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One of the great challenges in therapeutic oncology is determining who might achieve survival benefits from a particular therapy. Studies on longitudinal circulating tumor DNA (ctDNA) dynamics for the prediction of survival have generally been small or nonrandomized. We assessed ctDNA across 5 time points in 466 non-small-cell lung cancer (NSCLC) patients from the randomized phase 3 IMpower150 study comparing chemotherapy-immune checkpoint inhibitor (chemo-ICI) combinations and used machine learning to jointly model multiple ctDNA metrics to predict overall survival (OS). ctDNA assessments through cycle 3 day 1 of treatment enabled risk stratification of patients with stable disease (hazard ratio (HR) = 3.2 (2.0–5.3), P P P = 0.00012). Simulations of clinical trial scenarios employing our ctDNA model suggested that early ctDNA testing outperforms early radiographic imaging for predicting trial outcomes. Overall, measuring ctDNA dynamics during treatment can improve patient risk stratification and may allow early differentiation between competing therapies during clinical trials.

Geoscience data usually is complex and comes at different scales. Effective visualization tools are crucial for efficiently examining properties and correlations when working with the datasets and for telling geoscience stories around them. Virtual Reality (VR) leads users to an immersive experience and allows for true spatial awareness and depth perception. We find that VR enhances knowledge transfer and adds a gamification moment.In the energy industry and Academia, large amounts of multiscale geo data are compiled but often remain segregated and underutilized. Core data, for example, is sitting in remote core centers and is not readily available to be integrated for improving the quality of 3D geological models and interpretations.Likewise, numerous supplemental information and geological images are required to improve the quality of any geoscience simulations. Traditionally, most visualization is tied to display on 2D computer screens. Users (geologists, teachers, and students) rely on advanced real-time visualization and interaction methods customized to geospatial data at different scales. It is the user’s objective to improve their observations and interpretations at different dimensions (2D and 3D). In this work, we study the effectiveness and usability of Virtual Reality tools for training and collaborative decision purposes. The multiscale data includes sets of cores, logs, sedimentological descriptions, and seismic. All data is presented in a unique virtual data room and immersive presentation. The geological model and data of different scales are visualized simultaneously and interpreted jointly.Finally, we highlight the advantages of VR for training students in geoscience and geo data-data interpretation. This is not limited to but especially true for physical data sets (e.g., core) or models from remote locations (e.g., outcrop) that are difficult to visit. Specific VR tools allow students to navigate in an immersive way through virtual geological multiscale datasets. The interactive environment makes the process of learning fun, removes distractions, and immerses the students in the subject matter at hand. Together with dedicated VR storytelling tools and supplemental documentation, this results in a quicker and deeper understanding of complex geological settings.

High tumor mutational burden (TMB-H) correlates with improved immunotherapy response. We assessed atezolizumab 1,200 mg every 3 weeks for TMB-H tumors from MyPathway (NCT02091141), a phase IIa multibasket study. One hundred twenty-one patients had advanced solid tumors with TMB ≥10 mut/Mb by any Clinical Laboratory Improvement Amendments (CLIA)–certified assay. The preplanned primary endpoint was objective response rate (ORR) in patients with TMB ≥16 mut/Mb tumors by FoundationOne TMB testing [F1(CDx)]. Patients with F1(CDx) TMB ≥10 and Significance:Atezolizumab monotherapy had promising, durable clinical activity across a variety of advanced solid tumor types in patients with TMB ≥16 mut/Mb tumors lacking other suitable treatment options and who were immunotherapy-naïve at enrollment, regardless of microsatellite instability status. Limited activity was observed in tumors with TMB ≥10 and See related commentary by Maron and Klempner, p. 602.This article is highlighted in the In This Issue feature, p. 587

Supplementary Figure from Atezolizumab Treatment of Tumors with High Tumor Mutational Burden from MyPathway, a Multicenter, Open-Label, Phase IIa Multiple Basket Study

Supplementary Data from Atezolizumab Treatment of Tumors with High Tumor Mutational Burden from MyPathway, a Multicenter, Open-Label, Phase IIa Multiple Basket Study

Malignant peritoneal mesothelioma (MPeM) is a rare but aggressive malignancy with limited treatment options. VEGF inhibition enhances efficacy of immune-checkpoint inhibitors by reworking the immunosuppressive tumor milieu. Efficacy and safety of combined PD-L1 (atezolizumab) and VEGF (bevacizumab) blockade (AtezoBev) was assessed in 20 patients with advanced and unresectable MPeM with progression or intolerance to prior platinum–pemetrexed chemotherapy. The primary endpoint of confirmed objective response rate per RECISTv1.1 by independent radiology review was 40% [8/20; 95% confidence interval (CI), 19.1–64.0] with median response duration of 12.8 months. Six (75%) responses lasted for >10 months. Progression-free and overall survival at one year were 61% (95% CI, 35–80) and 85% (95% CI, 60–95), respectively. Responses occurred notwithstanding low tumor mutation burden and PD-L1 expression status. Baseline epithelial–mesenchymal transition gene expression correlated with therapeutic resistance/response (r = 0.80; P = 0.0010). AtezoBev showed promising and durable efficacy in patients with advanced MPeM with an acceptable safety profile, and these results address a grave unmet need for this orphan disease.Significance:Efficacy of atezolizumab and bevacizumab vis-à-vis response rates and survival in advanced peritoneal mesothelioma previously treated with chemotherapy surpassed outcomes expected with conventional therapies. Biomarker analyses uncovered epithelial–mesenchymal transition phenotype as an important resistance mechanism and showcase the value and feasibility of performing translationally driven clinical trials in rare tumors.See related commentary by Aldea et al., p. 2674.This article is highlighted in the In This Issue feature, p. 2659

Vituperation, disparagement, and debasement seem to have become part of the mainstream discourse in contemporary US-American media culture. Zooming in on a distinct televisual comedy genre, Katja Schulze explores the formal principles, media-specific realizations, and the cultural work of disparagement in contemporary female-led situation comedies. Subsequently, larger patterns of (gender-based) invective strategies and conventions that define the dynamism of this comedic genre come into view. Her study outlines case studies of popular sitcoms, like Parks and Recreation, Mike & Molly, and the revival of hit-sitcom Roseanne, thereby unearthing how the shows are able to stage humor as mass-mediated deprecation - a signifying practice with its own poetics and politics.

