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Objectives: KRAS mutations, particularly KRAS G12C , are prevalent in non-small cell lung cancer (NSCLC). Immune checkpoint inhibitors (ICIs) have been a frontline treatment, but recently developed KRAS G12C -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 KRAS G12C -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 KRAS G12C -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. KRAS G12C -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 KRAS G12C -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 KRAS G12C -targeted therapies., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The study was supported by Amgen. The authors have no other conflicts of interest to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

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 (PRS AD ) 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 PRS AD 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 PRS AD 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 PRS AD 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, PRS AD 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.

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 (PRS CD ) and UC (PRS UC ) 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 PRS UC predicts all-grade IMC (OR meta =1.35 per standard deviation [SD], 95% CI = 1.12-1.64, P = 2×10 -03 ) and severe IMC (OR meta =1.49 per SD, 95% CI = 1.18-1.88, P = 9×10 -04 ). PRS CD is not associated with IMC. Furthermore, PRS UC predicts severe IMC among patients treated with combination ICIs (OR meta =2.20 per SD, 95% CI = 1.07-4.53, P = 0.03). Overall, PRS UC can identify patients receiving ICI at risk of developing IMC and may be useful to monitor patients and improve patient outcomes., (© 2024. The Author(s).)

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 KRAS G12C -mutated NSCLC with de novo versus recurrent stage IV disease. Of 109 patients, 94% had a smoking history. When compared to patients with KRAS G12C -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 KRAS G12C -mutated NSCLCs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

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., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: M. S. Kuruvilla has received honorariums from and been involved in advisory boards for AstraZeneca, Bristol Myers Squibb (BMS), Merck, and Novartis. G. Liu has received institutional research grants from AstraZeneca and Takeda; he has also participated in advisory boards, provided consulting services, and/or received honoraria from AstraZeneca, BMS, EMD Serono, Jazz Pharmaceuticals, Merck, Novartis, Pfizer, Roche, and Takeda. I. Syed, D. Moldaver, and M.K. Shanahan are employees and shareholders of AstraZeneca Canada Inc. F. Gwadry-Sridhar is an employee and shareholder of Pulse Infoframe Inc. B.S. Sheffield has received grants, participated in advisory boards, and/or received consulting fees and honoraria from Amgen, AstraZeneca, Bayer, Biocartis, Boehringer-Ingelheim, Cell Marque, Elevation Oncology, Eli Lily, EMD Serono, Incyte, Janssen, Merck, Novartis, Pfizer, Roche, Thermo Fisher Scientific, and Turning Point Therapeutics. P.K. Cheema has received consulting fees from Amgen, AstraZeneca, Beigene, BMS, Janssen, Merck, Novartis, Pfizer, Roche, and Sanofi, and has received honoraria from Amgen and AstraZeneca. All other authors have no conflicts to disclose., (Copyright © 2022. Published by Elsevier B.V.)

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., (Copyright © 2022. Published by Elsevier B.V.)

Objective: Cancer patients may turn to social media (SM) to cope with distress. We investigated associations between distress and internet/SM use for cancer information/support., Methods: Adult patients at a Canadian cancer centre completed a cross-sectional survey on sociodemographics, health status, use of cancer online resources and distress (EQ5D-5L). Statistical models adjusted for relevant variables., Results: Of 376 participants, median age was 52 years, time since diagnosis was 1.63 years, 272 (74%) had post-secondary education and 192 (51%) were female. For cancer information/support, 276 (73%) used internet and 147 (39%) SM. Dose response relationships were observed between distress and cancer-related internet (p = 0.02), and SM use (p < 0.001). Respondents using internet/SM for cancer information/support reported greater internet confidence (internet OR = 4.0, 95% CI: 1.9-8.3; SM OR = 4.18, 95%, CI: 1.9-11.3), higher education (internet OR = 3.0, 95% CI: 1.7-5.2; SM OR = 2.21, 95% CI: 1.2-4.1) and were more likely female (internet OR = 2.6, 95% CI 1.5-4.6; SM OR = 2.1, 95% CI: 1.3-3.4). For SM for cancer information/support, more used SM > 30 min daily (OR = 3.4; 95% CI: 2.1-5.7), and were distressed (OR = 1.67, 95% CI: 1.0-2.7). SM benefits were to learn about cancer (93; 25%), distract from cancer (85; 23%) and connect with survivors (81; 22%). SM limitations were privacy (161; 43%), quality (90; 24%) and personal applicability (85; 23%). Females used SM more to connect with survivors than males (p = 0.001)., Conclusions: Greater internet confidence, higher education and being female were associated with cancer-related internet/SM use. Distressed cancer patients were also more likely to turn to SM. Privacy concerns may limit SM use for coping. Future research should determine how to optimize SM in caring for and connecting with patients and reduce cancer-related distress., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

