Serum interleukin-8 (IL-8) levels and tumor neutrophil infiltration are associated with worse prognosis in advanced cancers. Here, using a large-scale retrospective analysis, we show that elevated ...baseline serum IL-8 levels are associated with poor outcome in patients (n = 1,344) with advanced cancers treated with nivolumab and/or ipilimumab, everolimus or docetaxel in phase 3 clinical trials, revealing the importance of assessing serum IL-8 levels in identifying unfavorable tumor immunobiology and as an independent biomarker in patients receiving immune-checkpoint inhibitors.
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FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
In extensive-disease small-cell lung cancer (ED-SCLC), response rates to first-line platinum-based chemotherapy are robust, but responses lack durability. CheckMate 451, a double-blind phase III ...trial, evaluated nivolumab plus ipilimumab and nivolumab monotherapy as maintenance therapy following first-line chemotherapy for ED-SCLC.
Patients with ED-SCLC, Eastern Cooperative Oncology Group performance status 0-1, and no progression after ≤ 4 cycles of first-line chemotherapy were randomly assigned (1:1:1) to nivolumab 1 mg/kg plus ipilimumab 3 mg/kg once every 3 weeks for 12 weeks followed by nivolumab 240 mg once every 2 weeks, nivolumab 240 mg once every 2 weeks, or placebo for ≤ 2 years or until progression or unacceptable toxicity. Primary end point was overall survival (OS) with nivolumab plus ipilimumab versus placebo. Secondary end points were hierarchically tested.
Overall, 834 patients were randomly assigned. The minimum follow-up was 8.9 months. OS was not significantly prolonged with nivolumab plus ipilimumab versus placebo (hazard ratio HR, 0.92; 95% CI, 0.75 to 1.12;
= .37; median, 9.2
9.6 months). The HR for OS with nivolumab versus placebo was 0.84 (95% CI, 0.69 to 1.02); the median OS for nivolumab was 10.4 months. Progression-free survival HRs versus placebo were 0.72 for nivolumab plus ipilimumab (95% CI, 0.60 to 0.87) and 0.67 for nivolumab (95% CI, 0.56 to 0.81). A trend toward OS benefit with nivolumab plus ipilimumab was observed in patients with tumor mutational burden ≥ 13 mutations per megabase. Rates of grade 3-4 treatment-related adverse events were nivolumab plus ipilimumab (52.2%), nivolumab (11.5%), and placebo (8.4%).
Maintenance therapy with nivolumab plus ipilimumab did not prolong OS for patients with ED-SCLC who did not progress on first-line chemotherapy. There were no new safety signals.
Four programmed death ligand 1 (PD-L1) immunohistochemistry assays (28-8, 22C3, SP263, and SP142) have been approved for use by the US Food and Drug Administration (FDA). Analytical concordance ...between these assays has been evaluated in multiple studies. This systematic review included studies that investigated the analytical concordance of immunohistochemistry assays utilizing two or more PD-L1 antibodies from FDA-approved diagnostics for evaluation of PD-L1 expression on tumor or immune cells across a range of tumor types and algorithms.
Literature searches were conducted in MEDLINE (via PubMed) and EMBASE to identify studies published between January 1, 2010, and March 31, 2019, that evaluated analytical concordance between two or more assays based on antibodies from FDA-approved assays. Proceedings of key oncology and pathology congresses that took place between January 2016 and March 2019 were searched for abstracts of studies evaluating PD-L1 assay concordance.
A total of 42 studies across a range of tumor types met the selection criteria. Concordance between 28-8-, 22C3-, and SP263-based assays in lung cancer, urothelial carcinoma, and squamous cell carcinoma of the head and neck was high when used to assess PD-L1 expression on tumor cells (TCs). SP142-based assays had overall low concordance with other approved assays when used to assess PD-L1 expression on TCs. Analytical concordance for assessment of PD-L1 expression on immune cells was variable and generally lower than for PD-L1 expression on TCs.
A large body of evidence supports the potential interchangeability of 28-8-, 22C3-, and SP263-based assays for the assessment of PD-L1 expression on TCs in lung cancer. Further studies are required in tumor types for which less evidence is available.