The burden of large and rare copy number genetic variants (CNVs) as well as certain specific CNVs increase the risk of developing schizophrenia. Several cognitive measures are purported schizophrenia endophenotypes and may represent an intermediate point between genetics and the illness. This paper investigates the influence of CNVs on cognition. We conducted a systematic review and meta-analysis of the literature exploring the effect of CNV burden on general intelligence. We included ten primary studies with a total of 18,847 participants and found no evidence of association. In a new psychosis family study, we investigated the effects of CNVs on specific cognitive abilities. We examined the burden of large and rare CNVs (>200 kb, This work was supported by the Medical Research Council (G0901310) and the Wellcome Trust (grants 085475/B/08/Z, 085475/Z/08/Z). This study was supported by the NIHR Biomedical Research Centre at University College London Hospitals NHS Foundation Trust and University College London and by the NIHR Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust at King’s College London. Further support to EB: Mental Health Research UK’s John Grace QC award, BMA Margaret Temple grants 2016 and 2006, MRC—Korean Health Industry Development Institute Partnering Award (MC_PC_16014), MRC New Investigator Award and a MRC Centenary Award (G0901310), National Institute of Health Research UK post-doctoral fellowship, the Psychiatry Research Trust, the Schizophrenia Research Fund, the Brain and Behaviour Research foundation’s NARSAD Young Investigator Awards 2005, 2008, Wellcome Trust Research Training Fellowship, the NIHR Biomedical Research Centre at UCLH, and the NIHR Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust and Institute of Psychiatry King’s College London. Further support to co-authors: The Brain and Behaviour Research foundation’s (NARSAD’s) Young Investigator Award (Grant 22604, awarded to CI). The BMA Margaret Temple grant 2016 to JT. A 2014 European Research Council Marie Curie award to A Díez-Revuelta. HI has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 747429. A Medical Research Council doctoral studentship to JH-S, IA-Z and AB. A Mental Health Research UK studentship to RM. VB is supported by a Wellcome Trust Seed Award in Science (200589/Z/16/Z). FWO Senior Clinical Fellowship to RvW. The infrastructure for the GROUP consortium is funded through the Geestkracht programme of the Dutch Health Research Council (ZON-MW, grant number 10-000-1001), and matching funds from participating pharmaceutical companies (Lundbeck, AstraZeneca, Eli Lilly, Janssen Cilag) and universities and mental health care organisations (Amsterdam: Academic Psychiatric Centre of the Academic Medical Centre and the mental health institutions: GGZ Ingeest, Arkin, Dijk en Duin, GGZ Rivierduinen, Erasmus Medical Centre, GGZ Noord Holland Noord. Groningen: University Medical Centre Groningen and the mental health institutions: Lentis, GGZ Friesland, GGZ Drenthe, Dimence, Mediant, GGNet Warnsveld, Yulius Dordrecht and Parnassia psycho-medical centre The Hague. Maastricht: Maastricht University Medical Centre and the mental health institutions: GGZ Eindhoven en De Kempen, GGZ Breburg, GGZ Oost-Brabant, Vincent van Gogh voor Geestelijke Gezondheid, Mondriaan, Virenze riagg, Zuyderland GGZ, MET ggz, Universitair Centrum Sint-Jozef Kortenberg, CAPRI University of Antwerp, PC Ziekeren Sint-Truiden, PZ Sancta Maria Sint-Truiden, GGZ Overpelt, OPZ Rekem. Utrecht: University Medical Centre Utrecht and the mental health institutions Altrecht, GGZ Centraal and Delta). The Santander cohort was supported by Instituto de Salud Carlos III (PI020499, PI050427, PI060507), SENY Fundació (CI 2005-0308007), Fundacion Ramón Areces and Fundacion Marqués de Valdecilla (API07/011, API10/13). We thank Valdecilla Biobank for providing the biological PAFIP samples and associated data included in this study and for its help in the technical execution of this work; we also thank IDIVAL Neuroimaging Unit for its help in the acquisition and processing of imaging PAFIP data.

Summary Background Systemic therapies for metastatic biliary tract cancers are few, and patients have a median overall survival of less than 1 year. MyPathway evaluates the activity of US Food and Drug Administration-approved therapies in non-indicated tumours with potentially actionable molecular alterations. In this study, we present an analysis of patients with metastatic biliary tract cancers with HER2 amplification, overexpression, or both treated with a dual anti-HER2 regimen, pertuzumab plus trastuzumab, from MyPathway. Methods MyPathway is a non-randomised, multicentre, open-label, phase 2a, multiple basket study. Patients aged 18 years and older with previously treated metastatic biliary tract cancers with HER2 amplification, HER2 overexpression, or both and an Eastern Cooperative Oncology Group performance status of 0–2 were enrolled from 23 study sites in the USA and received intravenous pertuzumab (840 mg loading dose, then 420 mg every 3 weeks) plus trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks). The primary endpoint was investigator-assessed objective response rate according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The primary outcome and adverse events were analysed in all patients who received at least one dose of pertuzumab and trastuzumab. This trial is registered with ClinicalTrials.gov , NCT02091141 , and is ongoing. Findings 39 patients enrolled in the MyPathway HER2 biliary tract cancer cohort between Oct 28, 2014, and May 29, 2019, were evaluable for anti-tumour activity by the March 10, 2020, data cutoff date. Median follow-up was 8·1 months (IQR 2·7–15·7). Nine of 39 patients achieved a partial response (objective response rate 23% [95% CI 11–39]). Grade 3–4 treatment-emergent adverse events were reported in 18 (46%) of 39 patients, most commonly increased alanine aminotransferase and increased aspartate aminotransferase (each five [13%] of 39). Treatment-related grade 3 adverse events were reported in three (8%) of 39 patients, including increased alanine aminotransferase, aspartate aminotransferase, blood alkaline phosphatase, and blood bilirubin. Serious treatment-emergent adverse events were observed in ten (26%) of 39 patients, of which only abdominal pain occurred in more than one patient (two [5%] of 39). There were no treatment-related serious adverse events, treatment-related grade 4 events, or deaths. Interpretation Treatment was well tolerated in patients with previously treated HER2-positive metastatic biliary tract cancer. The response rate is promising for the initiation of randomised, controlled trials of pertuzumab plus trastuzumab in this patient population. Funding F Hoffmann-La Roche–Genentech.

Communicating the uncertainty underlying weather warnings appears promising. Information about uncertainty can increase confidence in the forecast and support the decision-making process (Joslyn and LeClerc, 2013; LeClerc and Joslyn, 2015; Fundel et al., 2019). However, probabilities can be misunderstood if they are not appropriately communicated (Murphy, 1980; Gigerenzer et al., 2005; Budescu et al., 2014). Uncertainty information in weather warnings might also reduce threat perception and intention to act (Taylor 2021; Schulze & Voss, in prep.).As part of the WEXICOM project (Weather warnings: from EXtreme event Information to COMunication and action), we conducted a representative experimental online survey in Germany (n=1 721). In close collaboration with Nathalie Popovic (MeteoSwiss), we investigated how the public perceives weather warnings with different formats of uncertainty information. The study tested three combinations of numerical and verbal uncertainty information in weather warnings (numerical probability & verbal probability vs. numerical probability & verbal frequency vs. numerical frequency & verbal frequency). Moreover, we tested all three conditions with and without additional explanation about the probability level at which the weather service typically issues a warning. All combinations were tested for three probability levels (20%; 40%; 60%) in two weather scenarios (hurricane force gale; thunderstorm with extremely heavy rainfall).We find that low probabilities decreased the perceived risk and warning response – in line with numerous findings in other domains that low probability events are often not taken seriously. Interestingly, the format in which probabilities were communicated did not make a difference: The warning response was independent of whether probability information was given in numerical or verbal form. What was striking, however, was that providing information about the low probability level at which weather services typically issue a warning improved the perception of the warning — especially at low probability levels. Thus, the main problem for the public might not be understanding the uncertainty information but interpreting its magnitude in the context of weather warnings. Here, a simple reference point can help to put low probabilities into perspective.

