Germline prediction of immune checkpoint inhibitor discontinuation for immune-related adverse events.

Introduction: Immune checkpoint inhibitors (ICIs) can yield remarkable clinical responses in subsets of patients with solid tumors but can also often lead to immune-related adverse events (irAEs). Predictive features of clinically severe irAEs leading to cessation of ICIs have yet to be established. Using data from 1,327 patients with lung cancer treated with ICIs between 2009 and 2022 at four academic medical centers, we evaluated the association of a germline polygenic risk score for autoimmune disease and discontinuation of ICIs due to irAEs. Methods: Using Cox proportional hazards model, we assessed the association between a polygenic risk score for autoimmune disease (PRSAD) and cessation of ICI therapy due to irAEs. All models were adjusted for age at diagnosis, sex, lung cancer histology, type of therapy, recruiting center, and the first 5 principal components. To further understand the differential effects of type of therapy and disease stage on the association between PRSAD and cessation of ICI due to irAEs, we conducted stratified logistic regression analysis by type of ICI therapy and disease stage. Results: We found an association between PRSAD and ICI cessation due to irAEs (HR per SD = 1.18, 95% CI = 1.02 - 1.37, P = 0.03). This association was particularly strong in patients who had ICI cessation due to irAEs within three months of therapy initiation (HR per SD = 1.38, 95% CI = 1.08 - 1.78, P = 0.01). Individuals in the top 20th percentile of PRSAD had 7.2% ICI discontinuation for irAEs by three months, compared to 3.9% discontinuation by three months among patients in the bottom 80th percentile (log-rank P = 0.02). In addition, among patients who received combination PD-1/PD-L1 and CTLA-4 inhibitor therapy, PRSAD had an OR per SD of 1.86 (95% CI = 1.08 - 3.51, P = 0.04). Conclusions: We demonstrate an association between a polygenic risk score for autoimmune disease and early ICI discontinuation for irAEs, particularly among patients treated with combination ICI therapy. Our results suggest that germline genetics may be used as an adjunctive tool for risk stratification around ICI clinical decision-making in solid tumor oncology.

Immediate Versus Deferred Systemic Therapy in Patients With Mesothelioma.

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

Polygenic risk score for ulcerative colitis predicts immune checkpoint inhibitor-mediated colitis.

Immune checkpoint inhibitor-mediated colitis (IMC) is a common adverse event of treatment with immune checkpoint inhibitors (ICI). We hypothesize that genetic susceptibility to Crohn's disease (CD) and ulcerative colitis (UC) predisposes to IMC. In this study, we first develop a polygenic risk scores for CD (PRSCD) and UC (PRSUC) in cancer-free individuals and then test these PRSs on IMC in a cohort of 1316 patients with ICI-treated non-small cell lung cancer and perform a replication in 873 ICI-treated pan-cancer patients. In a meta-analysis, the PRSUC predicts all-grade IMC (ORmeta=1.35 per standard deviation [SD], 95% CI = 1.12-1.64, P = 2×10-03) and severe IMC (ORmeta=1.49 per SD, 95% CI = 1.18-1.88, P = 9×10-04). PRSCD is not associated with IMC. Furthermore, PRSUC predicts severe IMC among patients treated with combination ICIs (ORmeta=2.20 per SD, 95% CI = 1.07-4.53, P = 0.03). Overall, PRSUC can identify patients receiving ICI at risk of developing IMC and may be useful to monitor patients and improve patient outcomes.

Real-World Treatment Sequencing, Toxicities, Health Utilities, and Survival Outcomes in Patients with Advanced ALK-Rearranged Non-Small-Cell Lung Cancer.

