 However, the bacteria linked to response differ between published studies.MethodsLongitudinal stool samples were collected from 69 patients with advanced melanoma receiving approved ICIs in the Cambridge (UK) MELRESIST study. Pretreatment samples were analysed by Microbiotica, using shotgun metagenomic sequencing. Microbiotica’s sequencing platform comprises the world’s leading Reference Genome Database and advanced Microbiome Bioinformatics to give the most comprehensive and precise mapping of the gut microbiome. This has enabled us to identify gut bacteria associated with ICI response missed using public reference genomes. Published microbiome studies in advanced melanoma,1–3renal cell carcinoma (RCC) and non-small cell lung cancer (NSCLC)4 were reanalysed with the same platform.ResultsAnalysis of the MELRESIST samples showed an overall change in the microbiome composition between advanced melanoma patients and a panel of healthy donor samples, but not between patients who subsequently responded or did not respond to ICIs. However, we did identify a discrete microbiome signature which correlated with response. This signature predicted response with an accuracy of 93% in the MELRESIST cohort, but was less predictive in the published melanoma cohorts.1–3 Therefore, we developed a bioinformatic analytical model, incorporating an interactive random forest model and the MELRESIST dataset, to identify a microbiome signature which was consistent across all published melanoma studies. This model was validated three times by accurately predicting the outcome of an independent cohort. A final microbiome signature was defined using the validated model on MELRESIST and the three published melanoma cohorts. This was very accurate at predicting response in all four studies combined (91%), or individually (82–100%). This signature was also predictive of response in a NSCLC study and to a lesser extent in RCC. The core of this signature is nine bacteria significantly increased in abundance in responders.ConclusionsAnalysis of the MELRESIST study samples, precision microbiome profiling by the Microbiotica Platform and a validated bioinformatic analysis, have enabled us to identify a unique microbiome signature predictive of response to ICI therapy in four independent melanoma studies. This removes the challenge to the field of different bacteria apparently being associated with response in different studies, and could represent a new microbiome biomarker with clinical application. Nine core bacteria may be driving response and hold potential for co-therapy with ICIs.Ethics ApprovalThe study was approved by Newcastle & North Tyneside 2 Research Ethics Committee, approval number 11/NE/0312.ReferencesMatson V, Fessler J, Bao R, et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 2018;359(6371):104–108.Gopalakrishnan V, Spencer CN, Nezi L, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 2018;359(6371):97–103.Frankel AE, Coughlin LA, Kim J, et al. Metagenomic shotgun sequencing and unbiased metabolomic profiling identify specific human gut microbiota and metabolites associated with immune checkpoint therapy efficacy in melanoma patients. Neoplasia 2017;19(10):848–855.Routy B, Le Chatelier E, Derosa L, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 2018;359(6371):91–97.

scholarly journals 630 Oncologists' perspectives on evolution of first-line immune checkpoint inhibitor maintenance therapy in management of advanced urothelial carcinoma in the US

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A660-A660
Author(s):  
Petros Grivas ◽  
Phani Veeranki ◽  
Kevin Chiu ◽  
Vivek Pawar ◽  
Jane Chang ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Disease Control ◽  
Urothelial Carcinoma ◽  
Real World ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Treatment Patterns ◽  
First Line ◽  
Platinum Based Chemotherapy

BackgroundAvelumab, a PD-L1 immune checkpoint inhibitor (ICI), was recently approved as first-line (1L) maintenance therapy for locally advanced/unresectable or metastatic urothelial carcinoma (aUC) after disease control with platinum-based chemotherapy.1 Given the evolving treatment landscape, the study aim was to gain real-world insights into clinical decision-making among oncologists for patients with aUC.MethodsIn March 2021, a cross-sectional web-based survey was administered to a sample of US oncologists treating patients with aUC. Oncologists' demographics, practice characteristics, and treatment patterns were obtained; descriptive statistics were used.ResultsThe study included 151 medical oncologists, who reported that 54% and 31% of their patients, on average, would be classified as cisplatin or carboplatin eligible for their 1L treatment, respectively. Approximately 78% of oncologists (n=118) considered using ICI maintenance in ≥40% of their patients following disease control with platinum chemotherapy and were categorized as the “high-consideration” group, for further exploratory analysis; the rest (22%) were in the low-consideration group (See table 1). Approximately, 31% and 27% of oncologists in the high- and low-consideration groups reported administering ICI maintenance with a 2–3-week gap after chemotherapy, while 45% and 46% reported administering it with a 4–6-week gap after chemotherapy, respectively.ConclusionsSurveyed oncologists reported that 85% of patients with aUC in US may be eligible for platinum-based chemotherapy. Further, 78% of the surveyed oncologists would consider 1L ICI maintenance therapy after disease control with platinum-based chemotherapy for over 40% of their patients. Future studies are warranted to evaluate real-world treatment patterns, barriers, and utilization of ICI maintenance therapy as the new 1L standard of care.AcknowledgementsThe authors would like to acknowledge all physicians at who participated and completed the survey for the study.ReferencePowles T, et al. N Engl J Med 2020;383(13):1218–1230.Ethics ApprovalThe study was reviewed and determined to be exempt by Advarra IRB.ConsentAll survey participated signed a consent form.Abstract 630 Table 1Oncologists characteristics and considerations for 1L ICI maintenance therapy