IMPORTANCE: Therapies for patients with advanced well-differentiated neuroendocrine tumors (NETs) have expanded but remain inadequate, with patients dying of disease despite recent advances in NET therapy. While patients with other cancers have seen long-term disease control and tumor regression with the application of immunotherapies, initial prospective studies of single-agent programmed cell death 1 inhibitors in NET have been disappointing. OBJECTIVE: To evaluate the response rate following treatment with the combination of the vascular endothelial growth factor inhibitor bevacizumab with the programmed cell death 1 ligand 1 inhibitor atezolizumab in patients with advanced NETs. DESIGN, SETTING, AND PARTICIPANTS: This single-arm, open-label nonrandomized clinical study in patients with rare cancers included 40 patients with advanced, progressive grade 1 to 2 NETs (20 with pancreatic NETs [pNETs] and 20 with extrapancreatic NETs [epNETs]) treated at a tertiary care referral cancer center between March 31, 2017, and February 19, 2019. Data were analyzed from June to September 2021. INTERVENTIONS: Patients received intravenous bevacizumab and atezolizumab at standard doses every 3 weeks until progression, death, or withdrawal. MAIN OUTCOMES AND MEASURES: The primary end point was objective radiographic response using Response Evaluation Criteria in Solid Tumors, version 1.1, with progression-free survival (PFS) as a key secondary end point. RESULTS: Following treatment of the 40 study patients with bevacizumab and atezolizumab, objective response was observed in 4 patients with pNETs (20%; 95% CI, 5.7%-43.7%) and 3 patients with epNETs (15%; 95% CI, 3.2%-37.9%). The PFS was 14.9 (95% CI, 4.4-32.0) months and 14.2 (95% CI, 10.2-19.6) months in these cohorts, respectively. CONCLUSIONS AND RELEVANCE: In this nonrandomized clinical trial, findings suggest that clinical responses in patients with NET may follow treatment with the combination of bevacizumab and atezolizumab, with a PFS consistent with effective therapies. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03074513

Background LCMC3 (NCT02927301), an open-label, single-arm Phase 2 study to investigate neoadjuvant (neoadj) and adj atezo (anti-PD-L1) in patients (pts) with early-stage non-small cell lung cancer (NSCLC), met its primary endpoint with a 20% major pathological response (MPR) rate after neoadj atezo. Here we report efficacy and safety from the adj phase. Methods Eligible pts aged ≥18 y had resectable stage IB-IIIA or select IIIB NSCLC and ECOG PS of 0 or 1. Pts received neoadj atezo 1200 mg IV for ≤2 cycles (Days 1 and 22) followed by surgery (Day 40±10). Pts deemed to have clinical benefit were offered the option to receive adj atezo every 3 weeks for up to 12 months. The primary endpoint was MPR rate (≤10% viable tumor cells at surgery) in pts without EGFR/ALK mutations. Exploratory endpoints included DFS and OS. Safety was assessed during the adj phase. Results Data cutoff was Oct 21, 2022. The primary efficacy population (PEP) was 137 pts without EGFR/ALK alterations who had surgery and MPR assessment. In the PEP, 53 pts (39%) received adj atezo and 84 (61%) did not. The 3-y DFS rate was 83% with adj atezo vs 64% without (HR, 0.43; 95% CI: 0.21, 0.90; P=0.025). 3-y OS and results by MPR status are provided in the table. In the adj atezo safety population (n=57), treatment-related (TR) AEs after adj atezo occurred in 55 pts (97%; Gr 3/4, 40%), including 11 TRAEs (19%; Gr 3/4, 16%) leading to discontinuation of adj atezo. No Gr 5 TRAEs were seen in the adj phase. Multivariate analysis also showed a trend toward better DFS for pts receiving adj atezo vs those with no adj atezo (HR, 0.52; 95% CI: 0.22, 1.21; P=0.126). Conclusions This exploratory analysis revealed that LCMC3 pts with resectable stage IB-IIIA or select IIIB NSCLC who received adj atezo had improved DFS and showed a trend toward improved OS vs pts who did not receive adj atezo. Furthermore, the non-MPR subgroup had the same trend toward improved DFS and OS with adj atezo vs pts who did not receive adj atezo. Adj atezo was well tolerated, with no new safety concerns. Table Adj atezoa n=53 No adj atezob n=84 Tx patterns Adj atezo + adj chemo, n (%) 17 (32) 0 Adj atezo, n (%) 36 (68) 0 Adj chemo, n (%) 0 36 (43) None, n (%) 0 48 (57) Tx cycles Adj atezo, n, median (range) 53, 16 (1-18) 0 Adj chemo, n, median (range) 16, 3 (0-4.2) 35, 3 (0-4.1) HR (95% CI) P PEP (N=137) 3-y DFS, % 83 64 0.43 (0.21, 0.90) 0.025 3-y OS, % 89 77 0.48 (0.19, 1.21) 0.118 MPR (n=29) n=22 n=7 3-y DFS, % 86 86 0.93 (0.10, 8.92) 0.948 Non-MPR (n=108) n=31 n=77 3-y DFS, % 80 62 0.48 (0.20, 1.12) 0.088 3-y OS, % 87 75 0.49 (0.17, 1.46) 0.202 Multivariable Cox regression (n=114)c MPR vs non-MPR 0.37 (0.11, 1.31) 0.125 Adj atezo vs no adj atezo 0.52 (0.22, 1.21) 0.126 Adj chemo vs no adj chemo 0.57 (0.27, 1.19) 0.133 Stage I/II vs III 0.71 (0.35, 1.43) 0.338 PD-L1 tumor proportion score ≥1% vs Citation Format: David Paul Carbone, Saiama N. Waqar, Jamie E. Chaft, Mark G. Kris, Bruce E. Johnson, Jay M. Lee, Ignacio I. Wistuba, David Kwiatkowski, Paul Bunn, Katja Schulze, Ann Johnson, Evelise Brandao, Mark Awad, Karen L. Reckamp, Anne C. Chiang, Alan Nicholas, Valerie Rusch. Efficacy and safety of adjuvant (adj) atezolizumab (atezo) from the Phase 2 LCMC3 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT215.

