Lymphodepleting chemotherapy practices and effect on safety and efficacy outcomes in patients with solid tumours undergoing T cell receptor-engineered T cell (TCR-T) Therapy: a systematic review and meta-analysis.

BACKGROUND: T cell receptor-engineered T cell (TCR-T) therapy has shown promising efficacy in advanced solid tumours. Lymphodepleting (LD) chemotherapy improves TCR-T cell therapy efficacy but is associated with significant toxicities. Evidence is sparse regarding the optimum LD regimen for TCR-T cell therapy in solid tumours. METHODS: A systematic review was conducted of interventional, prospective clinical trials describing LD practices prior to TCR-T cell therapy in patients with advanced solid tumours. The objective was to define LD regimens administered prior to TCR-T cell therapy and their effects on specific safety and efficacy outcomes in this patient population. RESULTS: Searches returned 484 studies, 19 (231 patients) met the eligibility criteria. Cyclophosphamide (cyclo) 60 mg/kg daily (2 days), plus fludarabine (fludara) 25 mg/m2 daily (5 days) was the most common LD regimen (38% of studies). Higher dose LD regimens were associated with increased pooled incidence rates of febrile neutropaenia compared to low dose (0.64, [95% Confidence interval (CI): 0.50-0.78], vs. 0.39 [95% CI: 0.25-0.53], respectively) but were not significantly associated with higher objective responses (odds ratio: 1.05, 95%CI: 0.60-1.82, p = 0.86). A major shortfall in safety data reporting was identified; determination of LD regimen effects on many safety outcomes was not possible. CONCLUSION: Standard consensus guidelines for the design and reporting of adoptive cell therapy (ACT) studies would facilitate accurate risk-benefit analysis for optimising LD regimens in patients with advanced solid tumours.

Serial ctDNA analysis predicts clinical progression in patients with advanced urothelial carcinoma.

BACKGROUND: Targeted sequencing of circulating tumour DNA (ctDNA) is a promising tool to monitor dynamic changes in the variant allele frequencies (VAF) of genomic alterations and predict clinical outcomes in patients with advanced urothelial carcinoma (UC). METHODS: We performed targeted sequencing of 182 serial ctDNA samples from 53 patients with advanced UC. RESULTS: Serial ctDNA-derived metrics predicted the clinical outcomes in patients with advanced UC. Combining serial ctDNA aggregate VAF (aVAF) values with clinical factors, including age, sex, and liver metastasis, improved the performance of prognostic models. An increase of the ctDNA aVAF by ≥1 in serial ctDNA samples predicted disease progression within 6 months in 90% of patients. The majority of patients with aVAFs ≤0.7 in three consecutive ctDNA samples achieved durable clinical responses (≥6 months). CONCLUSIONS: Serial ctDNA analysis predicts disease progression and enables dynamic monitoring to guide precision medicine in patients with advanced UC.

Programmed death-ligand 1 (PD-L1) expression predicts response to neoadjuvant chemotherapy in triple-negative breast cancer: a systematic review and meta-analysis.

BACKGROUND: In patients with metastatic triple-negative breast cancer (TNBC), programmed death-ligand 1 (PD-L1) expression has been demonstrated to predict response to immunotherapy. It is unclear whether PD-L1 expression measured with currently available validated assays can predict chemotherapy response in patients with non-metastatic TNBC. METHODS: We conducted a systematic review and meta-analysis of clinical studies to assess the PD-L1 expression as a predictor of response to chemotherapy in non-metastatic TNBC using validated assays. The primary endpoint was pathological complete response (pCR) rate to neoadjuvant chemotherapy. Secondary endpoints included the prevalence of PD-L1 expression in non-metastatic TNBC and its impact on disease-free survival (DFS) and overall survival (OS). Moreover, RNA sequence data from the TCGA breast cancer cohort was used to define the relationship between PDCD1 expression and response to chemotherapy and prognosis. RESULTS: Nineteen studies were eligible for the meta-analysis with a total of 2403 patients with non-metastatic TNBC disease. The PD-L1-positive cohort had a significantly higher likelihood of achieving pCR with neoadjuvant chemotherapy (pooled odds ratio = 1.95; 95% CI = 1.39-2.73, p < 0.0001). In studies which reported long-term outcomes, PD-L1 positivity was associated with significantly better DFS and OS compared to PD-L1 negative patients (pooled hazard ratio = 0.51; 95% CI = 0.35-0.74, p < 0.0001 and 0.51; 95% CI = 0.27-0.94, p = 0.031, respectively). Transcriptomic data suggested that PD-L1 expression is a surrogate marker for the upregulation of key immune-related genes that mediate response to chemotherapy in TNBC. CONCLUSION: This analysis clearly shows that patients with PD-L1 positive TNBC respond better to neoadjuvant chemotherapy and are associated with better survival outcomes compared to patients with PD-L1 negative tumours. The newly distinct quadruple negative breast cancer (QNBC) subtype should be defined as the BC subtype with the poorest outcome in the non-metastatic setting, highlighting the need for more aggressive therapy approaches.

