Immunotherapy in Patients with Advanced Non-Small-Cell Lung Cancer Under-Represented by Clinical Trials.

Since the initial US FDA approval of an immune checkpoint inhibitor (ICI) for the treatment of non-oncogene-driven non-small-cell lung cancer (NSCLC) nine years ago, this therapeutic strategy has been cemented as a crucial component of treatment for most of these patients. However, there is a clear efficacy-effectiveness gap whereby patients in the 'real world' seem to have more modest clinical outcomes compared to those enrolled in landmark clinical trials. This gap may be driven by the under-representation of important patient populations, including populations defined by clinical or molecular characteristics. In this review, we summarize the data outlining the evidence of ICIs in patients with poor Eastern Cooperative Oncology Group performance status (ECOG PS), underlying autoimmune disease (AID), older age, active brain metastases (BMs), and molecular aberrations such as EGFR mutations, ALK fusions, BRAF mutations and ROS1 fusions.

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.

Mental Disorders Among Adolescents and Young Adults With Cancer: A Canadian Population-Based and Sibling Cohort Study.

PURPOSE: To compare the cumulative incidence of mental disorders among adolescents and young adults (AYAs) diagnosed with cancer with the general population and their unaffected siblings. METHODS: A retrospective, population-based, matched cohort design was used to investigate the impact of cancer diagnosis on mental disorders among individuals age 15-39 diagnosed between 1989 and 2019. Two cancer-free cohorts were identified: matched population-based and sibling cohorts. Outcomes included incidence of mood and anxiety disorders, substance use disorders, suicide outcomes, psychotic disorders, and any of the preceding four categories within 5 years of cancer diagnosis. Competing risk regression was used to estimate adjusted subhazard ratios (aSHR) and 95% CIs. RESULTS: Among 3,818 AYAs with cancer matched to the population-based cancer-free cohort, individuals with cancer were more likely to be diagnosed with incident mental disorders than those without cancer; the risk was highest immediately after a cancer diagnosis and decreased over time with aSHR [95% CI] for mood and anxiety disorders at 0-6 months (11.27 [95% CI, 6.69 to 18.97]), 6-12 months (2.35 [95% CI, 1.54 to 3.58]), and 12-24 months (2.06 [95% CI, 1.55 to 2.75]); for substance use disorders at 0-6 months (2.73 [95% CI, 1.90 to 3.92]); for psychotic disorders at 0-6 months (4.69 [95% CI, 2.07 to 10.65]); and for any mental disorder at 0-6 months (4.46 [95% CI, 3.41 to 5.85]), 6-12 months (1.56 [95% CI, 1.14 to 2.14]), and 12-24 months (1.7 [95% CI, 1.36 to 2.13]) postcancer diagnosis. In sibling comparison, cancer diagnosis was associated with a higher incidence of mood and anxiety and any mental disorder during first 6 months of cancer diagnosis. CONCLUSION: AYAs with cancer experience a greater incidence of mental disorders after cancer diagnosis relative to population-based and sibling cohorts without cancer, primarily within first 2 years, underscoring the need to address mental health concerns during this period.

Real-world predictors of survival in patients with limited-stage small-cell lung cancer in Manitoba, Canada.