Introduction: Neoadjuvant chemoimmunotherapy is promising in improving outcomes for patients with resectable lung cancer in the phase III setting, though data are immature at this time for overall survival (OS). Here, we present outcomes after 3 years of follow-up from the first reported study of neoadjuvant immunotherapy + chemotherapy in this population. Methods: This open-label, multi-center single-arm investigator-initiated phase II study was conducted at three hospitals in the USA. Neoadjuvant atezolizumab, carboplatin, and nab-paclitaxel were administered for up to 4 cycles prior to surgical resection. The primary endpoint of major pathologic response (MPR) has been previously reported; here we report mature disease-free survival (DFS) and OS as well as clinical characteristics of patients with recurrent brain metastases (BM) with integrated data from tumor genomics, gene expression, and quantitative immunofluorescent (QIF) measurement of immune markers. Results: Of 30 enrolled patients, 29 were taken to the operating room with 26 completing successful R0 resection. 17 patients experienced MPR, of whom 10 had pathological complete response (pCR). The median follow-up time was 39.5 months (95% CI: 30.9-49.4). Median OS was 55.8 months (95% CI: 43.6-NA); median DFS was 34.5 months (95% CI: 18.4-NA). Landmark OS at 12, 24, and 36 months were 97%, 80%, and 77%, respectively; DFS: 80%, 60%, and 49%. Radiographic and pathologic measures of response, as well as baseline PD-L1 levels, did not statistically significantly associate with DFS or OS. The strongest trends were observed with pCR (OS: HR 0.22, 95% CI 0.03-1.83; DFS: HR 0.45, 95% CI 0.12-1.65). Percent decrease of radiographic response correlated inversely with percent pathological regression (Pearson correlation -0.44, 95% CI: -0.71—-0.08). Of 14 patients evaluable for site of recurrence, 6 developed BM. 5/6 patients with BM died, with median time to recurrence of 12.4 months (95% CI: 9.9-32.6) and time to death of 45.3 months (95% CI: 22.7-55.8). 3/6 patients who developed BM experienced MPR (2 achieved pCR). Radiographic response and PD-L1 level did not significantly associate with development of BM. Patients whose tumors had mutations in STK11 and KEAP1 did not experience statistically worse DFS/OS, though incidence of BM trended higher. Reduced copy number of STK11 and KEAP1, which both reside on chromosome 19p, was observed in about 1/3 of tumors. Deletion of either gene was significantly associated with worse pathologic response, lower levels of PD-L1+ cells by QIF, and BM. Conclusions: Mature OS data reveal sustained clinical benefit of neoadjuvant chemoimmunotherapy with atezolizumab. Predictivity of radiographic and pathologic surrogates for survival was limited. Further study is warranted to establish the associations between STK11 and KEAP1 genomic alterations and key clinical outcomes in early-stage NSCLC. Citation Format: Brian S. Henick, Justin F. Gainor, Mark M. Awad, Codruta Chiuzan, Stephanie Izard, Yohanna Georgis, Peter D. Koch, Robert F. Garofano, Cheryl V. Wong, Anjali Saqi, Jessica M. Grindheim, Katja Schulze, Naiyer A. Rizvi, Benjamin Izar, Alison M. Taylor, Catherine A. Shu. 3-year update of neoadjuvant atezolizumab + chemotherapy in patients with resectable non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT217.

Background: In recent years, a relationship between the tumor microenvironment (TME) and patient response to targeted cancer immunotherapy has been suggested. We applied machine-learning algorithms on H&E stained tissue to study the TME in metastatic non-small cell lung cancer (NSCLC) patients. Our goal was to identify digital pathology (DP) features associated with outcome under combination treatment or monotherapy with atezolizumab (atezo), an anti-PD-L1 therapy, and relate those features to other data modalities. We analyzed patient data from two phase 3 clinical trials, OAK (docetaxel versus atezo in 2L+ NSCLC) and IMpower150 (bevacizumab, carboplatin, and paclitaxel (BCP) versus BCP+atezo (ABCP) in advanced 1L non-squamous NSCLC). Methods: As part of our effort to build a DP-based tumor-immune microenvironment atlas, digitized H&E images were registered onto the PathAI research platform. Over 200K annotations from 90 pathologists were used to train convolutional neural networks (CNNs) that classify slide-level human-interpretable features (HIFs) of cells and tissue structures from images and deployed on images from OAK and IMpower150. HIFs and PD-L1 status were associated with outcome in all samples in each arm in OAK and results were validated in IMpower150, using Cox proportional hazard models. Bulk RNAseq was run using samples extracted from the same area as the H&E slide. Results: We identified a composite feature capturing the ratio of immune cells to fibroblasts in the stroma predictive of both overall survival (OS) (HR=0.74 p=0.0046) and progression-free survival (PFS) (HR=0.87 p=0.14). While patients primarily benefit from atezo if they are PD-L1 high, we found that even PD-L1 negative patients benefited from atezo when enriched for this feature (22C3 PD-L1 assay: OS HR=0.59 p=0.015, PFS HR=0.8 p=0.25; SP142 PD-L1 assay: OS HR=0.74 p=0.12, PFS HR=0.88 p=0.45). We thus recognized a DP feature that was predictive for positive outcome with atezo treatment, independent of PD-L1 levels. This association was then validated in IMpower150 comparing ABCP to BCP, both overall (OS HR=0.69 p=0.012) and in PD-L1 negative patients (SP263 assay OS HR=0.56 p=0.034). Integrating with RNAseq, patients enriched for this DP feature showed similar enrichment for B and T gene signatures and depletion in CAF-related gene signatures, thus showing the harmonization of TME between different data modalities. Conclusions: Using a deep learning-based assay for quantifying pathology features of the TME from H&E images in two NSCLC trials, we identified a novel biomarker predictive of outcome to PD-L1 targeting therapy, even in PD-L1 low & negative patients. Importantly, our work shows how different data modalities (DP, gene expression) can be integrated to further our understanding of the TME. Citation Format: Aditi Qamra, Minu K. Srivastava, Eloisa Fuentes, Ben Trotter, Raymond Biju, Guillaume Chhor, James Cowan, Steven Gendreau, Webster Lincoln, Lisa McGinnis, Luciana Molinero, Namrata S. Patil, Amber Schedlbauer, Katja Schulze, Adam Stanford-Moore, Laura Chambre, Ilan Wapinski, David S. Shames, Hartmut Koeppen, Stephanie Hennek, Jane Fridlyand, Jennifer M. Giltnane, Assaf Amitai. Digital pathology based prognostic & predictive biomarkers in metastatic non-small cell lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5705.

In an ongoing, open-label, single-arm phase II study ( NCT02927301 ), 181 patients with untreated, resectable, stage IB-IIIB non-small cell lung cancer received two doses of neoadjuvant atezolizumab monotherapy. The primary end point was major pathological response (MPR; ≤10% viable malignant cells) in resected tumors without EGFR or ALK alterations. Of the 143 patients in the primary end point analysis, the MPR was 20% (95% confidence interval, 14-28%). With a minimum duration of follow-up of 3 years, the 3-year survival rate of 80% was encouraging. The most common adverse events during the neoadjuvant phase were fatigue (39%, 71 of 181) and procedural pain (29%, 53 of 181), along with expected immune-related toxicities; there were no unexpected safety signals. In exploratory analyses, MPR was predicted using the pre-treatment peripheral blood immunophenotype based on 14 immune cell subsets. Immune cell subsets predictive of MPR in the peripheral blood were also identified in the tumor microenvironment and were associated with MPR. This study of neoadjuvant atezolizumab in a large cohort of patients with resectable non-small cell lung cancer was safe and met its primary end point of MPR ≥ 15%. Data from this single-arm, non-randomized trial suggest that profiles of innate immune cells in pre-treatment peripheral blood may predict pathological response after neoadjuvant atezolizumab, but additional studies are needed to determine whether these profiles can inform patient selection and new therapeutic approaches.

