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INTRODUCTION: Cancer of unknown primary remains a challenging clinical entity. Despite receiving empiric chemotherapy, median overall survival is approximately 6-12 months. Site-specific therapy based on molecular characterization has been shown to improve outcomes; however, feasibility outside of clinical trials, especially in community centers, is lacking. This study explores the application of rapid next-generation sequencing in defining cancer of unknown primary and to identify therapeutic biomarkers. METHODS: A retrospective chart review was performed by identifying pathological samples designated cancer of unknown primary. Next-generation sequencing testing was based on an automated workflow utilizing the Genexus integrated sequencer, validated for clinical use. Genomic profiling was further integrated within a routine immunohistochemistry service, with results reported directly by anatomic pathologists. RESULTS: Between October 2020 and October 2021, 578 solid tumor samples underwent genomic profiling. Among this cohort, 40 were selected based on an initial diagnosis of cancer of unknown primary. The median (range) age at diagnosis was 70 (42-85) and 23 (57%) were female. Genomic data were used to support a site-specific diagnosis in 6 patients (15%). Median turnaround time was 3 business days (IQR: 1-5). Most common alterations identified were KRAS (35%), CDKN2A (15%), TP53 (15%), and ERBB2 (12%). Actionable molecular targeted therapies were identified in 23 (57%) patients, including alterations in BRAF, CDKN2A, ERBB2, FGFR2, IDH1, and KRAS. Immunotherapy-sensitizing mismatch repair deficiency was identified in 1 patient. CONCLUSION: This study supports the adoption of rapid next-generation sequencing among patients with cancer of unknown primary. We also demonstrate the feasibility of integration of genomic profiling with diagnostic histopathology and immunohistochemistry in a community practice setting. Diagnostic algorithms incorporating genomic profiling to better define cancer of unknown primary should be considered for future study.
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Neoplasias Primarias Desconocidas , Humanos , Femenino , Masculino , Neoplasias Primarias Desconocidas/diagnóstico , Neoplasias Primarias Desconocidas/genética , Neoplasias Primarias Desconocidas/terapia , Estudios Retrospectivos , Estudios de Factibilidad , Sistemas de Atención de Punto , Proteínas Proto-Oncogénicas p21(ras)/genética , Mutación , Genómica/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Biomarcadores de Tumor/genéticaRESUMEN
Aim: To examine whether tumor-specific and tumor-agnostic oncology trials produce comparable estimates of objective response rate (ORR) in BRAF-altered cancers. Materials & methods: Electronic database searches were performed to identify phase I-III clinical trials testing tyrosine kinase inhibitors from 2000 to 2021. A random-effects model was used to pool ORRs. A total of 22 cohorts from five tumor-agnostic trials and 41 cohorts from 27 tumor-specific trials had published ORRs. Results: There was no significant difference between pooled ORRs from either trial design for multitumor analyses (37 vs 50%; p = 0.05); thyroid cancer (57 vs 33%; p = 0.10); non-small-cell lung cancer (39 vs 53%; p = 0.18); or melanoma (55 vs 51%; p = 0.58). Conclusion: For BRAF-altered advanced cancers, tumor-agnostic trials do not yield substantially different results from tumor-specific trials.
