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Patients with relapsed small-cell lung cancer (SCLC) have few treatment options and dismal survival. Phase I/II data show activity of nivolumab in previously treated SCLC.CheckMate 331 is a randomized, open-label, phase III trial of nivolumab versus standard chemotherapy in relapsed SCLC. Patients with relapse after first-line, platinum-based chemotherapy were randomized 1 : 1 to nivolumab 240 mg every 2 weeks or chemotherapy (topotecan or amrubicin) until progression or unacceptable toxicity. Primary endpoint was overall survival (OS).Overall, 284 patients were randomized to nivolumab and 285 to chemotherapy. Minimum follow-up was 15.8 months. No significant improvement in OS was seen with nivolumab versus chemotherapy [median OS, 7.5 versus 8.4 months; hazard ratio (HR), 0.86; 95% confidence interval (CI), 0.72-1.04; P = 0.11]. A survival benefit with nivolumab was suggested in patients with baseline lactate dehydrogenase ≤ upper limit of normal and in those without baseline liver metastases. OS (nivolumab versus chemotherapy) was similar in patients with programmed death-ligand 1 combined positive score ≥1% versus1%. Median progression-free survival was 1.4 versus 3.8 months (HR, 1.41; 95% CI, 1.18-1.69). Objective response rate was 13.7% versus 16.5% (odds ratio, 0.80; 95% CI, 0.50-1.27); median duration of response was 8.3 versus 4.5 months. Rates of grade 3 or 4 treatment-related adverse events were 13.8% versus 73.2%.Nivolumab did not improve survival versus chemotherapy in relapsed SCLC. No new safety signals were seen. In exploratory analyses, select baseline characteristics were associated with improved OS for nivolumab.

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. In a retrospective analysis of data from four phase 3 clinical trials, elevated baseline serum IL-8 levels were associated with worse clinical outcomes in patients with multiple tumor types treated with anti-PD-1 monotherapy or anti-PD-1 and anti-CTLA-4 combinatorial therapy.

PURPOSE 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. METHODS 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. RESULTS 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; P = .37; median, 9.2 v 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%). CONCLUSION 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.

Purpose: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.Patients and Methods:In post hoc 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.Results: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 (CD274, CD8A, LAG3, and STAT1), showed associations with response to NIVO ± IPI.Conclusions: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.See related commentary by Moutafi and Rimm, p. 3812