Background Microscopic examination of human blood samples is an excellent opportunity to assess general health status and diagnose diseases. Conventional blood tests are performed in medical laboratories by specialized professionals and are time and labor intensive. The development of a point-of-care system based on a mobile microscope and powerful algorithms would be beneficial for providing care directly at the patient's bedside. For this purpose human blood samples were visualized using a low-cost mobile microscope, an ocular camera and a smartphone. Training and optimisation of different deep learning methods for instance segmentation are used to detect and count the different blood cells. The accuracy of the results is assessed using quantitative and qualitative evaluation standards. Results Instance segmentation models such as Mask R-CNN, Mask Scoring R-CNN, D2Det and YOLACT were trained and optimised for the detection and classification of all blood cell types. These networks were not designed to detect very small objects in large numbers, so extensive modifications were necessary. Thus, segmentation of all blood cell types and their classification was feasible with great accuracy: qualitatively evaluated, mean average precision of 0.57 and mean average recall of 0.61 are achieved for all blood cell types. Quantitatively, 93% of ground truth blood cells can be detected. Conclusions Mobile blood testing as a point-of-care system can be performed with diagnostic accuracy using deep learning methods. In the future, this application could enable very fast, cheap, location- and knowledge-independent patient care.

High tumor mutational burden (TMB-H) correlates with improved immunotherapy response. We assessed atezolizumab 1,200 mg every 3 weeks for TMB-H tumors from MyPathway (NCT02091141), a phase IIa multibasket study. One hundred twenty-one patients had advanced solid tumors with TMB ≥10 mut/Mb by any Clinical Laboratory Improvement Amendments (CLIA)–certified assay. The preplanned primary endpoint was objective response rate (ORR) in patients with TMB ≥16 mut/Mb tumors by FoundationOne TMB testing [F1(CDx)]. Patients with F1(CDx) TMB ≥10 and Significance: Atezolizumab monotherapy had promising, durable clinical activity across a variety of advanced solid tumor types in patients with TMB ≥16 mut/Mb tumors lacking other suitable treatment options and who were immunotherapy-naïve at enrollment, regardless of microsatellite instability status. Limited activity was observed in tumors with TMB ≥10 and See related commentary by Maron and Klempner, p. 602. This article is highlighted in the In This Issue feature, p. 587

Multimodality treatment for resectable non-small cell lung cancer has long remained at a therapeutic plateau. Immune checkpoint inhibitors are highly effective in advanced non-small cell lung cancer and promising preoperatively in small clinical trials for resectable non-small cell lung cancer. This large multicenter trial tested the safety and efficacy of neoadjuvant atezolizumab and surgery.Patients with stage IB to select IIIB resectable non-small cell lung cancer and Eastern Cooperative Oncology Group performance status 0/1 were eligible. Patients received atezolizumab 1200 mg intravenously every 3 weeks for 2 cycles or less followed by resection. The primary end point was major pathological response in patients without EGFR/ALK+ alterations. Pre- and post-treatment computed tomography, positron emission tomography, pulmonary function tests, and biospecimens were obtained. Adverse events were recorded by Common Terminology Criteria for Adverse Events v.4.0.From April 2017 to February 2020, 181 patients were entered in the study. Baseline characteristics were mean age, 65.1 years; female, 93 of 181 (51%); nonsquamous histology, 112 of 181 (62%); and clinical stages IIB to IIIB, 147 of 181 (81%). In patients without EGFR/ALK alterations who underwent surgery, the major pathological response rate was 20% (29/143; 95% confidence interval, 14-28) and the pathological complete response rate was 6% (8/143; 95% confidence interval, 2-11). There were no grade 4/5 treatment-related adverse events preoperatively. Of 159 patients (87.8%) undergoing surgery, 145 (91%) had pathologic complete resection. There were 5 (3%) intraoperative complications, no intraoperative deaths, and 2 postoperative deaths within 90 days, 1 treatment related. Median disease-free and overall survival have not been reached.Neoadjuvant atezolizumab in resectable stage IB to IIIB non-small cell lung cancer was well tolerated, yielded a 20% major pathological response rate, and allowed safe, complete surgical resection. These results strongly support the further development of immune checkpoint inhibitors as preoperative therapy in locally advanced non-small cell lung cancer.

Summary Background Therapies targeting HER2 have improved clinical outcomes in HER2-positive breast and gastric cancers, and are emerging as potential treatments for HER2-positive metastatic colorectal cancer. MyPathway evaluates the activity of targeted therapies in non-indicated tumour types with potentially predictive molecular alterations. We aimed to assess the activity of pertuzumab and trastuzumab in patients with HER2-amplified metastatic colorectal cancer. Methods MyPathway is an ongoing, phase 2a, multiple basket study. Patients in this subset analysis were aged 18 years or older and had treatment-refractory, histologically confirmed HER2-amplified metastatic colorectal cancer with measurable or evaluable disease and an Eastern Cooperative Oncology Group performance status score of 2 or less, enrolled from 25 hospitals or clinics in 16 states of the USA. Patients received pertuzumab (840 mg loading dose, then 420 mg every 3 weeks, intravenously) and trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks, intravenously). The primary endpoint was the proportion of patients who achieved an objective response based on investigator-reported tumour responses. Analyses were done per protocol. This ongoing trial is registered with ClinicalTrials.gov , number NCT02091141 . Findings Between Oct 20, 2014, and June 22, 2017, 57 patients with HER2-amplified metastatic colorectal cancer were enrolled in the MyPathway study and deemed eligible for inclusionin this cohort analysis. Among these 57 evaluable patients, as of Aug 1, 2017, one (2%) patient had a complete response and 17 (30%) had partial responses; thus overall 18 of 57 patients achieved an objective response (32%, 95% CI 20–45). The most common treatment-emergent adverse events were diarrhoea (19 [33%] of 57 patients), fatigue (18 [32%] patients), and nausea (17 [30%] patients). Grade 3–4 treatment-emergent adverse events were recorded in 21 (37%) of 57 patients, most commonly hypokalaemia and abdominal pain (each three [5%] patients). Serious treatment-emergent adverse events were reported in ten (18%) patients and two (4%) of these adverse events (ie, chills and infusion-related reaction) were considered treatment related. There were no treatment-related deaths. Interpretation Dual HER2-targeted therapy with pertuzumab plus trastuzumab is well tolerated and could represent a therapeutic opportunity for patients with heavily pretreated, HER2-amplified metastatic colorectal cancer. Funding F Hoffmann-La Roche/Genentech.

BackgroundNon-small cell lung cancer (NSCLC) patients bearing targetable oncogene alterations typically derive limited benefit from immune checkpoint blockade (ICB), which has been attributed to low tumor mutation burden (TMB) and/or PD-L1 levels. We investigated oncogene-specific differences in these markers and clinical outcome.MethodsThree cohorts of NSCLC patients with oncogene alterations (n=4189 total) were analyzed. Two clinical cohorts of advanced NSCLC patients treated with ICB monotherapy [MD Anderson (MDACC; n=172) and Flatiron Health-Foundation Medicine Clinico-Genomic Database (CGDB; n=894 patients)] were analyzed for clinical outcome. The FMI biomarker cohort (n=4017) was used to assess the association of oncogene alterations with TMB and PD-L1 expression.ResultsHigh PD-L1 expression (PD-L1 ≥50%) rate was 19%–20% in classic EGFR, EGFR exon 20 and HER2-mutant tumors, and 34%–55% in tumors with ALK, BRAF V600E, ROS1, RET, or MET alterations. Compared with KRAS-mutant tumors, BRAF non-V600E group had higher TMB (9.6 vs KRAS 7.8 mutations/Mb, p=0.003), while all other oncogene groups had lower TMB (pEGFR, HER2, ALK, ROS1, RET, or MET alterations had short progression-free survival (PFS; 1.8–3.7 months), while BRAF V600E group was associated with greater clinical benefit from ICB (CGDB cohort: PFS 9.8 months vs KRAS 3.7 months, HR 0.66, p=0.099; MDACC cohort: response rate 62% vs KRAS 24%; PFS 7.4 vs KRAS 2.8 months, HR 0.36, p=0.026). KRAS G12C and non-G12C subgroups had similar clinical benefit from ICB in both cohorts. In a multivariable analysis, BRAF V600E mutation (HR 0.58, p=0.041), PD-L1 expression (HR 0.57, p=0.022), and high TMB (HR 0.66, pConclusionsHigh TMB and PD-L1 expression are predictive for benefit from ICB treatment in oncogene-driven NSCLCs. NSCLC harboring BRAF mutations demonstrated superior benefit from ICB that may be attributed to higher TMB and higher PD-L1 expression in these tumors. Meanwhile EGFR and HER2 mutations and ALK, ROS1, RET, and MET fusions define NSCLC subsets with minimal benefit from ICB despite high PD-L1 expression in NSCLC harboring oncogene fusions. These findings indicate a TMB/PD-L1-independent impact on sensitivity to ICB for certain oncogene alterations.