Two types of studies were sought, including studies that measured health outcomes in patients who were selected to receive medicine based on the location of their cancer (tumor), called tumor-specific studies; and studies that measured health outcomes in patients who were selected to receive cancer medicine regardless of the location of their cancer (tumor), called tumor-agnostic studies. From the studies found, only the studies that tested a specific type of cancer medicine (called tyrosine kinase inhibitors) on cancers with a specific genetic alteration (called BRAF-altered cancers) were identified. These studies were included in the analysis. The goal of the analysis was to determine if the two types of studies gave similar estimates of response rate, which is a type of trial outcome that measures whether the cancer shrinks or disappears. To do this, the results from the tumor-specific studies were combined with the results of the tumor-agnostic studies. No meaningful differences in the results from the tumor-specific studies compared with the tumor-agnostic studies were found. This suggests that tumor-specific studies do not yield very different results from tumor-agnostic studies.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Melanoma , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Proteínas Proto-Oncogénicas B-raf , Neoplasias Pulmonares/patología , Oncología MédicaRESUMEN
BACKGROUND: Small cell lung cancer (SCLC) represents approximately 15% of lung cancers, and approximately 70% are diagnosed as extensive-stage SCLC (ES-SCLC). Although ES-SCLC is highly responsive to chemotherapy, patients typically progress rapidly, and there is an urgent need for new therapies. Immune checkpoint inhibitors (ICIs) have recently been investigated in SCLC, and this review provides guidance on the use of these agents in ES-SCLC based on phase III evidence. METHODS: Published and presented literature on phase III data addressing use of ICIs in ES-SCLC was identified using the key search terms "small cell lung cancer" AND "checkpoint inhibitors" (OR respective aliases). Directed searches of eligible studies were periodically performed to ensure capture of the most recent data. RESULTS: Six phase III trials were identified, with four assessing the benefits of ICIs plus chemotherapy first-line, one evaluating ICIs as first-line therapy maintenance, and one assessing ICI monotherapy after progression on platinum-based chemotherapy. The addition of ipilimumab or tremelimumab to first-line treatment or as first-line maintenance did not improve survival. Two out of three studies combining PD-1/PD-L1 inhibitors with first-line platinum-based chemotherapy demonstrated significant long-lasting survival benefits and improved quality of life with no unexpected safety concerns. PD-1/PD-L1 inhibitors as first-line maintenance or in later lines of therapy did not improve survival. Biomarker research is ongoing as well as research into the role of ICIs in combination with radiation therapy in limited-stage SCLC. CONCLUSION: The addition of atezolizumab or durvalumab to first-line platinum-based chemotherapy for ES-SCLC prolongs survival and improves quality of life. IMPLICATIONS FOR PRACTICE: Platinum-based chemotherapy has been standard of care for extensive-stage small cell lung cancer (ES-SCLC) for more than a decade. Six recent phase III trials investigating immune checkpoint inhibitors (ICIs) have clarified the role of these agents in this setting. Although ICIs were assessed first-line, as first-line maintenance, and in later lines of therapy, the additions of atezolizumab or durvalumab to first-line platinum-based chemotherapy were the only interventions that significantly improved overall survival and increased quality of life. These combinations should therefore be considered standard therapy for first-line ES-SCLC. Biomarker research and investigations into the role of ICIs for limited-stage disease are ongoing.
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Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Humanos , Inhibidores de Puntos de Control Inmunológico , Inmunoterapia , Neoplasias Pulmonares/tratamiento farmacológico , Calidad de Vida , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológicoRESUMEN
Aim: Osimertinib is a third-generation, irreversible, oral EGFR tyrosine kinase inhibitor. We report real-world effectiveness and safety data. Patients & methods: EGFR T790M positive advanced non-small-cell lung cancer adults, who received ≥1 prior EGFR tyrosine kinase inhibitor, received osimertinib 80 mg daily. Primary effectiveness outcome: overall survival. Secondary effectiveness outcomes included: investigator-assessed clinical response, progression-free survival, time-to-treatment discontinuation. Results: At data cutoff, 3015 patients had enrolled: 57.1% had investigator-assessed response (95% CI: 55.2-58.9). Median progression-free survival: 11.1 months (95% CI: 11.0-12.0) and median time-to-treatment discontinuation: 13.5 months (95% CI: 12.6-13.9). Interstitial lung disease/pneumonitis-like events reported in 28 (1%) patients. Conclusion: Osimertinib demonstrated clinical effectiveness similar to efficacy observed in the clinical trial program with no new safety signals.