OBJECTIVES: This real-world analysis describes treatment patterns, sequencing and clinical effectiveness, toxicities, and health utility outcomes in advanced-stage, incurable ALK-positive NSCLC patients across five different ALK-TKIs. MATERIALS AND METHODS: Clinicodemographic, treatment, and toxicity data were collected retrospectively in patients with advanced-stage ALK-positive NSCLC at Princess Margaret Cancer Centre. Patient-reported symptoms, toxicities, and health utilities were collected prospectively. RESULTS: Of 148 ALK-positive NSCLC patients seen July 2009-May 2021, median age was 58.9 years; 84 (57%) were female; 112 (76%) never-smokers; 54 (47%) Asian and 40 (35%) white; 139 (94%) received at least one ALK-TKI: crizotinib (n = 74; 54%) and alectinib (n = 61; 44%) were administered mainly as first-line ALK-TKI, ceritinib, brigatinib and lorlatinib were administered primarily after previous ALK-TKI failure. Median overall survival (OS) was 54.0 months; 31 (21%) patients died within two years of advanced-stage diagnosis. Treatment modifications were observed in 35 (47%) patients with crizotinib, 19 (61%) with ceritinib, 41 (39%) with alectinib, 9 (41%) with brigatinib and 8 (30%) with lorlatinib. Prevalence of dose modifications and self-reported toxicities were higher with early versus later generation ALK-TKIs (P<.05). The presence of early treatment modification was not negatively associated with progression-free survival (PFS) and OS analyses. CONCLUSION: Serial ALK-TKI sequencing approaches are viable therapeutic options that can extend quality of life and quantity-of-life, though a fifth of patients died within two years. No best single sequencing approach could be determined. Clinically relevant toxicities occurred across all ALK-TKIs. Treatment modifications due to toxicity may not necessarily compromise outcomes, allowing multiple approaches to deal with ALK-TKI toxicities.

Presentation and outcomes of KRASG12C mutant non-small cell lung cancer patients with stage IV disease at diagnosis (de novo) versus at recurrence.

Close monitoring after diagnosis of patients with stage I-III non-small cell lung cancer (NSCLC) may result in fitter patients with lower disease burden at the time of metastatic recurrence or progression compared to patients diagnosed initially as stage IV (de novo). We compared the presentation, treatments, and outcomes of patients with KRASG12C-mutated NSCLC with de novo versus recurrent stage IV disease. Of 109 patients, 94% had a smoking history. When compared to patients with KRASG12C-mutated NSCLC who developed stage IV disease at recurrence (n = 38), de novo stage IV patients (n = 71) had worse ECOG performance status (p = 0.007), greater numbers of extra-thoracic metastatic sites (p = 0.001), and were less likely to receive 2nd/3rd line systemic therapy (p = 0.05, p = 0.002) or targeted therapy (p = 0.001). De novo metastatic patients had shorter overall survival than metastatic patients at recurrence (9.1 versus 24.2 months; adjusted-hazard-ratio=1.94 (95% CI: 1.14-3.28; p = 0.01)). There is a critical need for well-tolerated targeted therapies in the first-line setting for metastatic patients with de novo, high-burden, stage IV KRASG12C-mutated NSCLCs.

Polygenic risk score for ulcerative colitis predicts immune checkpoint inhibitor-mediated colitis.

Immune checkpoint inhibitors (ICIs) are a remarkable advancement in cancer therapeutics; however, a substantial proportion of patients develop severe immune-related adverse events (irAEs). Understanding and predicting irAEs is a key to advancing precision immuno-oncology. Immune checkpoint inhibitor-mediated colitis (IMC) is a significant complication from ICI and can have life-threatening consequences. Based on clinical presentation, IMC mimics inflammatory bowel disease, however the link is poorly understood. We hypothesized that genetic susceptibility to Crohn's disease (CD) and ulcerative colitis (UC) may predispose to IMC. We developed and validated polygenic risk scores for CD (PRSCD) and UC (PRSUC) in cancer-free individuals and assessed the role of each of these PRSs on IMC in a cohort of 1,316 patients with non-small cell lung cancer who received ICIs. Prevalence of all-grade IMC in our cohort was 4% (55 cases), and for severe IMC, 2.5% (32 cases). The PRSUC predicted the development of all-grade IMC (HR=1.34 per standard deviation [SD], 95% CI=1.02-1.76, P=0.04) and severe IMC (HR=1.62 per SD, 95% CI=1.12-2.35, P=0.01). PRSCD was not associated with IMC or severe IMC. The association between PRSUC and IMC (all-grade and severe) was consistent in an independent pan-cancer cohort of patients treated with ICIs. Furthermore, PRSUC predicted severe IMC among patients treated with combination ICIs (OR = 2.20 per SD, 95% CI = 1.07-4.53, P=0.03). This is the first study to demonstrate the potential clinical utility of a PRS for ulcerative colitis in identifying patients receiving ICI at high risk of developing IMC, where risk reduction and close monitoring strategies could help improve overall patient outcomes.

Treatment patterns and outcomes in early-stage ALK-rearranged non-small cell lung cancer.