Whereas tumor biopsy is the reference standard for genomic profiling of advanced NSCLC, there are now multiple assays approved by the Food and Drug Administration for liquid biopsy testing of circulating tumor DNA. Here, we study the incremental value that liquid biopsy comprehensive genomic profiling (CGP) adds to tissue molecular testing.Patients with metastatic NSCLC were enrolled in a prospective diagnostic study to receive circulating tumor DNA CGP; tissue CGP was optional in addition to their standard tissue testing. Focusing on nine genes listed per the National Comprehensive Cancer Network (NCCN) guidelines, liquid CGP was compared with available tissue testing results across three subcohorts: tissue CGP, standard-of-care testing of up to five biomarkers, or no tissue testing.A total of 515 patients with advanced nonsquamous NSCLC received liquid CGP. Among 131 with tissue CGP results, NCCN biomarkers were detected in 86 (66%) with tissue CGP and 56 (43%) with liquid CGP (For the detection of patients with advanced nonsquamous NSCLC harboring 9 NCCN biomarkers, liquid CGP increases detection in patients with limited tissue results, but does not increase detection in patients with tissue CGP results available. In contrast, tissue CGP can add meaningfully to liquid CGP for detection of NCCN biomarkers and should be considered as a follow-up when an oncogenic driver is not identified by liquid biopsy.

An augmented reality (AR) system is presented which enhances the real-time collaboration of domain experts involved in the geologic modeling of complex reservoirs. An evaluation of traditional techniques is compared with this new approach. The objective of geologic modeling is to describe the subsurface as accurately and in as much detail as possible given the available data. This is necessarily an iterative process since as new wells are drilled more data becomes available which either validates current assumptions or forces a re-evaluation of the model. As the speed of reservoir development increases there is a need for expeditious updates of the subsurface model as working with an outdated model can lead to costly mistakes. Common practice is for a geologist to maintain the geologic model while working closely with other domain experts who are frequently not co-located with the geologist. Time-critical analysis can be hampered by the fact that reservoirs, which are inherently 3D objects, are traditionally viewed with 2D screens. The system presented here allows the geologic model to be rendered as a hologram in multiple locations to allow domain experts to collaborate and analyze the reservoir in real-time. Collaboration on 3D models has not changed significantly in a generation. For co-located personnel the approach is to gather around a 2D screen. For remote personnel the approach has been sharing a model through a 2D screen along with video chat. These approaches are not optimal for many reasons. Over the years various attempts have been tried to enhance the collaboration experience and have all fallen short. In particular virtual reality (VR) has been seen as a solution to this problem. However, we have found that augmented reality (AR) is a much better solution for many subtle reasons which are explored in the paper. AR has already acquired an impressive track record in various industries. AR will have applications in nearly all industries. For various historical reasons, the uptake for AR is much faster in some industries than others. It is too early to tell whether the use of augmented reality in geological applications will be transformative, however the results of this initial work are promising.

A cloud-based augmented reality system is presented which is designed to enhance the real-time collaboration of domain experts involved in modeling large reservoirs. An evaluation of traditional techniques is compared with this new approach. Work-from-home (WFH) scenarios are becoming more important and, in some cases, critical. There is a need to untether the geologist and other domain experts from high end office-bound workstations. Reservoir models in recent years have become increasingly large. The volume of seismic, well data and modeling data structures presents a challenge in both management of the data and making it accessible to domain experts and others. The traditional practice of siloing data in various disconnected data repositories in various corporate data centers is becoming increasingly untenable. What is needed is a comprehensive approach that scales to the largest models and is accessible anywhere for time critical analysis and collaboration. The authors have created a prototype of a potential solution to this problem, where the model resides in the cloud and can be visualized in augmented reality either as a hologram through a head mounted display or through the AR capabilities of tablets and smartphones. This technology is ideal for WFH scenarios: it is light weight, inexpensive and does not require broadband speeds in excess of what most home users can access. What we have found is that AR based approaches to modeling large reservoirs can rival traditional workstation approaches. Furthermore, AR based approaches are superior for close collaboration among domain experts. Collaboration on 3D models has not changed significantly in a generation. For co-located personnel the approach is to gather around a 2D screen. For remote personnel the approach is sharing a model through a 2D screen along with video chat. Over the years various attempts have been tried to enhance the collaboration experience and have all fallen short. Virtual reality (VR) has been proposed as a solution. However, we have found that augmented reality (AR) is a much better solution for many reasons which are explored in the paper. The cloud has been transformative for nearly every industry. The oil and gas industry has been slow to adopt cloud technologies for many reasons that have largely been overcome. AR has already acquired an impressive track record in various industries. AR will have applications in nearly all industries. For various historical reasons, the uptake for AR is much faster in some industries than others. It is too early to tell whether the use of cloud-based augmented reality for modeling large reservoirs will be transformative, however the results of this initial work are promising.

Background The tumor immune microenvironment is a heterogeneous entity. Gene expression analysis allows us to perform comprehensive immunoprofiling and may assist in dissecting the different components of the immune infiltrate. As gene expression analysis also provides information regarding tumor cells, differences in interactions between the immune system and specific tumor characteristics can also be explored. This study aims to gain further insights in the composition of the tumor immune infiltrate and to correlate these components to histology and overall survival in non-small cell lung cancer (NSCLC). Methods Archival tissues from 530 early stage, resected NSCLC patients with annotated tumor and patient characteristics were analyzed using the NanoString nCounter Analysis system. Results Unsupervised clustering of the samples was mainly driven by the overall level of inflammation, which was not correlated with survival in this patient set. Adenocarcinoma (AD) showed a significantly higher degree of immune infiltration compared to squamous cell carcinoma (SCC). A 34-gene signature, which did not correlate with the overall level of immune infiltration, was identified and showed an OS benefit in SCC. Strikingly, this benefit was not observed in AD. This difference in OS in SCC specifically was confirmed in two independent NSCLC cohorts. The highest correlation between expression of the 34-gene signature and specific immune cell populations was observed for NK cells, but although a plausible mechanism for NK cell intervention in tumor growth could be established in SCC over AD, this could not be translated back to immunohistochemistry, which showed that NK cell infiltration is scarce irrespective of histology. Conclusions These findings suggest that the ability of immune cell infiltration and the interaction between tumor and immune cells may be different between AD and SCC histology and that a subgroup of SCC tumors seems more susceptible to Natural Killer cell recognition and killing, whereas this may not occur in AD tumors. A highly sensitive technique like NanoString was able to detect this subgroup based on a 34-gene signature, but further research will be needed to assist in explaining the biological rationale of such low-level expression signatures.