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Acrilamidas/uso terapéutico , Compuestos de Anilina/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Mutación , Acrilamidas/administración & dosificación , Acrilamidas/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Sustitución de Aminoácidos , Compuestos de Anilina/administración & dosificación , Compuestos de Anilina/efectos adversos , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Receptores ErbB/genética , Femenino , Humanos , Estimación de Kaplan-Meier , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéutico , Resultado del TratamientoRESUMEN
PURPOSE: Afatinib is a standard first-line therapy for advanced EGFR-positive NSCLC. We implemented a pharmacist-led proactive follow-up algorithm to identify and manage early afatinib-related adverse events (AEs). METHODS: We conducted a retrospective chart review of all patients treated with afatinib after implementation of the algorithm at the Sunnybrook Odette Cancer Centre (Toronto, ON, Canada) from April 1, 2015 to July 31, 2016. Our in-house algorithm involved consultations in person and proactive pharmacist-led callbacks on days 5, 10, and 17. All AEs were graded and documented in real time and management based on toxicity grade was standardized. This study evaluated the impact of our algorithm on real-world AEs. RESULTS AND DISCUSSION: Thirty-three patients were identified and reviewed. Median follow-up was 248 days. All patients experienced at least one drug-related AE; 18.2% were grade 3/4. The most common AEs were diarrhea 87.9%, rash 81.8%, stomatitis 57.6%, and paronychia 45.5%. Median dose of afatinib was 40 mg daily; 51.5% of patients had ≥ 1 dose reduction and 6.3% discontinued afatinib due to AEs. Proactive calls by the pharmacist identified 36.5% of all drug-related AEs, 33.3% of grade 3/4 AEs, 58.1% of first drug-related AEs and identified two patients that were non-compliant. Only 3.2% of AEs were identified by an emergency room/urgent clinic visit. CONCLUSIONS: This proactive multi-disciplinary AE management algorithm resulted in a low rate of urgent assessments and discontinuation due to toxicity while maintaining afatinib at ideal dose, thus providing a useful tool for centers prescribing afatinib.
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Afatinib/efectos adversos , Algoritmos , Antineoplásicos/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Afatinib/administración & dosificación , Anciano , Antineoplásicos/administración & dosificación , Canadá , Diarrea/inducido químicamente , Receptores ErbB/antagonistas & inhibidores , Exantema/inducido químicamente , Femenino , Humanos , Masculino , Persona de Mediana Edad , Quinazolinas/efectos adversos , Estudios RetrospectivosRESUMEN
Liquid biopsy is rapidly becoming an indispensable tool in the oncologist's arsenal; however, this technique remains elusive in a publicly funded healthcare system, and real-world evidence is needed to demonstrate utility and feasibility. Here, we describe the first experience of an in-house point of care liquid biopsy program at a Canadian community hospital. A retrospective review of consecutive cases that underwent plasma-based next-generation sequencing (NGS) was conducted. Liquid biopsy was initiated at the discretion of clinicians. Sequencing followed a point of care workflow using the Genexus™ integrated sequencer and the Oncomine precision assay, performed by histotechnologists. Results were reported by the attending pathologist. Eligible charts were reviewed for outcomes of interest, including the intent of the liquid biopsy, results of the liquid biopsy, and turnaround time from blood draw to results available. A total of 124 cases, with confirmed or suspected cancer, underwent liquid biopsy between January 2021 and November 2023. The median turnaround time for liquid biopsy results was 3 business days (range 1-12 days). The sensitivity of liquid biopsies was 71%, compared to tissue testing in cases with matched tissue results available for comparison. Common mutations included EGFR (29%), in 86 lung cancer patients, and PIK3CA (22%), identified in 13 breast cancer patients. Healthcare providers ordered liquid biopsies to inform diagnostic investigations and treatment decisions, and to determine progression or resistance mechanisms, as these reasons often overlapped. This study demonstrates that rapid in-house liquid biopsy using point of care methodology is feasible. The technique facilitates precision treatment and offers many additional advantages for cancer care.
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Considerable variety in how patients respond to treatments, driven by differences in their geno- and/ or phenotypes, calls for a more tailored approach. This is already happening, and will accelerate with developments in personalized medicine. However, its promise has not always translated into improvements in patient care due to the complexities involved. There are also concerns that advice for tests has been reversed, current tests can be costly, there is fragmentation of funding of care, and companies may seek high prices for new targeted drugs. There is a need to integrate current knowledge from a payer's perspective to provide future guidance. Multiple findings including general considerations; influence of pharmacogenomics on response and toxicity of drug therapies; value of biomarker tests; limitations and costs of tests; and potentially high acquisition costs of new targeted therapies help to give guidance on potential ways forward for all stakeholder groups. Overall, personalized medicine has the potential to revolutionize care. However, current challenges and concerns need to be addressed to enhance its uptake and funding to benefit patients.