INTRODUCTION: We evaluated the baseline demographics, treatment patterns, and outcomes of patients with ALK-rearranged early stage (Stage I-III) non-small cell lung cancer (NSCLC). We also evaluated the efficacy and toxicity of durvalumab consolidation treatment in patients with ALK-rearranged unresectable stage III disease. METHODS: Retrospective chart-review analysis of all patients with histologically confirmed stage I-III reflexively tested ALK-rearranged NSCLC managed with curative intent at two Canadian Centers. RESULTS: Of 48 patients, 19 (40%) were stage I, 5 (10%) were stage II and 24 (50%) were stage-III. Median progression-free survival (PFS) was 27.6 months overall (95%CI: 20.5-51.4) and 144.4 months in stage-I, 27.6 months in stage-II and 14.9 months in stage III patients. Of 20 patients with unresectable stage-III disease treated with chemoradiation (9 also received durvalumab consolidation), 18/90% have relapsed. Median PFS was 10.9 months (95%CI:5.9-22.5). A non-significant trend toward improved PFS was seen in patients receiving additional durvalumab compared to patients treated with chemoradiation alone (median PFS, 12.5 vs 5.9 months, p = 0.16). Toxicity-related treatment modifications on subsequent first ALK-TKI at time of metastatic disease were needed in three (33%) patients who had received chemoradiation alone and two (29%) patients with consolidation durvalumab; no relevant pulmonary or hepato-toxicity was observed overall. CONCLUSION: Treatment strategies and PFS of patients with Stage I-III ALK-rearranged NSCLC are similar to patients without molecular driver alterations. Durvalumab consolidation treatment appears generally safe in patients with unresectable stage III ALK-rearranged disease; however, the degree of benefit of such an approach remains unclear.

Out-of-pocket costs associated with head and neck cancer treatment.

BACKGROUND: Out-of-pocket costs (OOPC) associated with treatment have significant implications on quality of life and survival in cancer patients. Head and neck cancer patients face unique treatment-related challenges, but to date OOPC have been understudied in this population. AIMS: This study aims to identify and measure OOPC for patients with head and neck cancer (HNC) in Ontario. METHODS: HNC patients between 2015 and 2018 at Princess Margaret Cancer Centre in Toronto were recruited. Participants completed OOPC questionnaires and lost income questions during radiation, post-surgery, and 3, 6, 12, and 24 months after completion of treatment. Associations between OOPC and treatment modality and disease site were tested with multivariable hurdle regression. RESULTS: A total of 1545 questionnaires were completed by 657 patients. Median estimated OOPC for the total duration of treatment for participants undergoing chemoradiation was $1452 [$0-14 616], for surgery with adjuvant radiation or chemoradiation (C/RT) was $1626, for radiation therapy alone was $635, and for surgery alone was $360. The major expenses for participants at the mid-treatment time-point was travel (mean $424, standard error of the mean [SEM] $34) and meals, parking, and accommodations (mean $617, SEM $67). In multivariable analysis, chemoradiation, surgery with C/RT, and radiation were associated with significantly higher OOPC than surgery alone during treatment (791% higher, p < .001; 539% higher, p < .001; 370% higher, p < .001 respectively) among patients with non-zero OOPC. Participants with non-zero OOPC in the laryngeal cancer group paid 49% lower OOPC than those with oropharyngeal cancers in adjusted analysis (p = .025). CONCLUSIONS: Patients undergoing treatment for HNC pay significant OOPC. These costs are highest during treatment and gradually decrease over time. OOPC vary by patient demographics, clinical factors, and, in particular, treatment modality.

Treatment Patterns and Outcomes of Patients With Advanced Pleural Mesothelioma at an Academic Referral Centre.

BACKGROUND: Overall survival (OS) for malignant pleural mesothelioma (MPM) in vulnerable subgroups remains poorly understood with scarce data available to guide treatment decisions. The study describes real-world detailed treatment patterns and outcomes of patients with advanced MPM overall and specifically in elderly and poor performance status (PS) patients. METHODS: Retrospective chart review was performed for all patients with histologically confirmed MPM seen at University Health Network/Princess Margaret Cancer Centre (UHN-PM). RESULTS: A total of 667 patients with MPM were identified and 304 advanced-disease MPM (aMPM) patients had continuing care at UHN-PM (UP-cohort). In the UP-cohort, 77% of patients received ≥ one line of systemic treatment. Systemic therapy trial participation was 39%. Patients not treated with systemic therapy (29%) were more likely to be ≥ 75 years and PS ≥ 2. Median OS was 15.3 months (95%CI 13.6-18.3), with longer survival in treated vs. untreated patients (17.4 vs. 10.6 months; P = .01). Longer survival with systemic treatment was seen in patients ≥75 years (12.7 vs. 6.6 months) and patients with poor PS (9.1 vs. 5.9 months). Median progression-free-survival (PFS) and OS for patients treated with second-line therapy was poor (3.0 and 8.9 months, respectively). DISCUSSION: In our real-world analysis of patients with aMPM treated at an academic referral centre, systemic treatment was given to the majority of patients and benefit was seen even in the elderly and poor PS patients frequently underrepresented in clinical trials. Trial participation was potentially facilitated by the formation of a dedicated multidisciplinary MPM clinic.