Background: PD-L1 expression evaluated by immunohistochemistry (IHC) is a well-established predictor of anti-PD-L1/PD-1 cancer immunotherapy (CIT). The Phase II LCMC3 (NCT02927301) study evaluated pre-operative treatment (tx) with atezolizumab (anti-PD-L1) in pts with untreated early stage resectable NSCLC, achieving a 20% major pathologic response (MPR) rate (primary efficacy pts, n=143). A digital PD-L1 scoring method was developed to assess PD-L1 expression as a potential predictive marker for MPR in squamous and non-squamous tumor samples from LCMC3. Methods: Manual scoring was used to determine PD-L1 status on pre-tx biopsy samples using the tumor proportion score (TPS) with a positive threshold of TPS≥50 (22C3). Binary results were correlated with MPR and stratified by squamous/non-squamous histology. A digital pathology workflow for automated PD-L1 scoring was developed to yield a precise continuous PD-L1 TPS. Deep convolutional neural networks trained using pathologist annotations were used to detect individual cells within the tumor and tumor microenvironment and quantify their PD-L1 expression. These cell type predictions were used to compute a digital PD-L1 TPS. LCMC3 pts with available digital and manual PD-L1 scores were then used to assess the role of PD-L1 expression in predicting MPR. Results: PD-L1 scores were available for pre-tx biopsies from 108 pts. No significant difference in scores was seen between histological subtypes. At cutoff (Oct 15, 2021), TPS≥50 was seen in 41 (non-squamous, n=26 [39%]; squamous, n=15 [36%]) of 108 pts and was associated with MPR in non-squamous (odds ratio [OR], 28.6; P Conclusions: These findings support using digitally assessed PD-L1 IHC as a centralized and standardized scoring system and suggest that tumor histological subtype could be an important factor in the utility of PD-L1 as a predictive biomarker for neoadjuvant CIT in early stage NSCLC. Citation Format: John Abel, Christopher Rivard, Filip Kos, Guillaume Chhor, Yi Liu, Jennifer Giltnane, Sara Hoffman, Murray Resnick, Cyrus Hedvat, Amaro Taylor-Weiner, Farah Khalil, Alan Nicholas, Gregory A. Fishbein, Lynette M. Sholl, Natasha Rekhtman, Stephanie Hennek, Ilan Wapinski, Ann Johnson, Michael Montalto, Katja Schulze, Bruce E. Johnson, David P. Carbone, Konstantin Shilo, Andrew H. Beck, Sanja Dacic, William D. Travis, Ignacio Wistuba. AI-powered and manual assessment of PD-L1 are comparable in predicting response to neoadjuvant atezolizumab in patients (pts) with resectable non-squamous, non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT112.

Purpose: Alectinib is FDA-approved for ALK-positive, metastatic non-small cell lung cancer (NSCLC). We analyzed alectinib treatment in a pan-tumor population with ALK alterations from MyPathway (NCT02091141), a multi-basket study assessing approved therapies in non-indicated advanced solid tumors with relevant alterations. Methods: Enrolled patients (pts) were ≥18 yrs old and had metastatic tumors with ALK gene rearrangements, putative activating non-synonymous ALK mutations, and/or ALK gene amplification. Pts received alectinib 600 mg PO BID. The primary endpoint was investigator-assessed objective response rate (ORR; complete response [CR] + partial response [PR]). Other endpoints included duration of response (DOR), disease control rate (DCR; CR + PR + stable disease [SD] >4 mos), progression-free survival (PFS), and safety. Results: By the 11-18-2021 data cutoff, 21 pts with various tumor types had been enrolled and treated (ALK mutations or amplification, n=11 [52.4%]; ALK rearrangements +/- other ALK alterations, n=10 [47.6%]). Pts had a median of 2 (range, 1-5) prior lines of therapy. In the 10 pts with ALK rearrangements, there were 3 PRs (30.0%) with a median DOR of 6.8 mos (Table). An additional 3 pts in this group had SD >4 mos; DCR was 60.0% (6/10). In contrast, there were no responses among the 11 pts with ALK mutations or amplification. Confirmed ORR for the entire group was 14.3% (3/21), and DCR was 42.9% (9/21). Median PFS was 8.2 mos in pts with ALK rearrangements vs 1.8 mos for those with other ALK alterations. Alectinib-related adverse events (AEs) were observed in 85.7% of pts, with 3 (14.3%) experiencing grade 3 AEs (anemia; hypokalemia; and changes in AST, ALT, and/or blood creatinine levels). AEs were consistent with the known alectinib safety profile. Conclusions: Although the number of pts is small, alectinib appears active in those with non-NSCLC advanced solid tumors with ALK rearrangements. As in NSCLC, cancers with ALK mutations or amplification were not responsive to ALK inhibition. Table. Clinical outcomes Clinical Response Rearrangement (n=10) Mutation (n=7) Amplification (n=4) Median PFS, mos (all alterations) n Indications n Indications n Indications PR 3a Melanoma, Papillary urothelial carcinoma, Colon adenocarcinoma 0 NA 0 NA 9.3 SD >4 mos 3b,c Colon adenocarcinoma, Uterine leiomyosarcoma, Pancreatic adenocarcinoma 2 Squamous cell carcinoma, Soft tissue sarcoma 1 Uterine body clear cell carcinoma 5.7 SD ≤4 mos 0 NA 1 Fallopian tube serous carcinoma 0 NA PD 3d,e Colon adenocarcinoma, Esophageal adenocarcinoma, Uterine serous carcinoma 4 Anaplastic thyroid carcinoma, Esophageal adenocarcinoma, Colon adenocarcinoma (2) 3 Ovarian serous carcinoma, Gastric squamous cell carcinoma, Peritoneal non-small cell carcinoma 1.7 Non-evaluable 1f Uterine inflammatory myofibroblastic tumor 0 NA 0 NA NA aFusion gene partners: EMILIN1, DCTN1, and DIAPH2. bOne pt with ALK rearrangement and SD >4 mos also had ALK amplification. cFusion gene partners: STRN, IGFBP5, and EML4. dPts with ALK rearrangement and PD also had an ALK mutation (n=1) or ALK amplification (n=1). eFusion gene partner: STRN; fusion genes unknown for 2 pts. fPt withdrew prior to clinical assessment and was censored for PFS at 0.03 mos. NA, not applicable; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease. Citation Format: Charles Swanton, Claire F. Friedman, Christopher J. Sweeney, Funda Meric-Bernstam, David Spigel, Ron Bose, Howard Burris, Walter C. Darbonne, Julia Malato, Jonathan Levy, Yong Wang, Tania Szado, Katja Schulze, John Hainsworth, Razelle Kurzrock. Activity and safety of alectinib for ALK-altered solid tumors from MyPathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT032.