Background: Although therapy for limited-stage small-cell lung cancer (LS-SCLC) is administered with curative intent, most patients relapse and eventually die of recurrent disease. Chemotherapy (CT) with concurrent radiotherapy (RT) remains the standard of care for LS-SCLC; however, this could evolve in the near future. Therefore, understanding the current prognostic factors associated with survival is essential. Objective: This real-world analysis examines factors associated with long-term survival in patients with LS-SCLC treated with CT in Manitoba, Canada. Methods: A retrospective cohort study was conducted using Manitoba Cancer Registry and CancerCare Manitoba records. Eligible patients were aged >18 years and had cytologically confirmed LS-SCLC diagnosed between January 1, 2004, and December 31, 2018, for which they received CT ± RT. Baseline patient, disease, and treatment characteristics and survival duration, characterized as short (<6 months), medium (6-24 months), and long term (>24 months), were extracted. Overall survival (OS) was estimated at one, two, and five years and assessed using Kaplan-Meier methods and Cox proportional hazards models. Results: Over the 15-year study period, 304 patients met the eligibility criteria. Long-term survivors comprised 39.1% of the cohort; at diagnosis, this subgroup was younger, more likely to have Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0, and have normal lactate dehydrogenase, sodium, and hemoglobin levels. OS estimates for the entire cohort at one, two, and five years were 66%, 38%, and 18%, respectively. In the ECOG PS 0 subgroup, OS estimates at one, two, and five years were 85%, 52%, and 24%, respectively; OS estimates were 60%, 35%, and 17%, respectively, for ECOG PS 1-2 and were 47%, 23%, and 10%, respectively, for ECOG PS 3-4. OS was significantly higher among patients with normal serum sodium and hemoglobin levels than those with abnormal levels. Univariable hazard regression models found that ECOG PS, age at diagnosis, receipt of prophylactic cranial irradiation (PCI), and thoracic RT were associated with survival. On multivariable hazard regression, ECOG PS and receipt of PCI were associated with survival. Conclusion: Survival for greater than two years in patients with LS-SCLC treated with CT ± RT was associated with ECOG PS and receipt of PCI.

Real-world predictors of survival in patients with extensive-stage small-cell lung cancer in Manitoba, Canada: a retrospective cohort study.

Background: Extensive-stage small-cell lung cancer (ES-SCLC) is an incurable cancer with poor prognosis in which characteristics predictive of long-term survival are debated. The utility of agents such as immune checkpoint inhibitors highlights the importance of identifying key characteristics and treatment strategies that contribute to long-term survival and could help guide therapeutic decisions. Objective: This real-world analysis examines the characteristics, treatment patterns, and clinical outcomes of patients receiving chemotherapy without immunotherapy for ES-SCLC in Manitoba, Canada. Methods: A retrospective cohort study assessed patient characteristics, treatment, and survival duration (short: <6 months; medium: 6-24 months; long: >24 months) using the Manitoba Cancer Registry and CancerCare Manitoba records. Eligible patients were aged >18 years with cytologically confirmed ES-SCLC diagnosed between January 1, 2004, and December 31, 2018, and received cytotoxic chemotherapy (CT). The one-, two-, and five-year probabilities of overall survival (OS) were assessed relative to patient, disease, and treatment characteristics using Kaplan-Meier methods and Cox proportional hazards models. Results: This analysis included 537 patients. Cisplatin was used in 56.1% of patients, 45.6% received thoracic radiotherapy (RT), and few received prophylactic cranial irradiation (PCI). In the overall cohort, one-, two- and five-year OS rates were 26%, 8%, and 3%, respectively. For patients with Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0, OS rates at one, two, and five years were 43%, 17%, and 10%, respectively, vs. 27%, 8%, and 2% for those with ECOG PS 1-2, and 16%, 3%, and 3% for those with ECOG PS 3-4. In long-term survivors, ECOG PS scores were lower and abnormal laboratory test results were less frequent. Overall, 74.4% of long-term survivors received thoracic RT and 53.5% received PCI. Known poor prognostic factors - including brain/liver metastases, high lactate dehydrogenase (LDH), abnormal sodium, and low hemoglobin levels - were less common but still seen in long-term survivors. Conclusion: Although rare, patients with ES-SCLC may experience long-term survival with CT ± thoracic RT ± PCI. Factors predicting long-term survival include traditional prognostic factors such as ECOG PS, LDH level, and receipt of thoracic RT or PCI. These findings support current treatment algorithms for ES-SCLC and provide baseline survival estimates to assess the real-world impact of adding immune checkpoint inhibitors in the future.

Real-world experience of tyrosine kinase inhibitors in children, adolescents and adults with relapsed or refractory bone tumours: A Canadian Sarcoma Research and Clinical Collaboration (CanSaRCC) study.

