Repeat Next-Generation Sequencing (15-Gene Panel) in Unifocal, Synchronous, and Metachronous Non-Small-Cell Lung Cancer-A Single-Center Experience.

In advanced non-squamous non-small-cell lung cancer (NSCLC), routine testing with next-generation sequencing (NGS) is recommended to identify actionable genomic alterations (AGAs). The therapeutic implications of repeated NGS testing on synchronous and metachronous tumors are unclear. Between February 2017 and October 2020, NSCLC samples from a single institution were reflex-tested using a targeted 15-gene NGS panel (TruSight Tumor 15, Illumina). Thirty-eight patients were identified with multiple NGS results from 82 samples: 11% were from single unifocal, 51% were from synchronous, and 38% were from metachronous tumors. Changes in EGFR, KRAS, PI3KCA, and TP53 variants were found in 22 patients' samples (58%). No changes were seen with longitudinal testing of multiple samples from single unifocal tumors, while changes were observed in 60% of synchronous and 71% of metachronous tumors. Of these, 26% of patients had AGA differences between samples. Acknowledging the limited sample size, a significant difference in overall survival was observed between synchronous separate primaries and metastasis. Repeat NGS testing of synchronous and metachronous NSCLC tumors may identify differing variants in >50% of patients. These changes may reflect separate primary lung carcinomas, tumor heterogeneity among intrapulmonary metastases, and clonal evolution. NGS testing of multiple tumors may enhance the identification of therapeutic targets for treatment decisions.

Treatment patterns and outcomes in KRASG12C-positive advanced NSCLC patients previously treated with immune checkpoint inhibitors: A Canada-wide real-world, multi-center, retrospective cohort study.

OBJECTIVES: KRAS mutations, particularly KRASG12C, are prevalent in non-small cell lung cancer (NSCLC). Immune checkpoint inhibitors (ICIs) have been a frontline treatment, but recently developed KRASG12C-selective inhibitors, such as sotorasib, present new therapeutic options. We conducted a multi-center retrospective cohort study to gain insights into real-world treatment patterns and outcomes in patients with KRASG12C-positive advanced NSCLC receiving systemic therapy post-ICI treatment. METHODS: From the CAnadian CAncers With Rare Molecular Alterations-Basket Real-world Observational Study (CARMA-BROS), a cohort of 102 patients with KRASG12C-positive advanced NSCLC across 9 Canadian centers diagnosed between 2015 and 2021 was analyzed. Clinico-demographic and treatment data were obtained from electronic health records. Survival outcomes were assessed using Kaplan-Meier curves and Cox proportional hazards models. RESULTS: The patients (median age 66 years; 58 % female; 99 % current/former tobacco exposure; 59 % PD-L1 ≥ 50 %), exhibited heterogeneous treatment patterns post-ICI. Most patients received ICIs as a first-line therapy, with varying subsequent lines including chemotherapy and targeted therapy. In patients receiving systemic therapy post-ICI, median overall survival was 12.6 months, and real-world progression-free survival was 4.7 months. KRASG12C-selective targeted therapy post-ICI (n = 20) showed longer real-world progression-free survival compared to single-agent chemotherapy (aHR = 0.39, p = 0.012). CONCLUSION: This study contributes valuable real-world data on KRASG12C-positive advanced NSCLC post-ICI treatment. The absence of a standard treatment sequencing post-ICI underscores the need for further investigation and consensus-building in the evolving landscape of KRASG12C-targeted therapies.

Neurocognitive Adverse Events Related to Lorlatinib in Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis.

Lorlatinib has been FDA-approved as a systemic therapy for ALK/ROS1-positive non-small cell lung cancer (NSCLC) patients. However, it has been associated with an increased frequency of neurocognitive adverse events (NAEs). Therefore, we conducted a systematic review and meta-analysis to assess the NAEs related to lorlatinib therapy in NSCLC patients. PubMed, Scopus, the Cochrane Library, and prominent conference proceedings were searched for eligible studies of lorlatinib in NSCLC patients. NAEs included cognitive, mood, speech, and psychotic effects. A total of 1147 patients from 12 studies were included; 62% had brain metastases. A pooled analysis of NAEs showed frequencies of cognitive effects of 14.57% (95% CI, 8.37 to 24.14, I2 = 84%), mood effects of 11.17% (95% CI, 5.93 to 20.07, I2 = 84%), speech effects of 7.24% (95% CI, 3.39 to 15.20, I2 = 72%), and psychotic effects of 4.97% (95% CI, 3.27 to 7.49, I2 = 21%). Clinical trials reported a significantly higher frequency of mood effects than was indicated by real-world data. These results highlight the importance of educating patients and healthcare professionals about lorlatinib-related NAEs for early detection and management to improve NSCLC patients' quality of life.