Safety of Combination Immune Checkpoint Inhibitors Compared to Monotherapy; A Systematic Review and Meta-Analysis.

Combination immune checkpoint inhibitors (ICIs) achieved higher efficacy than monotherapy in many types of cancers. We searched PubMed, Scopus, and Cochrane databases for randomized phase II/III trials in cancer patients receiving combination ICIs vs. Monotherapy. Our search retrieved 934 records. Eight studies were found to be eligible for meta-analysis recruiting 2544 patients. Combined immunotherapy nivolumab plus ipilimumab was associated with statistically significant higher risk of all grade adverse events (AE), and discontinuation due to all grade AEs as compared to both ipilimumab or nivolumab. Although combination ICIs showed better oncological activity, it carried a higher risk of all grade irAEs.

Availability of Informal Caregivers for Palliative Care Patients with Cancer: Is there a Difference between Higher- and Lower-Income Settings.

OBJECTIVE: Family caregivers are the default caring personnel for terminal cancer patients. The characteristics, demographics, distribution, psychological burden, and socioeconomic standards differ between high- and low-income countries. We aimed to assess those factors and their direct reflection on both the patient and the caregiver. PATIENTS AND METHODS: This is a comparative cross-sectional study for terminal cancer patients in the palliative care unit between the United Kingdom (UK) as a high-income community and Egypt as a low-income community. We assessed the different characteristics, demographics, living place, the degree of relevance, and the availability of caregivers. RESULTS: We have recruited 216 patients from the UK and 117 patients from Egypt. Informal caregivers were available in 74.5% and 92.3% for these patients with a mean age of 71.5 (standard deviation [SD] 16) years and 50.9 (SD 15.18) years, respectively. There has been a statistically significant difference between the two countries' caregivers in being married, family, and living in the same household (P < 0.0001). CONCLUSION: Low-income countries are more common to have an informal caregiver who is a family member of different degree of relevance. Caregivers in low-income settings tend to be younger, of the female gender, married, and living in the same household than in high-income ones.

Endocrine Disorders Developing after Surgical Intervention of Craniopharyngioma in Children.

Craniopharyngiomas, albeit their benign nature, can cause severe damage to visual, hypothalamic, endocrine and neurologic functions which make their total resection an inevitable approach to save the patient's life. However, significant therapy-related long term complications make those traditional treatment options debatable and hazardous. This review will focus on the various complications that affect the childrens' quality of life considerably such as, diabetes insipidus, precocious puberty and hypothalamic obesity.

Leprosy Masquerading as Systemic Rheumatic Diseases.

Rheumatologic manifestations not only are encountered in leprosy but also can be the first and even the sole presenting manifestation. The hallmark of leprosy is skin and peripheral nerve affection; however, it can affect a wide range of other organs, with the joints being the commonest. We have searched PubMed with the key words leprosy, arthritis, vasculitis, rheumatic diseases, and autoantibodies in a proper combination. Relevant studies were retrieved from scanning of their abstracts. The relevant references provided in these articles were also selected and reviewed. We summarize the clinical and laboratory manifestations that make leprosy masquerade as a systemic rheumatic disease. Moreover, we report 4 Egyptian patients who presented with rheumatologic manifestations, namely, arthritis and vasculitis that turned out to be leprosy related.

The evolution of metastatic upper tract urothelial carcinoma through genomic-transcriptomic and single-cell protein markers analysis.