Objective Patients with advanced non-small-cell lung cancer (NSCLC) with an adenocarcinoma component are recommended to undergo epidermal growth factor receptor (EGFR) mutation testing when being considered for EGFR targeted therapy. We conducted an exploratory analysis to inform the clinical utility of EGFR mutation testing in blood cell-free DNA using the cobas® EGFR Mutation Test v2. Materials and methods Two EGFR mutation tests, a tissue-based assay (cobas® v1) and a tissue- and blood-based assay (cobas® v2) were used to analyze matched biopsy and blood samples (897 paired samples) from three Asian studies of first-line erlotinib with similar intent-to-treat populations. ENSURE was a phase III comparison of erlotinib and gemcitabine/platinum, FASTACT-2 was a phase III study of gemcitabine/platinum plus erlotinib or placebo, and ASPIRATION was a single-arm phase II study of erlotinib. Agreement statistics were evaluated, based on sensitivity and specificity between the two assays in subgroups of patients with increasing tumor burden. Results Patients with discordant EGFR (tissue+/plasma-) mutation status achieved longer progression-free and overall survival than those with concordant (tissue+/plasma+) mutation status. Tumor burden was significantly greater in patients with concordant versus discordant mutations. Pooled analyses of data from the three studies showed a sensitivity of 72.1% (95% confidence interval [CI] 67.8–76.1) and a specificity of 97.9% (95% CI 96.0–99.0) for blood-based testing; sensitivity was greatest in patients with larger baseline tumors. Conclusions Blood-based EGFR mutation testing demonstrated high specificity and good sensitivity, and offers a convenient and easily accessible diagnostic method to complement tissue-based tests. Patients with a discordant mutation status in plasma and tissue, had improved survival outcomes compared with those with a concordant mutation status, which may be due to their lower tumor burden. These data help to inform the clinical utility of this blood-based assay for the detection of EGFR mutations.

Purpose Targeted therapy of ALK in patients with metastatic nonsquamous non–small-cell lung cancer (NSCLC) and ALK rearrangements improves outcomes compared with chemotherapy. This study assessed real-world ALK testing patterns among community practices in the United States in patients with advanced (stage IIIB or IV) NSCLC. Methods Patients age ≥ 18 years with two or more visits within the Flatiron Health electronic health record–derived database after January 2011 and diagnosed with stage IIIB or IV NSCLC through May 2017 were included in this analysis. Logistic regression was used to examine the association between demographic and clinical characteristics and testing for ALK rearrangements. Results Of 31,483 patients analyzed from the database, 16,726 patients (53.1%) were tested for ALK rearrangements. ALK testing rates were 66.9% and 18.5% in patients with nonsquamous and squamous histology, respectively. Average ALK testing rates increased over time from 32.4% in 2011 to 62.1% in 2016. Fluorescent in situ hybridization was the most common ALK testing method. Agreement between fluorescent in situ hybridization and other assays ranged from 94.1% to 97.9%. Median (interquartile range) time from laboratory receipt of sample to first ALK test result was 7 (7) days; median time from advanced diagnosis to first ALK test result was 25 (29) days. Patients who were older, male, had a history of smoking, lived in non-Western US regions, and who had recurrent disease or squamous histology were less likely to be tested for ALK. Patients with Medicaid and Medicare insurance were less likely to be tested than patients with commercial insurance. Overall, 21.5% of patients initiated therapy (20.4% chemotherapy) before receiving test results. Conclusion ALK testing rates have increased over time. However, certain subgroups of patients are less likely to be tested, suggesting that additional education on molecular testing is warranted.

[EN] Background Reported prevalence of driver gene mutations in non-small-cell lung cancer (NSCLC) is highly variable and clinical correlations are emerging. Using NSCLC biomaterial and clinical data from the European Thoracic Oncology Platform Lungscape iBiobank, we explore the epidemiology of mutations and association to clinicopathologic features and patient outcome (relapse-free survival, time-to-relapse, overall survival). Methods Clinically annotated, resected stage I¿III NSCLC FFPE tissue was assessed for gene mutation using a microfluidics-based multiplex PCR platform. Mutant-allele detection sensitivity is¿>1% for most of the ~150 (13 genes) mutations covered in the multiplex test. Results Multiplex testing has been carried out in 2063 (76.2%) of the 2709 Lungscape cases (median follow-up 4.8¿years). FFPE samples mostly date from 2005 to 2008, yet recently extracted DNA quality and quantity was generally good. Average DNA yield/case was 2.63¿µg; 38 cases (1.4%) failed QC and were excluded from study; 95.1% of included cases allowed the complete panel of mutations to be tested. Most common were KRAS, MET, EGFR and PIK3CA mutations with overall prevalence of 23.0%, 6.8%, 5.4% and 4.9%, respectively. KRAS and EGFR mutations were significantly more frequent in adenocarcinomas: PIK3CA in squamous cell carcinomas. MET mutation prevalence did not differ between histology groups. EGFR mutations were found predominantly in never smokers; KRAS in current/former smokers. For all the above mutations, there was no difference in outcome between mutated and non-mutated cases. Conclusion Archival FFPE NSCLC material is adequate for multiplex mutation analysis. In this large, predominantly European, clinically annotated stage I¿III NSCLC cohort, none of the mutations characterized showed prognostic significance.

Combating disasters necessitates taking advantage of all means and resources that are available. A number of events in recent years have demonstrated the necessity, as well as the potential of well-integrated and coordinated action between unaffiliated and professional responders. Nevertheless, in practical situations this potential remains largely untapped. This article investigates the case in Germany and asks to which extent known and researched disaster myths impede the cooperation between unaffiliated and professional responders. We combine data from observations of a full-scale exercise, a representative population survey (N = 1.006), and expert interviews with professional rescue workers to answer our research question. With the results of our research, we have deduced that these disaster myths still significantly influence the perceptions and practical actions of the various involved actors and, as such, that approaches aiming to improve the various forms of cooperation between all available forces must take these underlying assumptions into account.

Introduction: In a well-defined NSCLC cohort of the ETOP Lungscape program, we explored the epidemiology of IHC MET overexpression and amplification, their inter-correlation, and their association to outcome.Methods: Resected NSCLC were assessed for MET gene copy number (GCN) and expression using silver in-situ hybridization (SISH) and immunohistochemistry (IHC) on TMAs in a multicenter setting. MET amplification was defined as MET/centromere ratio >= 2 (with average MET GCN >= 4), high MET GCN as CGN >= 5 and MET IHC + as >= 2 + intensity in >= 50% of tumor cells. A total of 182 MET IHC + and EGFR/KRAS WT tumors were analyzed for METex14 skipping mutation.Results: MET IHC+ was found in 23.8% of 2432 patients, significantly associated with female gender, small tumor size, and adenocarcinoma histology. We observed a high inter-laboratory variability in IHC and SISH analysis. MET amplification prevailed in 4.6% and MET GCN >= 5 in 4.1% of 1572 patients. MET amplification and MET GCN >= 5 were not significantly associated with any tumor characteristics or stage. Both were significantly associated with IHC MET positivity (p Conclusion: MET overexpression is found in 23.8% of surgically resected NSCLC. MET amplification prevails in 4.6% and is associated with MET overexpression. Both have no influence on prognosis. The large inter-laboratory variability in IHC highlights the challenge of MET IHC analysis in routine practice.