EGFR mutation prevalence, real-world treatment patterns, and outcomes among patients with resected, early-stage, non-small cell lung cancer in Canada.

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.

Stratification and management of patients ineligible for lung cancer screening.

This study identifies participants ineligible for lung cancer screening with the greatest likelihood of future eligibility. Lung cancer risk in participants enrolled in longitudinal lung screening was assessed using the Prostate, Lung, Colorectal and Ovarian lung cancer risk calculator (PLCOm2012) at two timepoints: baseline (T1) and follow-up (T2). Separate analyses were performed on four PLCOm2012 eligibility thresholds (3.25%, 2.00%, 1.50%, and 1.00%); only participants with a T1 risk less than the threshold were included in that analysis. Cox-models identified T1 risk factors associated with screen-eligibility at T2. Three models, applying differing assumptions of participant behavior, predicted future eligibility and were benchmarked against the observed cohort. Nine hundred and fifty-six participants had a T1 risk <3.25%; at 2.00% n= 755; at 1.50% n= 652; at 1.00% n= 484. Lung cancer risk increased over time in most screen-ineligible participants. However, risk increased much faster in participants who became screen-eligible at T2 compared to those who remained screen-ineligible (median per-year increase of 0.35% versus 0.02%, when using a 3.25% threshold). Participants smoking for >30 years, current smokers, less educated participants, and those with chronic obstructive pulmonary disease (COPD) at T1 were significantly more likely to become screen-eligible. New diagnoses of COPD and/or non-lung cancers between T1 and T2 precipitated eligibility in a subset of participants. The prediction model that assumed health behaviors observed at T1 continued to T2 reasonably predicted changes in lung cancer risk. This prediction model and the identified baseline risk factors can identify screen-ineligible participants who should be closely followed for future eligibility.

Association between Genetic Variants and Cisplatin-Induced Nephrotoxicity: A Genome-Wide Approach and Validation Study.

This study aims to evaluate genetic risk factors for cisplatin-induced nephrotoxicity by investigating not previously studied genetic risk variants and further examining previously reported genetic associations. A genome-wide study (GWAS) was conducted in genetically estimated Europeans in a discovery cohort of cisplatin-treated adults from Toronto, Canada, followed by a candidate gene approach in a validation cohort from the Netherlands. In addition, previously reported genetic associations were further examined in both the discovery and validation cohorts. The outcome, nephrotoxicity, was assessed in two ways: (i) decreased estimated glomerular filtration rate (eGFR), calculated using the Chronic Kidney Disease Epidemiology Collaboration formula (CKD-EPI) and (ii) increased serum creatinine according to the Common Terminology Criteria for Adverse Events v4.03 for acute kidney injury (AKI-CTCAE). Four different Illumina arrays were used for genotyping. Standard quality control was applied for pre- and post-genotype imputation data. In the discovery cohort (n = 608), five single-nucleotide polymorphisms (SNPs) reached genome-wide significance. The A allele in rs4388268 (minor allele frequency = 0.23), an intronic variant of the BACH2 gene, was consistently associated with increased risk of cisplatin-induced nephrotoxicity in both definitions, meeting genome-wide significance (ß = -8.4, 95% CI -11.4--5.4, p = 3.9 × 10-8) for decreased eGFR and reaching suggestive association (OR = 3.9, 95% CI 2.3-6.7, p = 7.4 × 10-7) by AKI-CTCAE. In the validation cohort of 149 patients, this variant was identified with the same direction of effect (eGFR: ß = -1.5, 95% CI -5.3-2.4, AKI-CTCAE: OR = 1.7, 95% CI 0.8-3.5). Findings of our previously published candidate gene study could not be confirmed after correction for multiple testing. Genetic predisposition of BACH2 (rs4388268) might be important in the development of cisplatin-induced nephrotoxicity, indicating opportunities for mechanistic understanding, tailored therapy and preventive strategies.