The Risk of Diarrhea and Colitis in Patients With Advanced Melanoma Undergoing Immune Checkpoint Inhibitor Therapy

2018 ◽  
Vol 41 (3) ◽  
pp. 101-108 ◽  
Author(s):  
Parul Tandon ◽  
Samuel Bourassa-Blanchette ◽  
Kirles Bishay ◽  
Simon Parlow ◽  
Scott A. Laurie ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Advanced Melanoma ◽  
Inhibitor Therapy ◽  
Checkpoint Inhibitor Therapy

Real-world evidence of the impact of prior antibiotic exposure on immune checkpoint inhibitor outcomes in patients with metastatic urothelial cancer.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 452-452
Author(s):  
Jean H. Hoffman-Censits ◽  
Lauren Christine Harshman ◽  
Meredith Metcalf ◽  
Sarah Abou Alaiwi ◽  
Craig S. Meyer ◽  
...  
Keyword(s):  
Treatment Outcomes ◽  
Real World ◽  
Immune Checkpoint ◽  
Urothelial Cancer ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Treatment Discontinuation ◽  
Time To Treatment ◽  
Metastatic Urothelial Cancer ◽  
The Impact

452 Background: Prior research suggests that systemic antibiotic (ABX) exposure may impact gut microbiome and potentially result in suboptimal immune checkpoint inhibitor (ICI) treatment outcomes. A recent real-world analysis demonstrated that cumulative ABX exposure was associated with poorer outcomes across multiple tumor types independent of known prognostic clinical factors. Given the paucity of real-world data, we set out to evaluate the association of prior ABX exposure with ICI treatment outcomes among patients with metastatic urothelial cancer (mUC). Methods: This was a retrospective analysis using Truven Health MarketScan Commercial, Medicare Supplemental, and Coordination of Benefits (Medicare) databases. Patients with mUC, ≥18 years old, who received first line (1L) ICI therapy between 1/1/2016 and 12/31/2018 were analyzed. Prior ABX exposure was defined as any use in the 90 days prior to 1L ICI therapy initiation. Time to treatment discontinuation was used as a proxy to quantify ICI treatment outcomes. Results: Among the 304 ICI treated patients, 128 (42%) had ABX exposure within 90 days prior to ICI initiation. Statistically significant differences in baseline co-morbidities and urinary tract infections (36% vs. 17%; p<0.001) were observed between patients with vs. without ABX exposure. The median time to treatment discontinuation was shorter for patients with ABX exposure (7.9 months) vs. without (9.3 months). In adjusted regression analysis, there was no statistically significant difference in time to treatment discontinuation between patients with vs. without ABX exposure (p=0.95). These findings were consistent in a sensitivity analysis looking at ABX exposure 30 and 60 days prior to 1L ICI initiation. Conclusions: In this real-world analysis of patients with mUC, those with ABX exposure within 90 days prior to 1L ICI initiation demonstrated similar outcomes to those without ABX exposure. While there was a shorter time to treatment discontinuation in the patients with vs. without ABX exposure, findings were not statistically significant. Further research is warranted to investigate the impact of concomitant ABX use on ICI outcomes.

Using precision microbiome profiling to develop a biomarker for immune checkpoint inhibitor response and a novel therapeutic.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21546-e21546
Author(s):  
Mat Robinson ◽  
Kevin Vervier ◽  
Amy Popple ◽  
Simon Harris ◽  
Robyne Hudson ◽  
...  
Keyword(s):  
Gut Microbiome ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Advanced Melanoma ◽  
Metagenomic Sequencing ◽  
Genome Database ◽  
Syngeneic Mouse Model ◽  
Melanoma Patients