Background: Programmed death ligand 1 (PD-L1) expression on tumor cells (TC), detected by immunohistochemistry (IHC), is associated with response to programmed death-1 (PD-1)/PD-L1 inhibitors in some tumor types. Manual review of PD-L1–positive (PD-L1+) tumors can be subjective, with the potential for misclassification of PD-L1–low tumors as PD-L1–negative due to weak positivity. We compared artificial-intelligence (digital) and manual scoring methods and assessed the association of PD-L1 expression with clinical outcomes in nivolumab (NIVO)-treated patients with urothelial carcinoma (UC) and melanoma (MEL). Methods: PD-L1 expression was determined in baseline samples from NIVO monotherapy-treated patients with UC (CM275, NCT02387996) and MEL (CM067, NCT01844505; CM238, NCT02388906) using the Dako PD-L1 IHC 28-8 pharmDx assay. PD-L1+ TC were scored using digital (PathAI research platform) and manual (LabCorp) methods. Prevalence of tumors with PD-L1+ TC ≥ 1% and ≥ 5% and associations between PD-L1 expression and outcomes with NIVO were evaluated. Results: Prevalence of UC and MEL tumors with ≥ 1% and ≥ 5% PD-L1+ TC was higher for digital vs manual scoring (Table). For all samples, digital and manual scoring was associated with response to NIVO for PD-L1 ≥ 1% and ≥ 5%, and associations were similar between digital and manual scoring (Table). Digital and manual PD-L1 scoring correlated across samples from all trials (Kendall's tau range: 0.57–0.62). TablePrevalence PD-L1+ TC ≥ 1%, n (%)Evaluable samples, nDigitalManualP valueSamples ≥ 1% by digital onlyCM275241166 (69)113 (47)1.61 × 10−658 (24)CM067264173 (66)160 (61)0.27936 (14)CM238377307 (81)259 (69)7.61 × 10−566 (18)PD-L1+ TC ≥ 1% vs < 1%DigitalManualORR, odds ratio (95% CI)CM275a2.15 (0.98–4.70)1.60 (0.82–3.14)CM067b1.99 (1.19–3.35)1.89 (1.12–3.18)Survival, hazard ratio (95% CI)CM275 (OS)a0.67 (0.48–0.92)0.66 (0.48–0.90)CM067 (OS)b0.57 (0.41–0.80)0.71 (0.50–1.00)CM238 (RFS)c0.53 (0.36–0.77)0.83 (0.57–1.21)Prevalence PD-L1+ TC ≥ 5%, n (%)Evaluable samples, nDigitalManualP valueSamples ≥ 5% by digital onlyCM27524190 (37)74 (31)0.14928 (12)CM067264103 (39)76 (29)0.01736 (14)CM238377234 (62)139 (37)7.54 × 10−12104 (28)PD-L1+ TC ≥ 5% vs < 5%DigitalManualORR, odds ratio (95% CI)CM275a3.50 (1.76–6.98)2.37 (1.18–4.73)CM067b2.33 (1.40–3.86)1.77 (1.01–3.09)Survival, hazard ratio (95% CI)CM275 (OS)a0.50 (0.36–0.71)0.58 (0.41–0.83)CM067 (OS)b0.67 (0.47–0.96)0.74 (0.51–1.09)CM238 (RFS)c0.50 (0.35–0.70)0.52 (0.36–0.76)Database lock 2019: CM275, June 14; CM067, January 18; CM238, April 3.aAdjusted for ECOG performance status, liver metastatic status, and hemoglobin.bAdjusted for ECOG performance status, liver metastatic status, lactate dehydrogenase, and BRAF mutation.cAdjusted for ECOG performance status, AJCC stage, lactate dehydrogenase, and BRAF mutation.AJCC, American Joint Committee on Cancer; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; ORR, objective response rate; OS, overall survival; PD-L1, programmed death ligand 1; RFS, recurrence-free survival; TC, tumor cells. Conclusion: In post-hoc exploratory analyses, digital scoring of PD-L1 expression identified higher prevalence of PD-L1+ tumors and shows good association with response to NIVO in UC and MEL samples compared with manual scoring. Digital quantification demonstrated higher sensitivity at low levels of PD-L1 expression and may identify patients who could benefit from NIVO. Further study of the association with clinical outcomes is warranted and exploratory studies are ongoing to assess the performance of digital scoring in additional tumor types. Citation Format: Chunzhe Duan, Michael Montalto, George Lee, Dimple Pandya, Daniel Cohen, Han Chang, Hao Tang, Nishant Agrawal, Hunter Elliott, Benjamin Glass, Ilan Wapinski, Robin Edwards, Andrew H. Beck, Vipul Baxi. Association of digital and manual quantification of tumor PD-L1 expression with outcomes in nivolumab-treated patients [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 2017.

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.

e15262 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]