Background: Systemic inflammatory response (SIR) may influence prognosis in epidermal growth factor receptor (EGFR)-mutated (m) non-small-cell lung cancer (NSCLC). Pretreatment SIR markers (neutrophil-to-lymphocyte ratio [NLR], platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio [LMR], lactate dehydrogenase [LDH], and lung immune prognostic index [LIPI]) were assessed as prognostic factors in NSCLC survival., Patients and Methods: Retrospective survival analysis (overall survival [OS] and progression-free survival [PFS]) of EGFR-mutated NSCLC patients at Princess Margaret Cancer Centre were performed separately for early (I-IIIa) and late (IIIb-IV) stage disease for individual SIR variables, dichotomized by optimal cutoff points by Kaplan-Meier survival analysis and multivariable Cox proportional hazard modeling. A systematic review and meta-analysis of known SIR studies in patients with late-stage EGFR-mutated were also performed., Results: From 2012 to 2019, in 530 patients, significant adjusted hazard ratios (aHR) for OS comparing high versus low NLR were 2.12 for early stage and 1.79 for late stage disease. Additionally, late stage cohorts had significant associations, as follows: high versus low derived NLR, aHR = 1.53; LMR, aHR = 0.62; LDH, aHR = 2.04; and LIPI, aHR = 2.04. Similar patterns were found for PFS in early stage NLR (aHR = 1.96) and late stage NLR (aHR = 1.46), while for PFS, only late stage derived NLR (aHR = 1.34), LDH (aHR = 1.75), and LIPI (aHR = 1.66) were significant. A meta-analysis confirmed that NLR, LMR, LDH, and LIPI were all significantly associated with OS and PFS in the late stage., Conclusion: This primary study and meta-analysis demonstrated that LMR and LDH were significantly associated with late stage EGFR-mutated NSCLC outcomes, and the LIPI scoring system was prognostic. NLR remained an independent prognostic factor across all stages and could represent an early marker of immuno-oncology interactions., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: Adolescents and young adults (AYA) with cancer are increasingly using the internet and social media (SM) for cancer-related information. AYA face specific challenges and thus require tailored resources that meet their needs. We describe the internet and SM preferences of AYA related to their cancer information seeking behaviors and their preferences for a future resource compared to middle-aged adults (MAA)., Methods: Cancer patients completed a cross-sectional survey related to their internet and SM usage, cancer information, and preferences for future resources. Chi-square tests were used to compare AYA and MAA., Results: The mean (±SD) age in the AYA group was 30±6.1 years (n = 129); in MAA 55±6.7 years (n = 157). In general, AYA preferred internet sites over SM platforms for cancer-related information and prefer a website platform over a SM platform for a new resource. Few AYA were aware of hospital-based AYA-specific resources. MAA were less likely to use SM compared with AYA (13% vs 4%, p = 0.01); however, websites and SM platforms that were used were similar between the 2 groups. Participants endorsed having already researched certain topics - yet, these were also those desired in a new resource. Compared to MAA, AYA sought more information on diet/nutrition, physical activity, exercise/fitness, fertility, sexual health, and body image (all p values < 0.05)., Conclusion: AYA and MAA use similar resources on the internet and SM, but AYA sought information related to specific needs. Development of future resources should focus on an internet-based platform rather than a SM platform, coupled with promoting awareness of the resource.

Objectives: The internet and social media provide information and support to cancer survivors, and adolescent and young adults (AYA, age < 40 years), adults, and older (age 65+ years) cancer survivors may have different needs. We evaluated the impact of age on cancer-related internet and social media use and confidence in evaluating online information for cancer-care decision making., Materials and Methods: Cancer survivors completed a convenience cross-sectional survey evaluating their cancer-related internet and social media use and their confidence in using these resources for decision making. Multivariable regression models evaluated the impact of age on usage patterns and confidence., Results: Among 371 cancer survivors, 58 were older adults and 138 were AYA; 74% used the internet and 39% social media for cancer care; 48% felt confident in using online information for cancer-care decisions. Compared to adult survivors, there was a non-significant trend for older survivors to be less likely to use the internet for cancer-care information(aOR = 0.49, 95% CI[0.23-1.03], P = .06), while AYA were more likely to use social media for cancer-care (aOR = 1.79[1.08-2.99], P = .03). Although confidence at using online information for cancer-care decision making did not differ between age groups, increasing age had a non-significant trend towards reduced confidence (aOR = 0.99 per year [0.97-1.00], P = .09). Most commonly researched and desired online information were causes/risk factors/symptoms, treatment options, and prognosis/outcomes., Conclusions: Age may influence the use of internet and social media for cancer-care, and older cancer survivors may be less confident at evaluating online information for cancer-care decision making. Future research should explore other strategies at meeting the informational needs of older cancer survivors., Competing Interests: Declaration of Competing Interest There are no conflicts of interest from any author. All authors have approved the final article., (Copyright © 2020 Elsevier Inc. All rights reserved.)