OBJECTIVES: We conducted a retrospective multi-centre study to assess the real-world outcome of regorafenib (REGO) and cabozantinib (CABO) in recurrent/refractory bone tumours (BTs) including osteosarcoma (OST), Ewing sarcoma (EWS) and chondrosarcoma (CS)/extra-skeletal mesenchymal CS (ESMC). METHODS: After regulatory approval, data from patients with recurrent BT (11 institutions) were extracted from CanSaRCC (Canadian Sarcoma Research and Clinical Collaboration) database. Patient characteristics, treatment and outcomes were collected. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. RESULTS: From July 2018 to May 2022, 66 patients received REGO or CABO; 39 OST, 18 EWS, 4 CS and 5 ESMC. Median age was 27.8 years (range 12-76); median starting dose was 60 mg for CABO (n = 37, range 40-60) and 120 mg for REGO (n = 29, range 40-160). Twenty-eight (42.4%) patients required dose reduction: hand-foot syndrome 7 (10.6%), nausea/vomiting 1 (1.5%), diarrhoea 1 (1.5%), 2 elevated LFTs (3%), elevated bilirubin 1 (1.5%) and mucositis 1 (1.5%). The median OS for patients with OST, EWS, CS and ESMC was 8.5 months (n = 39, 95% CI 7-13.1); 13.4 months (n = 18, 95% CI 3.4-27.2), 8.1 (n = 4, 95% CI 4.1-9.3) and 18.2 (n = 5, 95% CI (10.4-na), respectively. Median PFS for OST, EWS, CS and ECMS was 3.5 (n = 39, 95% CI 2.8-5), 3.9 (n = 18, 95% CI 2.1-5.9), 5.53 (n = 4. 95% CI 2.13-NA) and 11.4 (n = 5, 95% CI 1.83-14.7), respectively. Age, line of therapy, REGO versus CABO, or time from diagnosis to initiation of TKI were not associated with PFS on univariable analysis. CONCLUSION: Our real-world data show that TKIs have meaningful activity in recurrent BT with acceptable toxicities when started at modified dosing. Inclusion of TKIs in earlier lines of treatment and/or maintenance therapy could be questions for future research.

Canadian Consensus Recommendations on the Management of KRAS G12C-Mutated NSCLC.

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.

Lorlatinib Effectiveness and Quality-of-Life in Patients with ALK-Positive NSCLC Who Had Failed Second-Generation ALK Inhibitors: Canadian Real-World Experience.

Lorlatinib is the only targeted therapy approved in Canada to treat patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) whose tumor has progressed despite treatment with second-generation ALK tyrosine kinase inhibitor (TKI), a patient population with high unmet need and lack of publicly reimbursed targeted treatments in Canada. We prospectively examined the real-world effectiveness and impact of lorlatinib on quality-of-life in 59 lorlatinib-treated patients, characterized as: median age of 62.0 years; 47.5% were female; 32.2% had central nervous system metastases; 50.8% had 2+ prior ALK TKI lines; and alectinib was the most common ALK TKI (72.9%) administered before lorlatinib, including 44.1% who received first-line alectinib. With a median follow-up of 15.3 months (IQR: 6.2-19.2), median time-to-treatment discontinuation of lorlatinib was 15.3 months (95% CI: 7.9-not reached), with 54.2% (95% CI: 40.8-65.9%) of patients without treatment discontinuation at 12 months. At baseline, the mean health utility score (HUS) was 0.744 (SD: 0.200). At 3 months, patients receiving lorlatinib demonstrated a 0.069 (95% CI: 0.020-0.118; p = 0.007) average HUS increase over baseline; HUS was maintained at 6 and 12 months. Thus, patients with ALK-positive NSCLC post second-generation ALK TKI remained on lorlatinib for a meaningful duration of time while their quality-of-life was preserved.

Follow-Up Imaging Guidelines for Patients with Stage III Unresectable NSCLC: Recommendations Based on the PACIFIC Trial.

