Faculty Bibliography

OBJECTIVES/OBJECTIVE:Effective therapy for non-small-cell lung cancer (NSCLC) depends on morphological and genomic classification, with comprehensive screening for guideline-recommended biomarkers critical to guide treatment. Companion diagnostics, which provide robust genotyping results, represent an important component of personalized oncology. We evaluated the clinical validity of Guardant360 CDx as a companion diagnostic for sotorasib for detection of KRAS p.G12C, an important oncogenic NSCLC driver mutation. MATERIALS AND METHODS/METHODS:KRAS p.G12C was tested in NSCLC patients from CodeBreaK100 (NCT03600833) in pretreatment plasma samples using Guardant360 CDx liquid biopsy and archival tissue samples using therascreen® KRAS RGQ polymerase chain reaction (PCR) kit tissue testing. Matched tissue and plasma samples were procured from other clinical trials or commercial vendors, and results were compared. Demographics and clinical characteristics and objective response rate (ORR) were evaluated. RESULTS:Of 126 CodeBreaK patients, 112 (88.9%) were tested for KRASp.G12C mutations with Guardant360 CDx. Among 189 patients in the extended analysis cohort, the positive and negative percent agreement (95% CI) for Guardant360 CDx plasma testing relative to therascreen® KRAS RGQ PCR kit tissue testing were 0.71 (0.62, 0.79) and 1.00 (0.95, 1.00), respectively; overall percent agreement (95% CI) was 0.82 (0.76, 0.87). TP53 co-mutations were the most common regardless of KRAS p.G12C status (KRAS p.G12C-positive, 53.4%; KRAS p.G12C-negative, 45.5%). STK11 was co-mutated in 26.1% of KRAS p.G12C-positive samples. The ORR was similar among patients selected by plasma and tissue testing. CONCLUSION/CONCLUSIONS:Comprehensive genotyping for all therapeutic targets including KRAS p.G12C is critical for management of NSCLC. Liquid biopsy using Guardant360 CDx has clinical validity for identification of patients with KRASp.G12C-mutant NSCLC and, augmented by tissue testing methodologies as outlined on the approved product label, will identify patients for treatment with sotorasib.

Our aim was to evaluate real-world time on treatment (rwToT), overall and by KRAS mutation status, with first-line pembrolizumab monotherapy for advanced non-small cell lung cancer (NSCLC) in real-world oncology practice in the US. rwToT is a readily available, intermediate-range endpoint that is moderately to highly correlated with overall survival in clinical trials and real-world data. Using deidentified electronic medical record data, we studied patients with ECOG performance status (PS) of 0-2 who initiated pembrolizumab (1 November 2016 to 31 March 2020) for advanced NSCLC with programmed death-ligand 1 (PD-L1) expression ≥ 50% and without EGFR/ALK/ROS1 genomic alterations. The data cutoff was 31 March 2021, and the median study follow-up was 34 months. The Kaplan-Meier median rwToT with first-line pembrolizumab monotherapy was 7.4 months (95% CI, 6.3-8.1) for 807 patients with PS 0-1, which was consistent with the median treatment duration in the KEYNOTE-024 trial (7.9 months). The median rwToT for 237 patients with PS 2 was 2.1 months (95% CI, 1.4-2.8). For those with KRAS-mutated and KRAS wild-type nonsquamous NSCLC and PS 0-1, the median rwToT was 7.6 months and 7.0 months, respectively. Our findings suggest long-term benefit of first-line pembrolizumab monotherapy for advanced NSCLC with PD-L1 expression ≥ 50% in real-world settings in the US, particularly for patients with good performance status at the start of therapy, irrespective of KRAS status.