Subcutaneous versus Intravenous Amivantamab, both in Combination with Lazertinib, in Refractory EGFR-mutated NSCLC: Primary Results from the Phase 3 PALOMA-3 Study.

PURPOSE: Phase 3 studies of intravenous amivantamab demonstrated efficacy across EGFR-mutated advanced non-small cell lung cancer (NSCLC). A subcutaneous formulation could improve tolerability and reduce administration time while maintaining efficacy. PATIENTS AND METHODS: Patients with EGFR-mutated advanced NSCLC who progressed following osimertinib and platinum-based chemotherapy were randomized 1:1 to receive subcutaneous or intravenous amivantamab, both combined with lazertinib. Co-primary pharmacokinetic noninferiority endpoints were trough concentrations (Ctrough; on cycle-2-day-1 or cycle-4-day-1) and cycle-2 area under the curve (AUCD1-D15). Key secondary endpoints were objective response rate (ORR) and progression-free survival (PFS). Overall survival (OS) was a predefined exploratory endpoint. RESULTS: Overall, 418 patients underwent randomization (subcutaneous group, n=206; intravenous group, n=212). Geometric mean ratios of Ctrough for subcutaneous to intravenous amivantamab were 1.15 (90% CI, 1.04-1.26) at cycle-2-day-1 and 1.42 (90% CI, 1.27-1.61) at cycle-4-day-1; the cycle-2 AUCD1-D15 was 1.03 (90% CI, 0.98-1.09). ORR was 30% in the subcutaneous and 33% in the intravenous group; median PFS was 6.1 and 4.3 months, respectively. OS was significantly longer in the subcutaneous versus intravenous group (hazard ratio for death, 0.62; 95% CI, 0.42-0.92; nominal P=0.02). Fewer patients in the subcutaneous group experienced infusion-related reactions (13% versus 66%) and venous thromboembolism (9% versus 14%) versus the intravenous group. Median administration time for first infusion was reduced to 4.8 minutes (range, 0-18) for subcutaneous amivantamab from 5 hours (range, 0.2-9.9) for intravenous amivantamab. During cycle-1-day-1, 85% and 52% of patients in the subcutaneous and intravenous groups, respectively, considered treatment convenient; end-of-treatment rates were 85% and 35%, respectively. CONCLUSION: Subcutaneous amivantamab-lazertinib demonstrated noninferiority to intravenous amivantamab-lazertinib, offering a consistent safety profile with reduced infusion-related reactions, increased convenience, and prolonged survival.

Immediate Versus Deferred Systemic Therapy in Patients With Mesothelioma.

BACKGROUND: The 2018 ASCO pleural mesothelioma (PM) treatment guideline states that "a trial of expectant observation may be offered" in patients with asymptomatic inoperable epithelioid mesothelioma with low disease burden. The aim of our analysis was to evaluate clinical characteristics and outcomes in PM-patients managed with initial observation and deferred treatment initiation. METHODS: We retrospectively collected clinicodemograhic and outcome data of patients with inoperable PM. Patients were assigned to 2 treatment decision groups: decision to start immediate systemic treatment (Immediate Treatment Group) versus observation and deferring treatment (Deferred Treatment group). RESULTS: Of 222 patients with advanced PM, systemic treatment was started immediately in the majority of patients (189, 85%; immediate group); treatment was deferred in 33 (15%) patients (deferred group); systemic therapy was chemotherapy-based in 91% and 79% respectively. Patients in the deferred group were older (70 vs 67 years, p = .05), less likely to have stage IV disease (28% vs. 51%, p = .08) and more often had epithelioid histology (90% vs. 70%, p = .03). Nineteen patients (58%) in the deferred group eventually received treatment. With a median follow-up time of 10.9 months median overall survival (OS) in the entire cohort was 12.4 months and was significantly longer in the deferred group (20.6 months vs. 11.5 months, p = .02). No difference in median progression-free survival (PFS) in first-line treatment between groups was seen (5.4 and 5.3 months). CONCLUSION: This real-world analysis suggests that deferral of systemic therapy and close observation may not impact OS or physician-assessed PFS in selected PM-patients.