The PACIFIC trial showed a survival benefit with durvalumab through five years in stage III unresectable non-small cell lung cancer (NSCLC). However, optimal use of imaging to detect disease progression remains unclearly defined for this population. An expert working group convened to consider available evidence and clinical experience and develop recommendations for follow-up imaging after concurrent chemotherapy and radiation therapy (CRT). Voting on agreement was conducted anonymously via online survey. Follow-up imaging was recommended for all suitable patients after CRT completion regardless of whether durvalumab is received. Imaging should occur every 3 months in Year 1, at least every 6 months in Year 2, and at least every 12 months in Years 3-5. Contrast computed tomography was preferred; routine brain imaging was not recommended for asymptomatic patients. The medical oncologist should follow-up during Year 1 of durvalumab therapy, with radiation oncologist involvement if pneumonitis is suspected; medical and radiation oncologists can subsequently alternate follow-up. Some patients can transition to the family physician/community primary care team at the end of Year 2. In Years 1-5, patients should receive information regarding smoking cessation, comorbidity management, vaccinations, and general follow-up care. These recommendations provide guidance on follow-up imaging for patients with stage III unresectable NSCLC whether or not they receive durvalumab consolidation therapy.

Data-driven identification of plasma metabolite clusters and metabolites of interest for potential detection of early-stage non-small cell lung cancer cases versus cancer-free controls.

BACKGROUND: Metabolomics is a potential means for biofluid-based lung cancer detection. We conducted a non-targeted, data-driven assessment of plasma from early-stage non-small cell lung cancer (ES-NSCLC) cases versus cancer-free controls (CFC) to explore and identify the classes of metabolites for further targeted metabolomics biomarker development. METHODS: Plasma from 250 ES-NSCLC cases and 250 CFCs underwent ultra-high-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS) in positive and negative electrospray ionization (ESI) modes. Molecular feature extraction, formula generation, and find-by-ion tools annotated metabolic entities. Analysis was restricted to endogenous metabolites present in ≥ 80% of samples. Unsupervised hierarchical cluster analysis identified clusters of metabolites. The metabolites with the strongest correlation with the principal component of each cluster were included in logistic regression modeling to assess discriminatory performance with and without adjustment for clinical covariates. RESULTS: A total of 1900 UHPLC-QTOF-MS assessments identified 1667 and 2032 endogenous metabolites in the ESI-positive and ESI-negative modes, respectively. After data filtration, 676 metabolites remained, and 12 clusters of metabolites were identified from each ESI mode. Multivariable logistic regression using the representative metabolite from each cluster revealed effective classification of cases from controls with overall diagnostic accuracy of 91% (ESI positive) and 94% (ESI negative). Metabolites of interest identified for further targeted analysis include the following: 1b, 3a, 12a-trihydroxy-5b-cholanoic acid, pyridoxamine 5'-phosphate, sphinganine 1-phosphate, gamma-CEHC, 20-carboxy-leukotriene B4, isodesmosine, and 18-hydroxycortisol. CONCLUSIONS: Plasma-based metabolomic detection of early-stage NSCLC appears feasible. Further metabolomics studies targeting phospholipid, steroid, and fatty acid metabolism are warranted to further develop noninvasive metabolomics-based detection of early-stage NSCLC.

Consensus Recommendations to Optimize Testing for New Targetable Alterations in Non-Small Cell Lung Cancer.

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.

Histologic and Genotypic Characterization of Lung Cancer in the Inuit Population of the Eastern Canadian Arctic.

Inuit are the Indigenous Arctic peoples and residents of the Canadian territory of Nunavut who have the highest global rate of lung cancer. Given lung cancer's mortality, histological and genomic characterization was undertaken to better understand the disease biology. We retrospectively studied all Inuit cases from Nunavut's Qikiqtani (Baffin) region, referred to the Ottawa Hospital Cancer Center between 2001 and 2011. Demographics were compiled from medical records and tumor samples underwent pathologic/histologic confirmation. Tumors were analyzed by next generation sequencing (NGS) with a cancer hotspot mutation panel. Of 98 patients, the median age was 66 years and 61% were male. Tobacco use was reported in 87%, and 69% had a history of lung disease (tuberculosis or other). Histological types were: non-small cell lung carcinoma (NSCLC), 81%; small cell lung carcinoma, 16%. Squamous cell carcinoma (SCC) represented 65% of NSCLC. NGS on 55 samples demonstrated mutation rates similar to public lung cancer datasets. In SCC, the STK11 F354L mutation was observed at higher frequency than previously reported. This is the first study to characterize the histologic/genomic profiles of lung cancer in this population. A high incidence of SCC, and an elevated rate of STK11 mutations distinguishes this group from the North American population.