e21546 Background: Four independent groups have demonstrated that the pre-treatment gut microbiome of cancer patients impacts the subsequent response to Immune Checkpoint Inhibitor (ICIs) therapy [1-4]. However, the patient’s outcome was linked to different bacteria in each study, which has limited the development of drug response biomarkers and clinic-first design of novel microbiome-based therapeutics. Methods: The Cambridge (UK) MELRESIST study includes a cohort of advanced melanoma patients receiving approved ICIs. Pretreatment stool samples from MELRESIST were analysed by Microbiotica using shotgun metagenomic sequencing. Microbiotica’s platform comprises the world’s leading Reference Genome Database to give the most comprehensive and precise mapping of the gut microbiome. Results: MELRESIST samples showed an overall difference in the microbiome composition between advanced melanoma patients and healthy donors, but not between patients who did or did not respond to ICIs. However, we did identify a discrete microbiome signature that differentiated responders and non-responders with an accuracy of 93%. We extended this signature by reanalysing three published melanoma cohorts [1-3] using the Microbiotica platform, and a propriety bioinformatic model. The resultant bacterial signature was very accurate at predicting response in all 4 published studies combined (91%), and each cohort individually (82-100%). We validated the model using independent validation cohorts and the signature using lung and renal cancer studies [4]. At the core of our microbiome signature was 9 bacteria most significantly associated with ICI efficacy. All 9 were overrepresented in patients who responded to immunotherapy suggesting high abundance of these bacteria is a central driver of ICI response. A consortium comprised of all 9 strains had very potent anti-tumor efficacy in a cancer syngeneic mouse model. The bacteria also demonstrate multiple interactions with primary human immune cells in vitro leading to dendritic cells activation, Cytotoxic T lymphocyte activation and tumor cell killing. These validate the potential of this consortium as a novel therapy for use in combination with ICIs. Conclusions: We have identified a unique microbiome signature predictive of ICI response in 4 independent melanoma cancer cohorts. This removes a major challenge to the field, and could represent a new highly accurate biomarker with clinical application. Nine core bacteria appear to be driving response, and demonstrate anti-tumor activity in vivo and in vitro. This consortium holds great potential as a co-therapy with ICIs. References:1 Matson V et al, Science (2018) 359:104; 2 Gopalakrishnan V et al, Science (2018) 359:97; 3 Frankel AE et al, Neoplasia (2017) 19:848; 4 Routy B et al, Science (2018) 359:91.

Relatlimab (RELA) plus nivolumab (NIVO) versus NIVO in first-line advanced melanoma: Primary phase III results from RELATIVITY-047 (CA224-047).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9503-9503
Author(s):  
Evan J. Lipson ◽  
Hussein Abdul-Hassan Tawbi ◽  
Dirk Schadendorf ◽  
Paolo Antonio Ascierto ◽  
Luis Matamala ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Objective Response ◽  
Cell Activity ◽  
Advanced Melanoma ◽  
Phase Iii ◽  
Fixed Dose ◽  
First Line ◽  
Programmed Death

9503 Background: Immune checkpoint inhibitor therapy has revolutionized the treatment of patients with advanced melanoma. However, novel combinations are needed to optimize the benefit-risk profile. Lymphocyte-activation gene 3 (LAG-3) regulates an immune checkpoint pathway, which inhibits T-cell activity, and is upregulated in many tumor types including melanoma. Relatlimab (RELA), a human IgG4 LAG-3-blocking antibody, restores effector function of exhausted T cells. RELA in combination with nivolumab (NIVO; anti-programmed death [PD]-1) modulates potentially synergistic immune checkpoint pathways and can enhance antitumor immune responses. RELATIVITY-047 is a global, randomized, double-blind, phase II/III study evaluating a novel immune checkpoint inhibitor combination of RELA+NIVO as a fixed-dose combination (FDC) treatment in first-line advanced melanoma. Methods: Patients with previously untreated advanced melanoma were randomized 1:1 to receive RELA 160 mg + NIVO 480 mg FDC intravenously (IV) every 4 weeks (Q4W) or NIVO monotherapy 480 mg IV Q4W, stratified by LAG-3 expression, programmed death ligand 1 expression, BRAF mutation status, and AJCC (v8) M stage. The primary endpoint was progression-free survival (PFS) per RECIST v1.1 as assessed by blinded independent central review. Secondary endpoints were overall survival and objective response rate. PFS in prespecified subgroups and safety were additional objectives. Results: 714 patients were randomized to RELA+NIVO FDC (n = 355) or NIVO (n = 359). Patient characteristics were well balanced between treatment groups. Median follow-up was 13.2 months. Median PFS in the RELA+NIVO FDC group (10.1 months [95% CI, 6.4–15.7]) was significantly longer than in the NIVO group (4.6 months [95% CI, 3.4–5.6]; hazard ratio, 0.75 [95% CI, 0.6–0.9]; P = 0.0055). PFS rates at 12 months were 47.7% (95% CI, 41.8–53.2) and 36.0% (95% CI, 30.5–41.6) for RELA+NIVO FDC and NIVO, respectively. PFS favored RELA+NIVO FDC across key prespecified subgroups. The incidence of grade 3/4 treatment-related adverse events (TRAEs) was higher in the RELA+NIVO FDC group (18.9%) versus NIVO (9.7%). There were 3 treatment-related deaths with RELA+NIVO FDC and 2 with NIVO. TRAEs (any grade) led to treatment discontinuation in 14.6% and 6.7% of patients in the RELA+NIVO FDC and NIVO groups, respectively. Conclusions: First-line treatment with RELA+NIVO FDC demonstrated a statistically significant PFS benefit compared to NIVO monotherapy in patients with advanced melanoma. RELA+NIVO FDC was well tolerated with a manageable safety profile and without unexpected safety signals. This is the first phase III study of a novel FDC to demonstrate a clinically meaningful benefit by dual inhibition of the LAG-3 and PD-1 pathways. Clinical trial information: NCT03470922.

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