Recommendations for reporting tissue and circulating tumour (ct)DNA next-generation sequencing results in non-small cell lung cancer.

Non-small cell lung cancer is a heterogeneous disease and molecular characterisation plays an important role in its clinical management. Next-generation sequencing-based panel testing enables many molecular alterations to be interrogated simultaneously, allowing for comprehensive identification of actionable oncogenic drivers (and co-mutations) and appropriate matching of patients with targeted therapies. Despite consensus in international guidelines on the importance of broad molecular profiling, adoption of next-generation sequencing varies globally. One of the barriers to its successful implementation is a lack of accepted standards and guidelines specifically for the reporting and clinical annotation of next-generation sequencing results. Based on roundtable discussions between pathologists and oncologists, we provide best practice recommendations for the reporting of next-generation sequencing results in non-small cell lung cancer to facilitate its use and enable easy interpretation for physicians. These are intended to complement existing guidelines related to the use of next-generation sequencing (solid and liquid). Here, we discuss next-generation sequencing workflows, the structure of next-generation sequencing reports, and our recommendations for best practice thereof. The aim of these recommendations and considerations is ultimately to ensure that reports are fully interpretable, and that the most appropriate treatment options are selected based on robust molecular profiles in well-defined reports.

Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2024.1.

Living guidelines are developed for selected topic areas with rapidly evolving evidence that drives frequent change in recommended clinical practice. Living guidelines are updated on a regular schedule by a standing expert panel that systematically reviews the health literature on a continuous basis, as described in the ASCO Guidelines Methodology Manual. ASCO Living Guidelines follow the ASCO Conflict of Interest Policy Implementation for Clinical Practice Guidelines. Living Guidelines and updates are not intended to substitute for independent professional judgment of the treating provider and do not account for individual variation among patients. See appendix for disclaimers and other important information (Appendix 1 and Appendix 2). Updates are published regularly and can be found at https://ascopubs.org/nsclc-da-living-guideline.

Real-World Outcomes of Patients with Advanced Epidermal Growth Factor Receptor-Mutated Non-Small Cell Lung Cancer in Canada Using Data Extracted by Large Language Model-Based Artificial Intelligence.

Real-world evidence for patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC) in Canada is limited. This study's objective was to use previously validated DARWENTM artificial intelligence (AI) to extract data from electronic heath records of patients with non-squamous NSCLC at University Health Network (UHN) to describe EGFR mutation prevalence, treatment patterns, and outcomes. Of 2154 patients with NSCLC, 613 had advanced disease. Of these, 136 (22%) had common sensitizing EGFR mutations (cEGFRm; ex19del, L858R), 8 (1%) had exon 20 insertions (ex20ins), and 338 (55%) had EGFR wild type. One-year overall survival (OS) (95% CI) for patients with cEGFRm, ex20ins, and EGFR wild type tumours was 88% (83, 94), 100% (100, 100), and 59% (53, 65), respectively. In total, 38% patients with ex20ins received experimental ex20ins targeting treatment as their first-line therapy. A total of 57 patients (36%) with cEGFRm received osimertinib as their first-line treatment, and 61 (39%) received it as their second-line treatment. One-year OS (95% CI) following the discontinuation of osimertinib was 35% (17, 75) post-first-line and 20% (9, 44) post-second-line. In this real-world AI-generated dataset, survival post-osimertinib was poor in patients with cEGFR mutations. Patients with ex20ins in this cohort had improved outcomes, possibly due to ex20ins targeting treatment, highlighting the need for more effective treatments for patients with advanced EGFRm NSCLC.

Cabozantinib Response in a Patient With NSCLC Harboring Both MET Exon 14 Skipping Mutation and Secondary RET Fusion: A Case Report.

MET exon 14 skipping mutation has emerged as a new oncogenic driver in NSCLC with available targeted therapies, including Food and Drug Administration-approved inhibitors capmatinib and tepotinib. Potential resistance mechanisms are beginning to be described and include several on-target and off-target mutations. Here, we report an emergent secondary RET fusion in a patient with a primary MET exon 14 skipping mutation that progressed on capmatinib after the initial response. Subsequently, this patient received both a RET inhibitor (selpercatinib) followed by another MET-targeted treatment (tepotinib) without clinical benefit. Thereafter, cabozantinib, a multikinase inhibitor with activity against RET and MET was started with a rapid clinical and radiologic benefit.