Transitions between versions of the International Classification of Diseases and chronic disease prevalence estimates from administrative health data: a population-based study.

BACKGROUND: Diagnosis codes in administrative health data are routinely used to monitor trends in disease prevalence and incidence. The International Classification of Diseases (ICD), which is used to record these diagnoses, have been updated multiple times to reflect advances in health and medical research. Our objective was to examine the impact of transitions between ICD versions on the prevalence of chronic health conditions estimated from administrative health data. METHODS: Study data (i.e., physician billing claims, hospital records) were from the province of Manitoba, Canada, which has a universal healthcare system. ICDA-8 (with adaptations), ICD-9-CM (clinical modification), and ICD-10-CA (Canadian adaptation; hospital records only) codes are captured in the data. Annual study cohorts included all individuals 18 + years of age for 45 years from 1974 to 2018. Negative binomial regression was used to estimate annual age- and sex-adjusted prevalence and model parameters (i.e., slopes and intercepts) for 16 chronic health conditions. Statistical control charts were used to assess the impact of changes in ICD version on model parameter estimates. Hotelling's T2 statistic was used to combine the parameter estimates and provide an out-of-control signal when its value was above a pre-specified control limit. RESULTS: The annual cohort sizes ranged from 360,341 to 824,816. Hypertension and skin cancer were among the most and least diagnosed health conditions, respectively; their prevalence per 1,000 population increased from 40.5 to 223.6 and from 0.3 to 2.1, respectively, within the study period. The average annual rate of change in prevalence ranged from -1.6% (95% confidence interval [CI]: -1.8, -1.4) for acute myocardial infarction to 14.6% (95% CI: 13.9, 15.2) for hypertension. The control chart indicated out-of-control observations when transitioning from ICDA-8 to ICD-9-CM for 75% of the investigated chronic health conditions but no out-of-control observations when transitioning from ICD-9-CM to ICD-10-CA. CONCLUSIONS: The prevalence of most of the investigated chronic health conditions changed significantly in the transition from ICDA-8 to ICD-9-CM. These results point to the importance of considering changes in ICD coding as a factor that may influence the interpretation of trend estimates for chronic health conditions derived from administrative health data.

The impact of the modified frailty index on clinical outcomes for patients with stage IV non-small cell lung cancer receiving chemotherapy.

INTRODUCTION: Frailty impacts outcomes for patients with lung cancer, but no brief tools have been assessed in patients with metastatic disease. We evaluated the impact of the Modified Frailty Index (mFI) on clinical outcomes for patients with metastatic non-small cell lung cancer (NSCLC). METHODS: We conducted a retrospective cohort study of all patients with Stage IV NSCLC diagnosed in Manitoba between 2011 and 2016 who then received first-line cytotoxic chemotherapy. We assigned mFI scores based on documented comorbidities and collected data on toxicity, progression, and survival. Descriptive statistics characterized the cohort and toxicity experienced. Kaplan-Meier methods were used to evaluate progression-free survival (PFS) and overall survival (OS), followed by multivariable Cox proportional hazards models. RESULTS: Our cohort of 426 (mFI 0/1-2/3+ = 175/196/55) patients, showed no significant association between higher mFI score and incidence of overall chemotherapy toxicity. Patients with mFI 0 experienced more frequent thromboses (p=0.022) and a trend towards less nausea or vomiting (p = 0.059). There was no significant difference in PFS or OS among frailty groups. Poorer performance status, number of metastatic sites, and the absence of a driver mutation were independently associated with poorer PFS and OS. Male sex and not completing chemotherapy were also associated with worse OS. CONCLUSION: This study is the first to investigate the use of the mFI as a frailty tool in patients with metastatic NSCLC receiving cytotoxic chemotherapy. The mFI does not appear to be strongly associated with treatment-related toxicities, PFS, or OS in patients with metastatic NSCLC receiving first-line cytotoxic chemotherapy.