Elotuzumab is an immunostimulatory monoclonal antibody that binds to SLAMF7, a type-1 transmembrane protein expressed on myeloma and natural killer cells. We report a phase 1 study (NCT01241292) in ...which we evaluated the safety, efficacy and pharmacokinetics of elotuzumab combined with lenalidomide and dexamethasone in Japanese patients with relapsed/refractory multiple myeloma (RRMM). In 28-day cycles, patients received: elotuzumab (intravenously), lenalidomide (25 mg orally) and weekly dexamethasone (elotuzumab days: 28 mg orally plus 8 mg intravenously; non-elotuzumab days: 40 mg orally). Elotuzumab dose was initially 10 mg/kg (Cohort 1,
n
= 3) and, if no dose-limiting toxicities (DLTs) occurred, increased to 20 mg/kg (Cohort 2,
n
= 3). No DLTs occurred in the six patients treated. Maximum (median) durations of study therapy were 36.6 (35.2) months in Cohort 1 and 28.3 (9.2) months in Cohort 2. Leukopenia and lymphopenia were observed in all patients. No adverse events led to treatment discontinuation. Overall response was 83% (
n
= 5): one complete response, three very good partial responses, one partial response. Three patients are still undergoing treatment, with responses maintained. Expression of SLAMF7 was immunohistochemically detected in all patients. We find that elotuzumab combined with lenalidomide and dexamethasone exhibited acceptable safety/tolerability in Japanese patients with RRMM, with durable efficacy.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Patients with non–small-cell lung cancer were randomly assigned to three cycles of chemotherapy with or without nivolumab, an anti–PD-1 antibody. Event-free survival was longer with nivolumab than ...without it (31.6 months vs. 20.8 months), and the percentage of patients with a pathological complete response was 24.0% and 2.2%, respectively.
In advanced gastric cancer/gastroesophageal junction cancer (GC/GEJC), there is a need to identify biomarkers of response to therapies, such as immune checkpoint inhibitors.
In
exploratory analyses ...from CheckMate 032 (GC/GEJC cohort), we evaluated associations between nivolumab ± ipilimumab (NIVO ± IPI) efficacy and programmed death ligand 1 (PD-L1) expression, defined by tumor cells (% TC) or combined positive score (CPS; sum of PD-L1-staining TCs + immune cells, divided by total viable TCs, × 100) using the Dako PD-L1 IHC 28-8 pharmDx assay, or inflammatory gene expression.
There was a trend toward increased efficacy (objective response and overall survival) when PD-L1 expression was determined by CPS compared with % TC at higher cutoffs of ≥5 and ≥10 in the pooled analysis of all treatment regimens. In this analysis, 19% and 26% of patients with PD-L1-positive tumors at a CPS cutoff of ≥5 and ≥10, respectively, had an objective response compared with 8% and 9% of patients at the equivalent % TC cutoffs. Longer survival was demonstrated in patients with PD-L1-positive (defined by CPS cutoffs of ≥5 and ≥10) versus PD-L1-negative status. Similar results were observed in the NIVO 1 mg/kg + IPI 3 mg/kg subgroup. Multiple inflammatory gene signatures/transcripts, including a signature consisting of four genes (
, and
), showed associations with response to NIVO ± IPI.
This study suggests a greater association of PD-L1 expression by CPS with NIVO ± IPI efficacy compared with % TC PD-L1 expression in patients with GC/GEJC. Inflammatory signatures were also associated with NIVO ± IPI response, warranting further investigation.
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Abstract
Background: Programmed death-1/programmed death ligand 1 (PD-1/PD-L1) inhibitors are approved in a range of tumor types, including non-small cell lung cancer, with PD-L1 immunohistochemistry ...(IHC) diagnostic assays approved to inform treatment in some settings. There is evidence that PD-L1 expression can vary between primary tumors and metastatic sites, but the relationship remains unclear. In this real-world study, we compared PD-L1 expression between matched primary tumor and metastatic site biopsies in patients with lung cancer.
Methods: NeoGenomics Laboratories Inc (Fort Myers, FL), a US national reference laboratory, provided results for PD-L1 tests performed on samples from 21,224 patients with lung cancer between Oct 2015 and Mar 2018. Test results were linked to clinical characteristics provided by Symphony Healthcare Solutions using unique identifiers. PD-L1 tests were performed using the Dako PD-L1 IHC 28-8 or 22C3 pharmDx assays according to the manufacturers' protocols at the time. The percentage of tumor cells (TCs) expressing PD-L1 was determined by trained pathologists. Patients were included in the analysis if they had matched biopsies from a primary lung tumor and a metastatic site that were collected in any order within a 3-month period, and if both samples were tested with the same PD-L1 assay ≤ 3 months apart. Patients were excluded if they received treatment between biopsies or had > 2 biopsies. Statistical analysis was performed by BioStat Solutions Inc.
Results: In total, 121 patients had matched primary and metastatic biopsy samples, with sites biopsied in any order; a subgroup of 59 patients had their second biopsy obtained after the PD-L1 test result for the first biopsy was reported. Matched biopsy pairs showed modest concordance (Kendall's tau 0.43 95% CI, 0.33–0.54; Spearman's correlation 0.56 95% CI, 0.42–0.67). Overall percentage agreement was 69–80% (Cohen's kappa 0.34–0.53) across a range of PD-L1 expression cutoffs (1%, 5%, 10%, 25%, and 50% of TCs). Identical PD-L1 expression was observed in 26% of matched biopsy pairs; 44% of sample pairs had a < 5% difference and 35% of sample pairs had a > 20% difference in PD-L1 expression scores between primary and metastatic sites. PD-L1 expression in primary tumor and metastatic sites was heterogeneous, with no clear trends across biopsy sites. In the subgroup of 59 patients whose second biopsy was obtained after the test result for their first biopsy was reported, 50% of patients (15/30) with PD-L1 expression on < 1% of TCs in their first biopsy had PD-L1 expression on ≥ 1% of TCs in their second biopsy.
