IMPORTANCECheckpoint inhibitors targeting programmed cell death 1 or its ligand (PD-L1) as monotherapies or in combination with anti-cytotoxic T-lymphocyte-associated antigen 4 have shown clinical activity in patients with metastatic non-small cell lung cancer.OBJECTIVE To compare durvalumab, with or without tremelimumab, with chemotherapy as a first-line treatment for patients with metastatic non-small cell lung cancer. DESIGN, SETTING, AND PARTICIPANTSThis open-label, phase 3 randomized clinical trial (MYSTIC) was conducted at 203 cancer treatment centers in 17 countries. Patients with treatment-naive, metastatic non-small cell lung cancer who had no sensitizing EGFR or ALK genetic alterations were randomized to receive treatment with durvalumab, durvalumab plus tremelimumab, or chemotherapy. Data were collected from July 21, 2015, to October 30, 2018.INTERVENTIONS Patients were randomized (1:1:1) to receive treatment with durvalumab (20 mg/kg every 4 weeks), durvalumab (20 mg/kg every 4 weeks) plus tremelimumab (1 mg/kg every 4 weeks, up to 4 doses), or platinum-based doublet chemotherapy. MAIN OUTCOMES AND MEASURESThe primary end points, assessed in patients with Ն25% of tumor cells expressing PD-L1, were overall survival (OS) for durvalumab vs chemotherapy, and OS and progression-free survival (PFS) for durvalumab plus tremelimumab vs chemotherapy. Analysis of blood tumor mutational burden (bTMB) was exploratory.

In the PACIFIC trial, durvalumab significantly improved progression-free and overall survival (PFS/OS) versus placebo, with manageable safety, in unresectable, stage III non-small-cell lung cancer (NSCLC) patients without progression after chemoradiotherapy (CRT). We report exploratory analyses of outcomes by tumour cell (TC) programmed death-ligand 1 (PD-L1) expression. Patients and methods: Patients were randomly assigned (2:1) to intravenous durvalumab 10 mg/kg every 2 weeks or placebo 12 months, stratified by age, sex, and smoking history, but not PD-L1 status. Where available, pre-CRT samples were tested for PD-L1 expression (immunohistochemistry) and scored at pre-specified (25%) and post hoc (1%) TC cut-offs. Treatment-effect hazard ratios (HRs) were estimated from unstratified Cox proportional hazards models (KaplaneMeier-estimated medians). Results: In total, 713 patients were randomly assigned, 709 of whom received at least 1 dose of study treatment durvalumab (n ¼ 473) or placebo (n ¼ 236). Some 451 (63%) were PD-L1-assessable: 35%, 65%, 67%, 33%, and 32% had TC !25%, <25%, !1%, <1%, and 1%e24%, respectively. As of 31 January 2019, median follow-up was 33.3 months. Durvalumab improved PFS versus placebo (primary-analysis data cut-off, 13 February 2017) across all subgroups [HR, 95% confidence interval (CI); medians]: TC !25% (0.41, 0.26e0.65; 17.8 versus 3.7 months), <25% (0.59, 0.43e0.82; 16.9 versus 6.9 months), !1% (0.46, 0.33e0.64; 17.8 versus 5.6 months), <1% (0.73, 0.48e1.11; 10.7 versus 5.6 months), 1%e24% [0.49, 0.30e0.80; not reached (NR) versus 9.0 months], and unknown (0.59, 0.42 e0.83; 14.0 versus 6.4 months). Durvalumab improved OS across most subgroups (31 January 2019 data cut-off; HR, 95% CI; medians): TC ! 25% (0.50, 0.30e0.83; NR versus 21.1 months), <25% (0.89, 0.63e1.25; 39.7 versus 37.4 months), !1% (0.59, 0.41e0.83; NR versus 29.6 months), 1%e24% (0.67, 0.41e1.10; 43.3 versus 30.5 months), and unknown (0.60, 0.43e0.84; 44.2 versus 23.5 months), but not <1% (1.14, 0.71e1.84; 33.1 versus 45.6 months). Safety was similar across subgroups. Conclusions: PFS benefit with durvalumab was observed across all subgroups, and OS benefit across all but TC <1%, for which limitations and wide HR CI preclude robust conclusions.