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Atención a la Salud/métodos , Atención al Paciente/métodos , Medicina de Precisión/métodos , Atención a la Salud/tendencias , Estudios de Factibilidad , Predicción , Humanos , Atención al Paciente/tendencias , Farmacogenética/métodos , Farmacogenética/tendencias , Medicina de Precisión/tendenciasRESUMEN
Small-cell lung cancer (SCLC) is an aggressive, neuroendocrine tumour with high relapse rates, and significant morbidity and mortality. Apart from advances in radiation therapy, progress in the systemic treatment of SCLC had been stagnant for over three decades despite multiple attempts to develop alternative therapeutic options that could improve responses and survival. Recent promising developments in first-line and subsequent therapeutic approaches prompted a Canadian Expert Panel to convene to review evidence, discuss practice patterns, and reach a consensus on the treatment of extensive-stage SCLC (ES-SCLC). The literature search included guidelines, systematic reviews, and randomized controlled trials. Regular meetings were held from September 2022 to March 2023 to discuss the available evidence to propose and agree upon specific recommendations. The panel addressed biomarkers and histological features that distinguish SCLC from non-SCLC and other neuroendocrine tumours. Evidence for initial and subsequent systemic therapies was reviewed with consideration for patient performance status, comorbidities, and the involvement and function of other organs. The resulting consensus recommendations herein will help clarify evidence-based management of ES-SCLC in routine practice, help clinician decision-making, and facilitate the best patient outcomes.
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Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Humanos , Canadá , Terapia Combinada , Consenso , Neoplasias Pulmonares/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológicoRESUMEN
Activating mutations in Kirsten rat sarcoma viral oncogene homologue (KRAS), in particular, a point mutation leading to a glycine-to-cysteine substitution at codon 12 (G12C), are among the most frequent genomic alterations in non-small cell lung cancer (NSCLC). Several agents targeting KRAS G12C have recently entered clinical development. Sotorasib, a first-in-class specific small molecule that irreversibly inhibits KRAS G12C, has since obtained Health Canada approval. The emergence of novel KRAS-targeted therapies warrants the development of evidence-based consensus recommendations to help clinicians better understand and contextualize the available data. A Canadian expert panel was convened to define the key clinical questions, review recent evidence, and discuss and agree on recommendations for the treatment of advanced KRAS G12C-mutated NSCLC. The panel agreed that testing for KRAS G12C should be performed as part of a comprehensive panel that includes current standard-of-care biomarkers. Sotorasib, the only approved KRAS G12C inhibitor in Canada, is recommended for patients with advanced KRAS G12C-mutated NSCLC who progressed on guideline-recommended first-line standard of care for advanced NSCLC without driver alterations (immune-checkpoint inhibitor(s) [ICIs] +/- chemotherapy). Sotorasib could also be offered as second-line therapy to patients who progressed on ICI monotherapy that are not candidates for a platinum doublet and those that received first-line chemotherapy with a contraindication to ICIs. Preliminary data indicate the activity of KRAS G12C inhibitors in brain metastases; however, the evidence is insufficient to make specific recommendations. Regular liver function monitoring is recommended when patients are prescribed KRAS G12C inhibitors due to risk of hepatotoxicity.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Canadá , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Consenso , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Proteínas Proto-Oncogénicas p21(ras)/genéticaRESUMEN