Conclusion: This real-world study suggests that agreement of PD-L1 expression between matched primary and metastatic biopsy sites is low, further highlighting PD-L1 expression heterogeneity in lung cancer. Variation in PD-L1 expression between biopsy sites may affect treatment decisions relating to PD-1/PD-L1 inhibitors.
Citation Format: Emily A. Prince, Vladislav Chizhevsky, Josette William Ragheb, James L. Pratt, Dimple Pandya, David Huron. Comparison of PD-L1 expression in primary and metastatic lung cancer biopsies abstract. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2004.
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Background: The clinical benefit of immune checkpoint inhibitors (ICIs) targeting the programmed death-1/programmed death ligand 1 (PD-L1) pathway has previously been ...demonstrated across a range of tumor types, including in PD-L1+ patients with metastatic triple-negative breast cancer (TNBC). Various PD-L1 immunohistochemistry (IHC) assays and scoring algorithms are being investigated to select patients with breast cancer (BC) most likely to respond to ICIs. Scoring algorithms include PD-L1 expression on tumor cells, immune cells (ICs), or both. We compared the analytical concordance of 3 PD-L1 IHC assays and evaluated PD-L1+ prevalence, using combined positive score (CPS) and % IC scoring algorithms in commercially procured TNBC and hormone receptor–positive, HER2-negative (HR+/HER2−) BC samples. Methods: PD-L1 expression was assessed by HistoGeneX (Naperville, IL) in 163 commercially procured, surgically resected, formalin-fixed, paraffin-embedded BC samples (mostly stage I–III) using the Ventana PD-L1 (SP142) and Dako PD-L1 IHC 28-8 and 22C3 pharmDx assays in conjunction with the CPS (28-8 and 22C3 assays) and % IC algorithms (SP142 and 28-8 assays). PD-L1+ prevalence with each assay and concordance between assays were calculated using CPS ≥ 1 and IC ≥ 1% cutoffs, with a single pathologist assigned to each scoring algorithm. Results: 93 HR+/HER2− BC and 70 TNBC samples were evaluable for PD-L1 expression across all assays and algorithms. Overall concordance was higher between the 28-8 and 22C3 assays (CPS cutoff of 1) than between the 28-8 and SP142 assays (IC cutoff of 1%). PD-L1+ prevalence was similar with the 28-8 and 22C3 assays (CPS ≥ 1) and higher with the 28-8 assay (IC ≥ 1%) than with the SP142 assay (IC ≥ 1%). PD-L1+ samples identified by the SP142 assay (IC ≥ 1%) were mostly included within PD-L1+ sample sets defined by the 28-8 assay (IC ≥ 1% and CPS ≥ 1). PD-L1+ prevalence was higher in TNBC vs HR+/HER2− BC for all assays (Table). No clear trend in PD-L1+ prevalence was observed across tumor grade and stage. Conclusions: High analytical concordance was observed between the 28-8 and 22C3 assays (CPS cutoff of 1) in both HR+/HER2− BC and TNBC samples. PD-L1+ prevalence varied according to IHC assay, scoring algorithm, and cutoff used. Further studies are needed to select the most appropriate PD-L1 assay and scoring algorithm for BC clinical trials. Table: see text
Assessment of programmed death ligand 1 (PD-L1) expression by immunohistochemistry (IHC) has emerged as an important predictive biomarker across multiple tumor types. However, manual quantitation of ...PD-L1 positivity can be difficult and leads to substantial inter-observer variability. Although the development of artificial intelligence (AI) algorithms may mitigate some of the challenges associated with manual assessment and improve the accuracy of PD-L1 expression scoring, use of AI-based approaches to oncology biomarker scoring and drug development has been sparse, primarily due to the lack of large-scale clinical validation studies across multiple cohorts and tumor types. We developed AI-powered algorithms to evaluate PD-L1 expression on tumor cells by IHC and compared it with manual IHC scoring in urothelial carcinoma, non-small cell lung cancer, melanoma, and squamous cell carcinoma of the head and neck (prospectively determined during the phase II and III CheckMate clinical trials). 1,746 slides were retrospectively analyzed, the largest investigation of digital pathology algorithms on clinical trial datasets performed to date. AI-powered quantification of PD-L1 expression on tumor cells identified more PD-L1–positive samples compared with manual scoring at cutoffs of ≥1% and ≥5% in most tumor types. Additionally, similar improvements in response and survival were observed in patients identified as PD-L1–positive compared with PD-L1–negative using both AI-powered and manual methods, while improved associations with survival were observed in patients with certain tumor types identified as PD-L1–positive using AI-powered scoring only. Our study demonstrates the potential for implementation of digital pathology-based methods in future clinical practice to identify more patients who would benefit from treatment with immuno-oncology therapy compared with current guidelines using manual assessment.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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