Screening for lung cancer with computed tomography: protocol for systematic reviews for the Canadian Task Force on Preventive Health Care.

PURPOSE: Lung cancer is the leading cause of cancer deaths in Canada, and because early cancers are often asymptomatic screening aims to prevent mortality by detecting cancer earlier when treatment is more likely to be curative. These reviews will inform updated recommendations by the Canadian Task Force on Preventive Health Care on screening for lung cancer. METHODS: We will update the review on the benefits and harms of screening with CT conducted for the task force in 2015 and perform de novo reviews on the comparative effects between (i) trial-based selection criteria and use of risk prediction models and (ii) trial-based nodule classification and different nodule classification systems and on patients' values and preferences. We will search Medline, Embase, and Cochrane Central (for questions on benefits and harms from 2015; comparative effects from 2012) and Medline, Scopus, and EconLit (for values and preferences from 2012) via peer-reviewed search strategies, clinical trial registries, and the reference lists of included studies and reviews. Two reviewers will screen all citations (including those in the previous review) and base inclusion decisions on consensus or arbitration by another reviewer. For benefits (i.e., all-cause and cancer-specific mortality and health-related quality of life) and harms (i.e., overdiagnosis, false positives, incidental findings, psychosocial harms from screening, and major complications and mortality from invasive procedures as a result of screening), we will include studies of adults in whom lung cancer is not suspected. We will include randomized controlled trials comparing CT screening with no screening or alternative screening modalities (e.g., chest radiography) or strategies (e.g., CT using different screening intervals, classification systems, and/or patient selection via risk models or biomarkers); non-randomized studies, including modeling studies, will be included for the comparative effects between trial-based and other selection criteria or nodule classification methods. For harms (except overdiagnosis) we will also include non-randomized and uncontrolled studies. For values and preferences, the study design may be any quantitative design that either directly or indirectly measures outcome preferences on outcomes pertaining to lung cancer screening. We will only include studies conducted in Very High Human Development Countries and having full texts in English or French. Data will be extracted by one reviewer with verification by another, with the exception of result data on mortality and cancer incidence (for calculating overdiagnosis) where duplicate extraction will occur. If two or more studies report on the same comparison and it is deemed suitable, we will pool continuous data using a mean difference or standardized mean difference, as applicable, and binary data using relative risks and a DerSimonian and Laird model unless events are rare (< 1%) where we will pool odds ratios using Peto's method or (if zero events) the reciprocal of the opposite treatment arm size correction. For pooling proportions, we will apply suitable transformation (logit or arcsine) depending on the proportions of events. If meta-analysis is not undertaken we will synthesize the data descriptively, considering clinical and methodological differences. For each outcome, two reviewers will independently assess within- and across-study risk of bias and rate the certainty of the evidence using GRADE (Grading of Recommendations Assessment, Development, and Evaluation), and reach consensus. DISCUSSION: Since 2015, additional trials and longer follow-ups or additional data (e.g., harms, specific patient populations) from previously published trials have been published that will improve our understanding of the benefits and harms of screening. The systematic review of values and preferences will allow fulsome insights that will inform the balance of benefits and harms. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022378858.

Therapy for Stage IV Non-Small Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, Version 2023.3.

PURPOSE: To provide evidence-based recommendations for patients with stage IV non-small cell lung cancer (NSCLC) without driver alterations. METHODS: This ASCO living guideline offers continually updated recommendations based on an ongoing systematic review of randomized clinical trials (RCTs), with the latest time frame spanning February to October 2023. An Expert Panel of medical oncology, pulmonary, community oncology, research methodology, and advocacy experts were convened. The literature search included systematic reviews, meta-analyses, and randomized controlled trials. Outcomes of interest include efficacy and safety. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations. RESULTS: This guideline consolidates all previous updates and reflects the body of evidence informing this guideline topic. Ten new RCTs were identified in the latest search of the literature to date. RECOMMENDATIONS: Evidence-based recommendations were updated to address first, second, and subsequent treatment options for patients without driver alterations.Additional information is available at www.asco.org/living-guidelines.

Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2023.3.