Introduction: In the phase 3 KEYNOTE-604 study (NCT03066778), pembrolizumab plus etoposide and platinum chemotherapy (EP) significantly (p = 0.0023) improved progression-free survival versus placebo plus EP in previously untreated extensive-stage SCLC (ES-SCLC). We present health-related quality of life (HRQoL) results from KEYNOTE-604. Methods: Patients with stage IV SCLC were randomized 1:1 to pembrolizumab 200 mg or placebo every 3 weeks for 35 cycles plus four cycles of EP. Secondary end points included mean change from baseline to week 18 in the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire-Core 30 (QLQ-C30) global health status/quality of life (GHS/QoL) scale and time to deterioration in the composite outcome of cough, chest pain, or dyspnea from QLQ-C30 and QLQ-Lung Cancer Module 13. Two-sided, nominal p values are reported. Results: A total of 439 patients completed at least one QLQ-C30 and QLQ-Lung Cancer Module 13 assessment (pembrolizumab + EP, n = 221; placebo + EP, n = 218). GHS/QoL scores improved from baseline to week 18: least squares mean (95% confidence interval [CI]) changes were 8.7 (5.3-12.1) for pembrolizumab plus EP and 4.2 (0.9-7.5) for placebo plus EP. Between-group differences in least squares mean scores were improved for pembrolizumab plus EP (4.4 [95% CI: 0.2-8.7], p = 0.040]). Median time to deterioration for the composite end point was not reached and 8.7 (95% CI: 5.9-not reached) months, respectively (hazard ratio = 0.80 [95% CI: 0.56-1.14], p = 0.208). Conclusions: First-line pembrolizumab plus EP therapy maintained HRQoL in patients with ES-SCLC and may be associated with greater improvement than placebo plus EP. Together with the efficacy and safety findings in KEYNOTE-604, HRQoL data support the benefit of pembrolizumab in ES-SCLC.
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Intracranial metastatic disease (IMD) is a prevalent complication of cancer that significantly limits patient survival and quality of life. Over the past half-century, our understanding of the epidemiology and pathogenesis of IMD has improved and enabled the development of surveillance and treatment algorithms based on prognostic factors and tumor biomolecular characteristics. In addition to advances in surgical resection and radiation therapy, the treatment of IMD has evolved to include monoclonal antibodies and small molecule antagonists of tumor-promoting proteins or endogenous immune checkpoint inhibitors. Moreover, improvements in the sensitivity and specificity of imaging as well as the development of new serological assays to detect brain metastases promise to revolutionize IMD diagnosis. In this review, we will explore current treatment principles in patients with IMD, including the emerging role of targeted and immunotherapy in select primary cancers, and discuss potential areas for further investigation.
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BACKGROUND: The safety impact of radiotherapy (RT) timing relative to immune checkpoint inhibitors (ICIs) for advanced non-small-cell lung cancer (NSCLC) is unclear. We investigated if RT within 14 days (Interval 1) and 90 days (Interval 2) of ICI use is associated with toxicities compared to RT outside these intervals. METHODS: Advanced NSCLC patients treated with both RT and ICIs were reviewed. Toxicities were graded as per CTCAE v4.0 and attributed to either ICIs or RT by clinicians. Associations between RT timing and Grade ≥2 toxicities were analyzed using logistic regression models adjusted for patient, disease, and treatment factors (α = 0.05). RESULTS: Sixty-four patients were identified. Twenty received RT within Interval 1 and 40 within Interval 2. There were 20 Grade ≥2 toxicities in 18 (28%) patients; pneumonitis (6) and nausea (2) were most prevalent. One treatment-related death (immune encephalitis) was observed. Rates of patients with Grade ≥2 toxicities were 35%/25% in the group with/without RT within Interval 1 and 30%/25% in the group with/without RT within Interval 2. No significant association between RT timing relative to ICI use period and Grade ≥2 toxicities was observed. CONCLUSION: Albeit limited by the small sample size, the result suggested that pausing ICIs around RT use may not be necessary.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/radioterapiaRESUMEN
Purpose: Biomarker data are critical to the delivery of precision cancer care. The average turnaround of next-generation sequencing (NGS) reports is over 2 weeks, and in-house availability is typically limited to academic centers. Lengthy turnaround times for biomarkers can adversely affect outcomes. Traditional workflows involve moving specimens through multiple facilities. This study evaluates the feasibility of rapid comprehensive NGS using the Genexus integrated sequencer and a novel streamlined workflow in a community setting. Methods: A retrospective chart review was performed to assess the early experience and performance characteristics of a novel approach to biomarker testing at a large community center. This approach to NGS included an automated workflow utilizing the Genexus integrated sequencer, validated for clinical use. NGS testing was further integrated within a routine immunohistochemistry (IHC) service, utilizing