The successful use of artificial intelligence (AI) for diagnostic purposes has prompted the application of AI-based cancer imaging analysis to address other, more complex, clinical needs. In this Perspective, we discuss the next generation of challenges in clinical decision-making that AI tools can solve using radiology images, such as prognostication of outcome across multiple cancers, prediction of response to various treatment modalities, discrimination of benign treatment confounders from true progression, identification of unusual response patterns and prediction of the mutational and molecular profile of tumours. We describe the evolution of and opportunities for AI in oncology imaging, focusing on hand-crafted radiomic approaches and deep learning-derived representations, with examples of their application for decision support. We also address the challenges faced on the path to clinical adoption, including data curation and annotation, interpretability, and regulatory and reimbursement issues. We hope to demystify AI in radiology for clinicians by helping them to understand its limitations and challenges, as well as the opportunities it provides as a decision-support tool in cancer management.

Declaration de liens d'interets: B. Besse : Research Funding-4D Pharma (Inst); Abbvie (Inst); Amgen (Inst); Aptitude Health (Inst); AstraZeneca (Inst); BeiGene (Inst); Blueprint Medicines (Inst); Boehringer Ingelheim (Inst); Bristol-Myers Squibb (Inst); Celgene (Inst); Cergentis (Inst); Cristal Therapeutics (Inst); Daiichi Sankyo (Inst); GlaxoSmithKline (Inst); Inivata (Inst); Janssen Oncology (Inst); Lilly (Inst); Onxeo (Inst); OSE Immunotherapeutics (Inst); Pfizer (Inst); Roche/Genentech (Inst); Sanofi (Inst); Takeda (Inst); Tolero Ph. F. Skoulidis : Honoraria-Bristol-Myers Squibb Research Funding-AIMM Therapeutics (I); Amgen (Inst) Travel, Accommodations, Expenses-Tango Therapeutics. B.T. Li : Amgen (Inst); AstraZeneca (Inst); Bolt Biotherapeutics (Inst); Daiichi Sankyo (Inst); GRAIL (Inst); Guardant Health (Inst); Hengrui Therapeutics (Inst); Lilly (Inst); MORE Health (Inst); Roche/Genentech (Inst)Karger Publishers-Book royalty; Shanghai Jiao Tong University Press-Book royalty; US62/514,661 (Inst); US62/685,057 (Inst)Jiangsu Hengrui Medicine; MORE Health; Boehringer Ingelheim; Genentech; Lilly. G. Ramaswamy : Honoraria-Abbvie; Genentech/Abbvie; Geneplus Consulting or Advisory Role-Abbvie; Achilles Therapeutics; Amgen; AstraZeneca/MedImmune; Bristol-Myers Squibb; Celgene; EMD Serono; Genentech/Roche; GlaxoSmithKline; Ignyta; Janssen; Jounce Therapeutics; Lilly; Merck Serono; Nektar; Pfizer; Phillips Gilmore Oncology; Roche. G.K. Dy : Honoraria-AstraZeneca/MedImmune; GlaxoSmithKline Consulting or Advisory Role-AstraZeneca; GlaxoSmithKline; Takeda Research Funding-AMGEN (Inst); AstraZeneca (Inst); Bristol-Myers Squibb (Inst); Tesaro (Inst). G. Shapiro : Almac Dc; Angiex; Artios; Astex Ph; Atrin Ph; Bayer; Bicycle Th; Boehringer Ingelheim; Concarlo; Cybrexa Th; CytomX Th; Daiichi; Sankyo; Fusion Ph; G1 Th; Ipsen; Lilly; Merck Serono; Pfizer; Roche; Seattle Gen; Sierra Oncology; Syros Ph; Zentalis; Aileron Th; Amgen; Array BioPharma; AstraZeneca; BMS; CanBas; Cellceutix; Clovis Oncology; Covidien; Curis; Cyclacel; Esperas Ph; Exelixis; Genentech; GSK; Immune Design; Millennium; Mirati Th; Novartis; PharmaMar; PTC Th; PumaBiotechnology; Sanofi; Tensha Th; Tesaro; Vertex. J. Bauml : Consulting or Advisory Role-AstraZeneca; Ayala Pharmaceuticals; Boehringer Ingelheim; Bristol-Myers Squibb; Celgene; Foundation Medicine; Genentech; Guardant Health; Inivata; Janssen; Merck; Novartis; Novartis; Regeneron; Takeda