The Role of Immunotherapy in the Treatment of Malignant Pleural Mesothelioma.

Malignant pleural mesothelioma is a rare and aggressive malignancy arising from mesothelial cells that line the serous membranes of the body. Cytotoxic chemotherapy has been a mainstay of therapy, resulting in a modest improvement in overall survival, but toxicity limits the eligible patient population. Few targeted agents beyond bevacizumab have demonstrated superior efficacy compared to placebos. With an improved understanding of the relationship between the immune system and cancer progression, immunotherapies are playing a greater role in the treatment of many cancers. Several early- and late-phase trials in malignant pleural mesothelioma, including assessments of the first-line efficacy of combination ipilimumab/nivolumab treatment, have now demonstrated promising results for both immune checkpoint inhibition and cell-based therapies. These immune therapies are likely to play a central role in the treatment of this disease going forward.

Canadian Consensus Recommendations on the Management of MET-Altered NSCLC.

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.

Treatment and Prevention of Brain Metastases in Small Cell Lung Cancer.

Central nervous system (CNS) metastasis will develop in 50% of small cell lung cancer (SCLC) patients throughout disease course. Development of CNS metastasis poses a particular treatment dilemma due to the accompanied cognitive changes, poor permeability of the blood-brain barrier to systemic therapy and relatively advanced state of disease. Survival of patients with untreated SCLC brain metastases is generally <3 months with whole brain radiotherapy used as first-line management in most SCLC patients. To prevent development of CNS metastasis prophylactic cranial irradiation (PCI) is recommended in limited stage disease, after response to chemotherapy and radiation, while PCI may be considered in extensive stage disease after favorable response to upfront treatment. Neurocognitive toxicity with whole brain radiotherapy and PCI is a concern and remains difficult to predict. The mechanism of toxicity is likely multifactorial, but a potential mechanism of injury to the hippocampus has led to hippocampal sparing radiation techniques. Treatment of established non-small cell lung cancer CNS metastases has increasingly focused on using stereotactic radiotherapy (SRS) and it is tempting to extrapolate these results to SCLC. In this review, we explore the evidence surrounding the prediction, prevention, detection, and treatment of CNS metastases in SCLC. We further review whether existing evidence supports extrapolating less toxic treatments to SCLC patients with CNS metastases and discuss trials that may shed more light on this question.

Canadian consensus on TRK-inhibitor therapy for NTRK fusion-positive sarcoma.

Malignant sarcomas are rare accounting for <1% of all adult solid malignancies and approximately 11% to 13% of all pediatric malignancies. TRK-inhibitors have demonstrated robust and long-lasting responses in patients with NTRK fusion-positive solid tumors, including sarcoma. Access to these agents in many jurisdictions such as Canada remains limited. We undertook a modified Delphi consensus to articulate and convey the clinical importance of these agents for the Canadian sarcoma community. A systematic search of published and presented literature was conducted to identify clinical trials reporting outcomes on the use of TRK-inhibitors in relapsed/refractory NTRK fusion-positive sarcoma. Three main consensus questions were identified: (a) is there currently an unmet clinical need for systemic therapy options in relapsed/refractory sarcoma? (b) do TRK-inhibitors confer a clinical benefit to patients with NTRK fusion-positive sarcoma? (c) do phase I/II basket trials provide sufficient evidence to justify funding of TRK-inhibitors in NTRK fusion-positive sarcoma? Response rates to the first and second surveys were 57% (n = 30) and 42% (n = 22), respectively. There was strong agreement among the Canadian sarcoma community that there was unmet clinical need for effective systemic therapy options in relapsed/refractory sarcoma, that TRK-inhibitors are a safe and effective treatment option for patients with NTRK fusion-positive sarcoma, and that available phase I/II basket trials provide sufficient evidence to support funding of these agents in relapsed/refractory NTRK fusion-positive sarcoma. TRK-inhibitors are a safe and effective systemic therapy option for patients with relapsed/refractory NTRK fusion-positive sarcoma.

