Faculty Bibliography

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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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/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.

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.

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.

Rearranged during transfection (RET) is involved in the physiological development of some organ systems. Activating RET alterations via either gene fusions or point mutations are potent oncogenic drivers in non-small cell lung cancer, thyroid cancer, and in multiple diverse cancers. RET-altered cancers were initially treated with multikinase inhibitors (MKIs). The efficacy of MKIs was modest at the expense of notable toxicities from their off-target activity. Recently, highly potent and RET-specific inhibitors selpercatinib and pralsetinib were successfully translated to the clinic and FDA approved. We summarize the current state-of-the-art therapeutics with preclinical and clinical insights of these novel RET inhibitors, acquired resistance mechanisms, and future outlooks.

Screening for therapeutic targets is standard of care in the management of advanced non-small cell lung cancer. However, most molecular assays utilize tumor tissue, which may not always be available. "Liquid biopsies" are plasma-based next generation sequencing (NGS) assays that use circulating tumor DNA to identify relevant targets. To compare the sensitivity, specificity, and accuracy of a plasma-based NGS assay to solid-tumor-based NGS we retrospectively analyzed sequencing results of 100 sequential patients with lung adenocarcinoma at our institution who had received concurrent testing with both a solid-tissue-based NGS assay and a commercially available plasma-based NGS assay. Patients represented both new diagnoses (79%) and disease progression on treatment (21%); the majority (83%) had stage IV disease. Tissue-NGS identified 74 clinically relevant mutations, including 52 therapeutic targets, a sensitivity of 94.8%, while plasma-NGS identified 41 clinically relevant mutations, a sensitivity of 52.6% (p < 0.001). Tissue-NGS showed significantly higher sensitivity and accuracy across multiple patient subgroups, both in newly diagnosed and treated patients, as well as in metastatic and nonmetastatic disease. Discrepant cases involved hotspot mutations and actionable fusions including those in EGFR, ALK, and NTRK1. In summary, tissue-NGS detects significantly more clinically relevant alterations and therapeutic targets compared to plasma-NGS, suggesting that tissue-NGS should be the preferred method for molecular testing of lung adenocarcinoma when tissue is available. Plasma-NGS can still play an important role when tissue testing is not possible. However, given its low sensitivity, a negative result should be confirmed with a tissue-based assay.