histotechnologists to perform technical aspects of NGS, with results reported directly by anatomic pathologists. Results: Between October 2020 and October 2021, 578 solid tumor samples underwent genomic profiling. Median turnaround time for biomarker results was 3 business days (IQR: 2-5). Four hundred eighty-one (83%) of the cases were resulted in fewer than 5 business days, and 66 (11%) of the cases were resulted simultaneously with diagnosis. Tumor types included lung cancer (310), melanoma (97), and colorectal carcinoma (68), among others. NGS testing detected key driver alterations at expected prevalence rates: lung EGFR (16%), ALK (3%), RET (1%), melanoma BRAF (43%), colorectal RAS/RAF (67%), among others. Conclusion: This is the first study demonstrating clinical implementation of rapid NGS. This supports the feasibility of automated comprehensive NGS performed and interpreted in parallel with diagnostic histopathology and immunohistochemistry. This novel approach to biomarker testing offers considerable advantages to clinical cancer care.
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Neoplasias Pulmonares , Melanoma , Biomarcadores de Tumor/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Neoplasias Pulmonares/patología , Mutación , Sistemas de Atención de Punto , Estudios RetrospectivosRESUMEN
Non-small cell lung cancer (NSCLC) has historically been associated with a poor prognosis and low 5-year survival, but the use of targeted therapies in NSCLC has improved patient outcomes over the past 10 years. The pace of development of new targeted therapies is accelerating, with the associated need for molecular testing of new targetable alterations. As the complexity of biomarker testing in NSCLC increases, there is a need for guidance on how to manage the fluid standard-of-care in NSCLC, identify pragmatic molecular testing requirements, and optimize result reporting. An expert multidisciplinary working group with representation from medical oncology, pathology, and clinical genetics convened via virtual meetings to create consensus recommendations for testing of new targetable alterations in NSCLC. The importance of accurate and timely testing of all targetable alterations to optimize disease management using targeted therapies was emphasized by the working group. Therefore, the panel of experts recommends that all targetable alterations be tested reflexively at NSCLC diagnosis as part of a comprehensive panel, using methods that can detect all relevant targetable alterations. In addition, comprehensive biomarker testing should be performed at the request of the treating clinician upon development of resistance to targeted therapy. The expert multidisciplinary working group also made recommendations for reporting to improve clarity and ease of interpretation of results by treating clinicians and to accommodate the rapid evolution in clinical actionability of these alterations. Molecular testing of all targetable alterations in NSCLC is the key for treatment decision-making and access to new therapies. These consensus recommendations are intended as a guide to further optimize molecular testing of new targetable alterations.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Consenso , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologíaRESUMEN
The increased use of immune checkpoint inhibitors across cancer programs has created the need for standardized patient assessment, education, monitoring, and management of immune-related adverse events (irAEs). At William Osler Health System in Brampton, Ontario, a practical step-wise approach detailing the implementation of cancer immunotherapy in routine practice was developed. The approach focuses on four key steps: (1) identification of patient educators; (2) development of patient education materials; (3) development of patient monitoring tools; (4) involvement and education of multidisciplinary teams. Here, we provide an in-depth description of what was included in each step and how we integrated the different elements of the program. For each step, resources, tools, and materials that may be useful for patients, healthcare providers, and multidisciplinary teams were developed or modified based on existing materials. At our centre, the program led to improved patient comprehension of irAEs, the ability to act on symptoms (patient self-efficacy), and low rates of emergency room visits at first presentation for irAEs. We recognize that centres may need to tailor the approaches to their institutional policies and encourage centres to adapt and modify the forms and tools according to their needs and requirements.