Background: In the CheckMate 032 phase 1/2 study, NIVO ± IPI demonstrated clinically meaningful antitumor activity in patients with chemotherapy-refractory mGEC. Archival or fresh tumor biopsies were analyzed to determine whether expression of PD-L1 and selected immune gene signatures were predictive of response to NIVO ± IPI. Methods: Pooled analyses included all treatment regimens (NIVO 3 mg/kg, NIVO 1 mg/kg + IPI 3 mg/kg, NIVO 3 mg/kg + IPI 1 mg/kg, and patients treated with NIVO 1 mg/kg + IPI 1 mg/kg in the dose-escalation phase). PD-L1 immunohistochemistry (IHC; Dako PD-L1 IHC 28-8 pharmDx assay) was used to evaluate tumor PD-L1 expression, referred to as tumor proportion score (TPS). Combined positive score (CPS) was determined by evaluating PD-L1 expression on previously stained IHC slides using the CPS algorithm. Gene expression profiling (GEP) by RNA sequencing was used to evaluate immune cell activation and infiltration signatures, a Bristol-Myers Squibb (BMS) inflammatory signature, and PD-L1 gene expression. Results: The pooled CPS (N = 104), TPS (N = 130), and GEP (N = 40) cohorts were mostly representative of the overall CheckMate 032 mGEC cohort (N =163). At a median (range) follow-up of 23.4 (17.0-35.4) months, CPS at higher cutoffs correlated better with efficacy and had higher prevalence than TPS in all analyses (Table). For all immune gene signatures examined, responders had higher signature scores in aggregate. For the BMS inflammatory signature, the association between signature score and response was significant (P = 0.004; false discovery rate = 0.037). Conclusions: CPS demonstrated stronger association with efficacy of NIVO ± IPI than TPS in mGEC. Prevalence of CPS was higher than that of TPS. Among immune gene signatures examined, the BMS inflammatory signature achieved the best association with efficacy and warrants further investigation. All treatments combinedMethodNCutoffResponse rate, %Prevalence, %All patients163NA9.8100CPS1041026.533519.250114.168TPS130109.1857.710117.531NIVO 1 mg/kg + IPI 3 mg/kgMethodNCutoffResponse rate, %Prevalence, %All patients49NA20.4100CPS331054.533541.252128.076TPS421002502140.024CPS = combined positive score (number of PD-L1-staining tumor cells, lymphocytes, and macrophages relative to all viable tumor cells x 100); IPI = ipilimumab; NA, not applicable; NIVO = nivolumab; TPS = tumor proportion score Citation Format: Ming Lei, Nathan Siemers, Dimple Pandya, Han Chang, Teresa Sanchez, Cecile Dorange, Christopher Harbison, Peter M. Szabo, Yelena Janjigian, Patrick A. Ott, Padmanee Sharma, Johanna Bendell, Jeffry Evans, Filippo de Braud, Ian Chau, Zachary Boyd. Association of PD-L1 combined positive score and immune gene signatures with efficacy of nivolumab (NIVO) ± ipilimumab (IPI) in patients with metastatic gastroesophageal cancer (mGEC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2673.

2594 Background: Distribution patterns of CD8+ T cells within the tumor microenvironment (TME) can be assessed by IA, which may reflect underlying tumor biology and serve as a potential biomarker to assess the utility of I-O therapy. These patterns are variable and may be classified as immune desert (minimal infiltrate), excluded (T cells confined to tumor stroma or to the invasive margin), or inflamed (T cells diffusely infiltrating tumor parenchyma and stroma). We hypothesized that association of a GEP signature with abundance of parenchymal and stromal T-cell infiltrates may identify biomarkers of response or resistance to I-O therapy. To test this, we applied an AI-powered IA platform to quantify CD8+ T cells by geographical location and used GEP to define both CD8 abundance and associated geographic localization to tumor parenchyma and stroma. Methods: We performed an analysis using a tumor inflammatory GEP assay and CD8 immunohistochemistry on procured specimens (335 melanoma, 391 SCCHN). Digitized slides were used to train a convolutional neural network to quantify the number of CD8+ T cells in stroma, tumor parenchyma, parenchyma-stromal interface, and invasive margin. Generalized constrained regression models were used to predict GEP signatures specifically for stromal and parenchymal CD8+ T cells. Results: Parenchymal and stromal GEP scores were highly concordant with CD8+ infiltrate geography (adj- r2: 0.67, 0.65, respectively; P ≤ 0.01). Little overlap existed between gene sets associated with parenchymal and stromal CD8 T-cell geographies. CSF1R and NECTIN2 gene expression was observed to correlate inversely with parenchymal localization and directly with stromal CD8+ T-cell abundance. Conclusions: GEP signatures can be identified that are concordant with various CD8+ T-cell localization patterns in melanoma and SCCHN, demonstrating that GEP-IA can be developed to identify the immune status of interest in the TME. The specific genes identified have potential to elucidate mechanisms of resistance and/or inform I-O targets that can be further evaluated in relation to clinical significance in future studies.

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.

3020Background: Colony stimulating factor 1 receptor (CSF-1R) signaling supports recruitment, development, and maintenance of immune suppressive macrophages within the tumor. Combining anti–CSF-1R ...