Evaluation of tumoral programmed cell death ligand-1 (PD-L1) expression is standard practice for patients with advanced non-small-cell lung cancer (NSCLC) who may be candidates for treatment targeting the programmed cell death-1 (PD-1)/PD-L1 pathway. Currently, all of the commercially available immunohistochemistry assays have been validated for use with histology specimens although, in routine clinical practice, approximately 30-40 % of patients with advanced NSCLC have only cytology specimens available for diagnosis, staging, and biomarker analysis. This systematic review evaluated the success rate, concordance, and clinical utility of using cytology specimens to assess tumor PD-L1 expression levels compared with histology specimens from patients with advanced NSCLC. EMBASE and PubMed database searches identified 142 unique, relevant publications, of which 15 met the inclusion criteria for at least one analysis. In 709 specimens, across seven publications, the proportion of cytology specimens evaluable for PD-L1 testing was 92.0 %. Among nine studies eligible for concordance analysis between cytology and histology specimens at a PD-L1 tumor cell expression cutoff of ≥50 %, overall percentage agreement was 89.7 % (n = 428), 72.0 % for positive percentage agreement (n = 218), and 95.0 % for negative percentage agreement (n = 258); results using a tumor PD-L1 expression cutoff of ≥1 % were similar. Our analyses suggest that using cytology specimens to assess PD-L1 expression is feasible, with good levels of concordance between cytology and histology specimens using PD-L1 tumor cell expression cutoffs of ≥1 % and ≥50 %. In conclusion, there is no convincing evidence that cytology specimens are inadequate or inferior to histology specimens for assessing PD-L1 expression in patients with NSCLC.

Introduction: We evaluated the impact of patient characteristics, sample types, and prior non-immunotherapy treatment on tumor cell (TC) programmed cell death ligand 1 (PD-L1) expression using samples from patients with advanced NSCLC. Methods: Patients (N ¼ 1590) screened for the ATLANTIC study submitted a recently acquired (3 months) or archival (>3 months to >3 years old) tumor sample for PD-L1 assessment using the VENTANA PD-L1 (SP263) Assay with a cutoff of !25% of TCs expressing PD-L1 (TC !25%). Samples were acquired either before or after the two or more treatment regimens required for study entry and sample age varied among patients. A subset of patients (n ¼ 123) provided both recent and archival samples. Results: A total of 517 of 1590 (32.5%) patients had TC greater than or equal to 25%: prevalence was greater in smokers versus nonsmokers (p ¼ 0.0005) and those with EGFRÀ versus EGFRþ tumors (p ¼ 0.0002); these effects were independent. Prevalence of TC greater than or equal to 25% was increased in recent metastatic versus primary (p ¼ 0.005) and recent versus archival (p ¼ 0.039) samples. Chemotherapy or radiotherapy, but not tyrosine kinase inhibition, before sampling was associated with significantly increased PD-L1 prevalence. PD-L1 status (TC !25% cutoff) remained unchanged in 74.0% of patients with recent and archival samples; where PD-L1 status changed, it was more likely to increase than decrease over time or with intervening treatment. Conclusions: Several factors potentially impact PD-L1 TC greater than or equal to 25% prevalence in advanced NSCLC; however, no characteristic can be considered a surrogate for PD-L1 expression. Fresh biopsy may provide more accurate assessment of current tumoral PD-L1 expression where a low/negative result is seen in an archival sample, especially if the patient has received intervening therapy.

1021 Background: Breast cancer patients with HER2 low expression by immunohistochemistry (IHC), defined as IHC1+ or IHC2+ without gene amplification (ISH-) do not respond to conventional anti-HER2 therapies such as trastuzumab or pertuzumab. The HER2-targeted antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) showed efficacy in late line HER2-overexpressing patients, with some responses in patients with low HER2 expression. Two of the market leading IHC IVDs are Dako Herceptest and Ventana 4B5. T-DXd is being investigated in HER2 low patients as determined by the VENTANA anti-HER2/neu (4B5) assay in the phase III DESTINY-Breast04 study. There is a paucity of information on prevalence of IHC1+/2+ in different breast cancer subtypes, which this study aims to address. Methods: HER2 status was calculated from 3750 consecutive primary or metastatic breast cancer patient samples successfully stained using the 4B5 assay and scored locally according to ASCO/CAP 2018 guidelines. Samples were obtained from 3 anatomic pathology labs that support networks of US community hospitals. 500 additional breast cancer samples, pre-selected to include a range of IHC staining (concordance cohort), were stained with both 4B5 and HercepTest (Dako/Agilent) and scored (IHC0, IHC1+, IHC2+, IHC3+) at a central laboratory. Results: Prevalence of HER2 categories in 3750 consecutive breast cancer samples is presented in the table below. >50% of estrogen-receptor positive (ER+ve) and progesterone receptor positive (PR+ve) subtypes are HER2 low. In the 500 sample concordance cohort, 28.0% were IHC1+/2+ using the 4B5 assay compared with 11.6% using HercepTest. HercepTest identified IHC1+/2+ staining in 21.6% [95%CI:15.1,29.4] of the patients classified as IHC1+/2+ by 4B5. 98.3% [95%CI: 96.2, 99.5] of samples IHC0 by 4B5 were also IHC0 by Herceptest. Conclusions: HER2 IHC1+/2+ (ISH-) by Ventana 4B5 represent a significant proportion of breast cancer patients and more than 50% of ER+ve and PR+ve subtypes. The 4B5 assay classed several patients as IHC1+/2+ that are IHC0 by Herceptest, but almost all patients IHC0 by 4B5 were also IHC0 by Herceptest.[Table: see text]