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Inhibidores de Puntos de Control Inmunológico , Neoplasias , Servicio de Urgencia en Hospital , Humanos , Inmunoterapia/efectos adversos , Neoplasias/tratamiento farmacológico , OntarioRESUMEN
OBJECTIVES: The ADAURA trial demonstrated the benefit of adjuvant osimertinib among patients with resected, early-stage, epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC). To understand the potential population impact, it is critical to deduce the prevalence, management, and outcomes of this patient population in the real-world setting before use of adjuvant osimertinib. MATERIALS AND METHODS: Using PALEOS (Pan-cAnadian Lung cancEr Observational Study) data (2012-2019), a retrospective, multi-center, observational cohort study was conducted among patients with early-stage (IB-IIIA) resected NSCLC who had not received neoadjuvant therapy. Study outcomes included EGFRm prevalence, treatment patterns, recurrence outcomes, and overall and disease-free survival (OS/DFS). RESULTS: Among patients undergoing reflexive EGFRm testing by a pathologist at time of diagnosis irrespective of disease stage (N = 535), 23 % were EGFRm-positive; 15.9 % had common mutations and 5.6 % had uncommon mutations. Within the EGFRm-positive cohort (N = 156), mean age at diagnosis was 68 years, 65 % of patients were female, and 35 % were of Asian descent. At diagnosis, 48 %, 31 %, and 21 % had stage IB, II, or IIIA disease, respectively; 46 % received adjuvant therapy after resection. Half of patients experienced disease recurrence, typically involving distant sites; central nervous system metastasis varied from 12 % to 15.0 % across disease stages. EGFR tyrosine kinase inhibitors were the most commonly received therapy after first metastatic recurrence. Median OS (DFS) was not reached, 71.2 (22.8) months, and 50.1 (18.0) months among stage IB, II, and IIIA patients. Patients with uncommon EGFRm had a lower probability of survival than those with common EGFRm (2 years: 87 % vs 91 %-94 %; 4 years: 56 % vs 73 %-82 %). CONCLUSION: Approximately-one-quarter of patients with resected, early-stage NSCLC were EGFRm-positive in this study. These patients had high recurrence rates and suboptimal long-term survival after treatment with current therapies. New adjuvant treatments are warranted.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Humanos , Femenino , Masculino , Carcinoma de Pulmón de Células no Pequeñas/epidemiología , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Neoplasias Pulmonares/epidemiología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/cirugía , Estudios Retrospectivos , Prevalencia , Estadificación de Neoplasias , Quimioterapia Adyuvante , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Canadá/epidemiología , Receptores ErbB/genética , Mutación , Inhibidores de Proteínas Quinasas/efectos adversos , Carcinoma Pulmonar de Células Pequeñas/patologíaRESUMEN
The management of Stage III non-small cell lung cancer (NSCLC) is complex and requires multidisciplinary input. Since the publication of the PACIFIC trial (consolidative durvalumab post concurrent chemotherapy and radiation in Stage III disease) which showed improved survival for patients in the immunotherapy arm, there has been much interest in the use of immunotherapy in the Stage III setting. In this review, we explore the biologic and clinical rationale for the use of immunotherapy in Stage III NSCLC, present previously published and upcoming data in the neoadjuvant, adjuvant, and concurrent realms of Stage III management, and discuss unanswered questions and challenges moving forward.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Humanos , Factores Inmunológicos/uso terapéutico , Inmunoterapia , Neoplasias Pulmonares/tratamiento farmacológico , Estadificación de NeoplasiasRESUMEN
In Canada, the therapeutic management of patients with advanced non-small cell lung cancer (NSCLC) with rare actionable mutations differs between provinces, territories, and individual centres based on access to molecular testing and funded treatments. These variations, together with the emergence of several novel mesenchymal-epithelial transition (MET) factor-targeted therapies for the treatment of NSCLC, warrant the development of evidence-based consensus recommendations for the use of these agents. A Canadian expert panel was convened to define key clinical questions, review evidence, discuss practice recommendations and reach consensus on the treatment of advanced MET-altered NSCLC. Questions addressed by the panel include: 1. How should the patients most likely to benefit from MET-targeted therapies be identified? 2. What are the preferred first-line and subsequent therapies for patients with MET exon 14 skipping mutations? 