Selpercatinib in RET fusion-positive non-small-cell lung cancer (SIREN): a retrospective analysis of patients treated through an access program.

INTRODUCTION: Rearranged during transfection (RET) gene fusions are rare genetic drivers in non-small cell lung cancer (NSCLC). Selective RET-inhibitors such as selpercatinib have shown therapeutic activity in early clinical trials; however, their efficacy in the real-world setting is unknown. METHODS: A retrospective efficacy and safety analysis was performed on data from RET fusion-positive NSCLC patients who participated in a selpercatinib access program (named patient protocol) between August 2019 and January 2021. RESULTS: Data from 50 patients with RET fusion-positive advanced NSCLC treated with selpercatinib at 27 centers in 12 countries was analyzed. Most patients were Non-Asian (90%), female (60%), never-smokers (74%), with a median age of 65 years (range, 38-89). 32% of the patients had known brain metastasis at the time of selpercatinib treatment. Overall, 13 patients were treatment-naïve, while 37 were pretreated with a median of three lines of therapy (range, 1-8). The objective response rate (ORR) was 68% [95% confidence interval (CI), 53-81] in the overall population. The disease control rate was 92%. The median progression-free survival was 15.6 months (95% CI, 8.8-22.4) after a median follow-up of 9 months. In patients with measurable brain metastases (n = 8) intracranial ORR reached 100%. In total, 88% of patients experienced treatment-related adverse events (TRAEs), a large majority of them being grade 1 or 2. The most common grade ⩾ 3 TRAEs were increased liver enzyme levels (in 10% of patients), prolonged QTc time (4%), abdominal pain (4%), hypertension (4%), and fatigue/asthenia (4%). None of patients discontinued selpercatinib treatment for safety reasons. No new safety concerns were observed, nor where there any treatment-related death. CONCLUSIONS: In this real-world setting, the selective RET-inhibitor selpercatinib demonstrated durable systemic and intracranial antitumor activity in RET fusion-positive NSCLC and was well tolerated.

Mapping three versions of the international classification of diseases to categories of chronic conditions.

INTRODUCTION: Administrative health data capture diagnoses using the International Classification of Diseases (ICD), which has multiple versions over time. To facilitate longitudinal investigations using these data, we aimed to map diagnoses identified in three ICD versions - ICD-8 with adaptations (ICDA-8), ICD-9 with clinical modifications (ICD-9-CM), and ICD-10 with Canadian adaptations (ICD-10-CA) - to mutually exclusive chronic health condition categories adapted from the open source Clinical Classifications Software (CCS). METHODS: We adapted the CCS crosswalk to 3-digit ICD-9-CM codes for chronic conditions and resolved the one-to-many mappings in ICD-9-CM codes. Using this adapted CCS crosswalk as the reference and referring to existing crosswalks between ICD versions, we extended the mapping to ICDA-8 and ICD-10-CA. Each mapping step was conducted independently by two reviewers and discrepancies were resolved by consensus through deliberation and reference to prior research. We report the frequencies, agreement percentages and 95% confidence intervals (CI) from each step. RESULTS: We identified 354 3-digit ICD-9-CM codes for chronic conditions. Of those, 77 (22%) codes had one-to-many mappings; 36 (10%) codes were mapped to a single CCS category and 41 (12%) codes were mapped to combined CCS categories. In total, the codes were mapped to 130 adapted CCS categories with an agreement percentage of 92% (95% CI: 86%-98%). Then, 321 3-digit ICDA-8 codes were mapped to CCS categories with an agreement percentage of 92% (95% CI: 89%-95%). Finally, 3583 ICD-10-CA codes were mapped to CCS categories; 111 (3%) had a fair or poor mapping quality; these were reviewed to keep or move to another category (agreement percentage = 77% [95% CI: 69%-85%]). CONCLUSIONS: We developed crosswalks for three ICD versions (ICDA-8, ICD-9-CM, and ICD-10-CA) to 130 clinically meaningful categories of chronic health conditions by adapting the CCS classification. These crosswalks will benefit chronic disease studies spanning multiple decades of administrative health data.