Research Funding-Amgen (Inst); AstraZeneca (Inst); Bayer (Inst); Carevive Systems (Inst); Incyte (Inst); Janssen (Inst); Merck (Inst); Mirati Therapeutics (Inst); Novartis (Inst); Pfizer (Inst); Takeda (Inst). M.H. Schuler : Honoraria-Amgen; Boehringer Ingelheim; Bristol-Myers Squibb; Janssen-Cilag; Novartis; Roche Pharma AG Consulting or Advisory Role-Amgen; AstraZeneca; Boehringer Ingelheim; Bristol-Myers Squibb; GlaxoSmithKline; MorphoSys; Novartis; Roche; Takeda Research Funding-AstraZeneca (Inst); Boehringer Ingelheim (Inst); Bristol-Myers Squibb (Inst); Novartis (Inst) Patents, Royalties, Other Intellectual Property-Highly sensitive method for mutation detection by PCR (Inst). A. Addeo : Consulting or Advisory Role-Amgen; Astellas Pharma; AstraZeneca; Bristol-Myers Squibb; Lilly; MSD; Novartis; Pfizer; Roche. T. Kato : AZ; Boehringer Ingelheim; BMS; Chugai Pharma; Daiichi Sankyo; Lilly; Merck Serono; Merck Sharp & Dohme; Nippon Kayaku; Novartis; Ono Ph; Pfizer; Taiho Ph; Takeda; Lilly; Abbvie; Amgen; BMS; Regeneron; Taiho Pharmaceutical. A. Anderson : Employment-Amgen Stock and Other Ownership Interests-Amgen Patents, Royalties, Other Intellectual Property-I am listed as an inventor on several Amgen patents. I do not receive royalties on these patents. Travel, Accommodations, Expenses-Amgen. A. Ang : Employment-Amgen Stock and Other Ownership Interests-Amgen. G. Ngarmchamnanrith : Employment-Amgen Stock and Other Ownership Interests-Amgen. Q. Tran : Employment-Amgen Stock and Other Ownership Interests-Amgen. V. Velcheti : Consulting or Advisory Role-AstraZeneca/MedImmune; Boston Scientific; Bristol-Myers Squibb; EMD Serono; Foundation Medicine; GlaxoSmithKline; Lilly; Merck; Novartis; Novocure Research Funding-Alkermes (Inst); Altor BioScience (Inst); Atreca (Inst); Bristol-Myers Squibb (Inst); Eisai (Inst); Genentech (Inst); Genoptix (Inst); GlaxoSmithKline (Inst); Heat Biologics (Inst); Leap Therapeutics (Inst); Merck (Inst); NantWorks (Inst); OncoPlex Diagnostics (Inst); RSIP Vision (Inst); Trovagene.
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Objectives: Despite availability of new treatments, the prognosis of lung cancer remains poor. This study aims to provide recent estimates of survival in patients with advanced non-small cell lung cancer (NSCLC) in the US.
Method(s): The survival of patients with advanced NSCLC was estimated using two US databases together covering 2010-2020. The study included patients with stage III or IV NSCLC diagnosed between 2010-2016 in the Surveillance, Epidemiology, and End Results Program (SEER) database, and patients with stage IIIB, IIIC or IV NSCLC, diagnosed between 2017-2020, without known oncogenic driver mutations who had completed >=4 cycles of 1L treatment (restricted to platinum-based combinations, immuno-oncology monotherapy, or ipilimumab/nivolumab) in the Flatiron Health database, a US Oncology Electronic Medical Record database. Overall survival (OS) was defined as time from diagnosis of stage III or IV NSCLC to death or to date of last confirmed activity.
Result(s): A total of 49,298 and 133,395 patients with stage III and IV diagnosis respectively were identified in SEER. The 1-, 3- and 5-year OS for patients with Stage III disease were 55.1%, 26.3% and 17.5%, and for stage IV disease were 25.8%, 7.4% and 4.0%, respectively. The Flatiron database had 1,045 patients with stage IIIB, 130 patients with stage IIIC and 3,210 patients with stage IV disease at diagnosis. The 1- and 3-year OS for stage IIIB/IIIC disease were 72.5% and 36.4%, and for patients with stage IV disease were 65.9% and 24.6%, respectively.