3. What are the preferred first-line and subsequent therapies for advanced NSCLC patients with de novo MET amplification? 4. What is the preferred therapy for patients with advanced epidermal growth factor receptor (EGFR)-mutated NSCLC with acquired MET amplification progressing on EGFR inhibitors? 5. What are the potential strategies for overcoming resistance to MET inhibitors? Answers to these questions, along with the consensus recommendations herein, will help streamline the management of MET-altered NSCLC in routine practice, assist clinicians in therapeutic decision-making, and help ensure optimal outcomes for NSCLC patients with MET alterations.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Canadá , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Consenso , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
OBJECTIVES: Treatment of advanced NSCLC (aNSCLC) is rapidly evolving, as new targeted and immuno-oncology (I-O) treatments become available. The iTEN model was developed to predict the cost and survival benefits of changing aNSCLC treatment patterns from a Canadian healthcare system perspective. This report describes iTEN model development and validation. MATERIALS & METHODS: A discrete event patient simulation of aNSCLC was developed. A modified Delphi process using Canadian clinical experts informed the development of treatment sequences that included commonly used, Health Canada approved treatments of aNSCLC. Treatment efficacy and the timing of progression and death were estimated from published Kaplan-Meier progression free and overall survival data. Costs (2018 CDN$) included were: drug acquisition and administration, imaging, monitoring, adverse events, physician visits, best supportive care, and end-of-life. RESULTS AND CONCLUSION: Clinical validity of the iTEN model was assessed by comparing model survival predictions to published real-world evidence (RWE). Four RWE studies that reported the overall survival of patients treated with a broad sampling of common aNSCLC treatment patterns were used for validation. The validation coefficient of determination was R2â¯=â¯0.95, with the model generally producing estimates that were neither optimistic nor conservative. The model estimated that current Canadian practice patterns yield a median survival of almost 13 months, a five-year survival rate of 3% and a life-time per-treated-patient cost of $110,806. Cost and survival estimates are presented and were found to vary by aNSCLC subtype. In conclusion, the iTEN model is a reliable tool for forecasting the impact on cost and survival of new treatments for aNSCLC.
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Protocolos de Quimioterapia Combinada Antineoplásica/economía , Biomarcadores de Tumor/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/economía , Análisis Costo-Beneficio , Neoplasias Pulmonares/economía , Modelos Estadísticos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Estudios de Seguimiento , Costos de la Atención en Salud , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidad , Pronóstico , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
PURPOSE: Plasma detection of EGFR T790M mutations is an emerging alternative to tumor rebiopsy in acquired epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor resistance. Validation of analytical sensitivity and clinical utility is required before routine diagnostic use in clinical laboratories. PATIENTS AND METHODS: Sixty-three patients with advanced EGFR-mutant lung cancer at 7 Canadian centers, who were being screened for the ASTRIS trial (ClinicalTrials.gov identifier: NCT02474355), participated in this companion study. Plasma T790M mutation was detected using droplet digital polymerase chain reaction, Cobas (Roche Diagnostics, Indianapolis, IN), or next-generation sequencing in 4 laboratories. T790M concordance was assessed between plasma and tumor samples. RESULTS: Assessment of T790M in tumor biopsy tissue was successful in 81% of patients; 49% had confirmed T790M results (tumor or plasma) for ASTRIS. Plasma testing in this companion study yielded T790M results in 97% of patients; 62% had T790M-positive results, 36% had negative results, and 2% had indeterminate results. Of 38 patients with negative or indeterminate biopsy results, 55% had positive plasma T790M results, increasing the proportion with T790M-positive results to 73%. Sensitivity of plasma T790M testing was 75%. Overall concordance between tissue and plasma was 64%, and concordance among laboratories was 90.3%. Response to osimertinib and duration of therapy were similar irrespective of testing method (overall response rate, 62.5% for tissue, 66.7% for plasma, and 70.6% for both). CONCLUSION: This multicenter validation study demonstrates that plasma EGFR T790M testing can identify significantly more patients than biopsy alone who may benefit from targeted therapy.