PURPOSE: To provide evidence-based recommendations for patients with stage IV non-small cell lung cancer with driver alterations. METHODS: This ASCO living guideline offers continually updated recommendations based on an ongoing systematic review of randomized clinical trials (RCTs), with the latest time frame spanning February to October 2023. An Expert Panel of medical oncology, pulmonary, community oncology, research methodology, and advocacy experts were convened. The literature search included systematic reviews, meta-analyses, and randomized controlled trials. Outcomes of interest include efficacy and safety. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations. RESULTS: This guideline consolidates all previous updates and reflects the body of evidence informing this guideline topic. Eight new RCTs were identified in the latest search of the literature to date. RECOMMENDATIONS: Evidence-based recommendations were updated to address first, second, and subsequent treatment options for patients based on targetable driver alterations.Additional information is available at www.asco.org/living-guidelines.

The Perceived Value of Liquid Biopsy: Results From a Canadian Validation Study of Circulating Tumor DNA T790M Testing-Patient's Willingness-to-Pay: A Brief Report.

Introduction: Liquid biopsy is recommended to diagnose molecular resistance to targeted therapy in patients with lung cancer. Nevertheless, not all jurisdictions provide funding and patient access. We report patients' perceived value of liquid biopsy in targeted therapy resistance. Methods: Canadian patients participating in a national EGFR T790M liquid biopsy validation study completed structured interviews measuring perceived value and willingness-to-pay for plasma circulating tumor DNA testing as an alternative to tumor biopsy using open-ended and iterative bidding approaches. Results: A total of 60 patients with advanced lung cancer participated with a median age of 64 years (range: 31-87 y); 69% were Asian and 45% female. All had received prior EGFR tyrosine kinase inhibitor; 17% also received chemotherapy. All patients preferred to have plasma testing over repeat tumor biopsy. In the context of the Canadian publicly funded system, patients estimated that a median of 300 (interquartile range: 150-800) Canadian dollars was a reasonable price to pay for liquid biopsy. Patients were personally willing to pay a median 100 (interquartile range: 33-350) Canadian dollars. Conclusions: In a system that covers the cost of standard diagnostic tests, patients with lung cancer indicated high willingness-to-pay out-of-pocket for liquid biopsy in the setting of acquired targeted therapy resistance. Patients have high perceived value of plasma genotyping and prefer it to repeat tumor biopsy.

Matching-adjusted indirect comparison of amivantamab vs mobocertinib in platinum-pretreated EGFR Exon 20 insertion-mutated non-small-cell lung cancer.

Aim: We assessed relative efficacy and safety of amivantamab versus mobocertinib in patients with non-small-cell lung cancer with EGFR exon 20 insertion (exon20ins) mutations who progressed on prior platinum-based chemotherapy. Materials & methods: This matching-adjusted indirect comparison used patient-level data from CHRYSALIS (NCT02609776) and aggregate data from a mobocertinib trial (NCT02716116) to match populations on all clinically relevant confounders. Results: While both agents had similar efficacy for time-to-event outcomes, objective response rate was significantly higher for amivantamab. 15 of 23 any-grade treatment-related adverse events reported for mobocertinib were significantly less common for amivantamab versus only two for mobocertinib. Conclusion: Results suggest that amivantamab has an improved response rate with similar survival and a more favorable safety profile versus mobocertinib in EGFR exon20ins non-small-cell lung cancer.

The Use of Wearable Devices in Oncology Patients: A Systematic Review.

INTRODUCTION: The aim of this systematic review was to summarize the current literature on wearable technologies in oncology patients for the purpose of prognostication, treatment monitoring, and rehabilitation planning. METHODS: A search was conducted in Medline ALL, Cochrane Central Register of Controlled Trials, Embase, Emcare, CINAHL, Scopus, and Web of Science, up until February 2022. Articles were included if they reported on consumer grade and/or non-commercial wearable devices in the setting of either prognostication, treatment monitoring or rehabilitation. RESULTS: We found 199 studies reporting on 18 513 patients suitable for inclusion. One hundred and eleven studies used wearable device data primarily for the purposes of rehabilitation, 68 for treatment monitoring, and 20 for prognostication. The most commonly-reported brands of wearable devices were ActiGraph (71 studies; 36%), Fitbit (37 studies; 19%), Garmin (13 studies; 7%), and ActivPAL (11 studies; 6%). Daily minutes of physical activity were measured in 121 studies (61%), and daily step counts were measured in 93 studies (47%). Adherence was reported in 86 studies, and ranged from 40% to 100%; of these, 63 (74%) reported adherence in excess of 80%. CONCLUSION: Wearable devices may provide valuable data for the purposes of treatment monitoring, prognostication, and rehabilitation. Future studies should investigate live-time monitoring of collected data, which may facilitate directed interventions.