Conclusion(s): Despite differences in study population characteristics between the two databases, the study shows that mortality in patients with advanced NSCLC remains high, underscoring the need for continued efforts to identify novel treatments and synergetic treatment combinations to improve patient outcomes.
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Objectives/UNASSIGNED:Immune checkpoint inhibitors (ICIs) of programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) have been rapidly adopted in US clinical practice for first-line therapy of metastatic non-small cell lung cancer (NSCLC) since regulatory approval in October 2016, and a better understanding is needed of long-term outcomes of ICI therapy administered in real-world settings outside of clinical trials. Our aim was to describe long-term outcomes of first-line pembrolizumab monotherapy at US oncology practices for patients with metastatic NSCLC, PD-L1 expression ≥50%, and good performance status. Methods/UNASSIGNED:genomic aberration, and ECOG performance status 0-1 who initiated first-line pembrolizumab monotherapy from 1-November-2016 to 31-March-2020 (EHR cohort, with data cutoff 31-March-2021) or from 1-December-2016 to 30-November-2017 (spotlight cohort, with data cutoff 31-August-2020). Kaplan-Meier analysis was used to determine overall survival (OS; both cohorts) and, for the spotlight cohort, real-world progression-free survival (rwPFS) and real-world tumor response (rwTR). Results/UNASSIGNED:The EHR cohort included 566 patients (298 [53%] men); the spotlight cohort included 228 (105 [46%] men); median age in both cohorts was 71. Median follow-up from pembrolizumab initiation to data cutoff was 35.1 months (range, 12.0-52.7) and 38.4 months (range, 33.1-44.9) in EHR and spotlight cohorts, respectively. Median OS was 19.6 months (95% CI, 16.6-24.3) and 21.1 months (95% CI, 16.2-28.9), respectively; 3-year OS rates were 36.2% and 38.2% in EHR and spotlight cohorts, respectively. In the spotlight cohort, median rwPFS was 7.3 months (95% CI, 5.7-9.2); 88 patients (38.6%; 95% CI, 32.2-45.2) experienced rwTR of complete or partial response. For 151/228 patients (66%) who discontinued pembrolizumab, the most common reasons were disease progression (70 [46%]) and therapy-related adverse effects (35 [23%]). Conclusions/UNASSIGNED:Real-world outcomes remain consistent with outcomes observed in clinical trials, supporting long-term benefits of first-line pembrolizumab monotherapy for patients with metastatic NSCLC, PD-L1 expression ≥50%, and good performance status.

Objective/UNASSIGNED:(AIS), minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma (INV). We sought to develop and evaluate a quantitative imaging method to determine invasiveness of small, ground-glass lesions on computed tomography (CT) chest scans. Methods/UNASSIGNED:N=162). Results/UNASSIGNED:(AUC=0.909, p<0.001). Conclusions/UNASSIGNED:radiomics to the routine visual assessment of CT scans help better differentiate adenocarcinoma subtypes and can aid in clinical decision making. Further prospective validation in this direction is warranted.

Many decades in the making, immunotherapy has demonstrated its ability to produce durable responses in several cancer types. In the last decade, immunotherapy has shown itself to be a viable therapeutic approach for non-small cell lung cancer (NSCLC). Several clinical trials have established the efficacy of immune checkpoint blockade (ICB), particularly in the form of anti-programmed death 1 (PD-1) antibodies, anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibodies and anti-programmed death 1 ligand (PD-L1) antibodies. Many trials have shown progression free survival (PFS) and overall survival (OS) benefit with either ICB alone or in combination with chemotherapy when compared to chemotherapy alone. The identification of biomarkers to predict response to immunotherapy continues to be evaluated. The future of immunotherapy in lung cancer continues to hold promise with the development of combination therapies, cytokine modulating therapies and cellular therapies. Lastly, we expect that innovative advances in technology, such as artificial intelligence (AI) and machine learning, will begin to play a role in the future care of patients with lung cancer.

Objectives/UNASSIGNED:The availability of immunotherapies has expanded the options for treating metastatic NSCLC, but information is needed regarding outcomes of immunotherapy for patients treated outside of clinical trials. The aim of this retrospective study was to evaluate the outcomes of therapy with first-line pembrolizumab plus pemetrexed and carboplatin (pembrolizumab-combination) for patients with metastatic nonsquamous NSCLC in the real-world setting of oncology clinics in the United States (US). Methods/UNASSIGNED:genomic alterations, who had received no previous systemic anticancer therapy. Eligible patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and initiated first-line pembrolizumab-combination therapy from 11-May-2017 to 31-January-2019; data cutoff was 31-August-2020. Patients treated in a clinical trial were excluded. Manual chart review supplemented technology-enabled abstraction to identify disease progression and tumor response. Time-to-event endpoints from initiation of pembrolizumab-combination therapy were determined using Kaplan-Meier. Results/UNASSIGNED:Of 377 patients with metastatic nonsquamous NSCLC, 105 (28%), 104 (28%), and 103 (27%) had programmed death-ligand 1 (PD-L1) expression ≥50%, 1-49%, and <1%, respectively; PD-L1 expression was not documented for 65 patients (17%). Median age was 66 years, and 227 patients (60%) were men. Median follow-up time from first-line therapy initiation to data cutoff was 31.2 months (range, 19.0-39.6 months). Median pembrolizumab real-world time on treatment (rwToT) was 5.8 months (95% CI, 5.0-6.7); 12- and 24-month on-treatment rates for pembrolizumab were 28.0% and 14.9%, respectively. Median overall survival (OS) was 17.2 months (95% CI, 13.6-19.9). For patients in PD-L1 expression ≥50%, 1-49%, <1%, and unknown cohorts, the 12-month survival rates were 66.0%, 58.5%, 54.5%, and 58.3%, respectively, and 24-month survival rates were 43.1%, 37.2%, 35.6%, and 42.0%, respectively. Median real-world progression-free survival was 6.2 months (95% CI, 5.5-7.1); and the real-world response rate was 39.3%, with median duration of response of 13.1 months (95% CI, 10.5-16.8). Conclusions/UNASSIGNED:-wild-type, metastatic nonsquamous NSCLC and good performance status who are treated at US community oncology clinics.

OBJECTIVE:Patients with non-small cell lung cancer (NSCLC) metastatic to the brain are living longer. The risk of new brain metastases when these patients stop systemic therapy is unknown. The authors hypothesized that the risk of new brain metastases remains constant for as long as patients are off systemic therapy. METHODS:A prospectively collected registry of patients undergoing radiosurgery for brain metastases was analyzed. Of 606 patients with NSCLC, 63 met the inclusion criteria of discontinuing systemic therapy for at least 90 days and undergoing active surveillance. The risk factors for the development of new tumors were determined using Cox proportional hazards and recurrent events models. RESULTS:The median duration to new brain metastases off systemic therapy was 16.0 months. The probability of developing an additional new tumor at 6, 12, and 18 months was 26%, 40%, and 53%, respectively. There were no additional new tumors 22 months after stopping therapy. Patients who discontinued therapy due to intolerance or progression of the disease and those with mutations in RAS or receptor tyrosine kinase (RTK) pathways (e.g., KRAS, EGFR) were more likely to develop new tumors (hazard ratio [HR] 2.25, 95% confidence interval [CI] 1.33-3.81, p = 2.5 × 10-3; HR 2.51, 95% CI 1.45-4.34, p = 9.8 × 10-4, respectively). CONCLUSIONS:The rate of new brain metastases from NSCLC in patients off systemic therapy decreases over time and is uncommon 2 years after cessation of cancer therapy. Patients who stop therapy due to toxicity or who have RAS or RTK pathway mutations have a higher rate of new metastases and should be followed more closely.