The molecular characteristics of metastatic upper tract urothelial carcinoma (UTUC) are not well understood, and there is a lack of knowledge regarding the genomic and transcriptomic differences between primary and metastatic UTUC. To address these gaps, we integrate whole-exome sequencing, RNA sequencing, and Imaging Mass Cytometry using lanthanide metal-conjugated antibodies of 44 tumor samples from 28 patients with high-grade primary and metastatic UTUC. We perform a spatially-resolved single-cell analysis of cancer, immune, and stromal cells to understand the evolution of primary to metastatic UTUC. We discover that actionable genomic alterations are frequently discordant between primary and metastatic UTUC tumors in the same patient. In contrast, molecular subtype membership and immune depletion signature are stable across primary and matched metastatic UTUC. Molecular and immune subtypes are consistent between bulk RNA-sequencing and mass cytometry of protein markers from 340,798 single cells. Molecular subtypes at the single-cell level are highly conserved between primary and metastatic UTUC tumors within the same patient.

Molecular Basis of Tumorigenesis of Bladder Cancer and Emerging Concepts in Developing Therapeutic Targets.

BACKGROUND: Advanced urothelial carcinoma (UC) is an aggressive disease whose mutagenic processes are yet to be elucidated. Targeted therapies are urgently needed, but the road from bench to bedside is slowly progressing. In this review, we discuss urothelial carcinoma etiology, along with the most recent advances in UC candidate targeted therapies. METHODOLOGY: A comprehensive database search was performed. We aimed to review the most recent updates on UC genomics and targeted therapies. Pre-clinical as well as clinical studies were included. RESULTS: Our review highlights the advances in understanding the molecular basis of urothelial tumorigenesis, including smoking, chemical parasitic carcinogens, inheritance, and APOBEC3 editing enzymes. We discussed how these factors contributed to the current mutational landscape of UC. Therapeutic options for UC are still very limited. However, several promising therapeutic approaches are in development to leverage our knowledge of molecular targets, such as targeting fibroblast growth factor receptors (FGFR), DNA damage repair pathways, and HER2. CONCLUSIONS: Blindly testing targeted therapies based on other cancer data is not sufficient. UC-specific biomarkers are needed to precisely use the appropriate drug for the appropriate population. More efforts to understand UC biology and evolution are urgently needed.

Evidence of clinical efficacy of a first generation CD19 CAR T cell in B cell malignancies.

The persistence and reactivity of CAR T cells were enhanced by adding co-stimulatory domains, which is the basis of currently approved CAR-T cell therapies. However, this comes at the expense of increasing toxicities from the strong cytokine release effect. This is the first report from anti-CD19 CAR-T cell therapy with a single activation domain to show a favourable safety profile and clinical efficacy with two patients who achieved durable responses up to 28 months in a cohort with heavily pretreated B cell malignancies.

The Landscape of BRCA Mutations among Egyptian Women with Breast Cancer.

BACKGROUND: Deleterious germline mutations in BRCA1 and BRCA2 genes are associated with a high risk of breast and ovarian cancer. In many developing countries, including Egypt, the prevalence of BRCA1/2 mutations among women with breast cancer (BC) is unknown. AIM: We aimed to determine the prevalence of deleterious germline BRCA mutations in Egyptian patients with breast cancer. METHODS: We report the results of a cohort study of 81 Egyptian patients with breast cancer who were tested for germline BRCA1/2 mutations during routine clinical practice, mostly for their young age of presentation, BC subtype, or presence of family history. In addition, we searched five databases to retrieve studies that reported the prevalence of BRCA1/2 mutation status in Egyptian women with BC. A systematic review of the literature was performed, including prospective and retrospective studies. RESULTS: In our patient cohort study, 12 patients (14.8%) were positive for either BRCA1/2 deleterious mutations. Moreover, 13 (16.1%) patients had a variant of unknown significance (VUS) of BRCA1/2 genes. Twelve studies were eligible for the systematic review, including 610 patients. A total of 19 deleterious germline mutations in BRCA1/2 were identified. The pooled prevalence of BRCA1/2 mutations was 40% (95% confidence interval 1-80%). CONCLUSION: The reported prevalence was highly variable among the small-sized published studies that adopted adequate techniques. In our patient cohort, there was a high incidence of VUS in BRCA1/2 genes. Accordingly, there is an actual demand to conduct a prospective well-designed national study to accurately estimate the prevalence of BRCA1/2 mutations among patients with BC in Egypt.

The Emerging Treatment Options of Plasmablastic Lymphoma: Analysis of 173 Individual Patient Outcomes.

Plasmablastic lymphoma (PBL) is a newly recognized aggressive subtype of non-Hodgkin lymphoma. Its rarity hinders testing effective treatment options in clinical trials. We conducted a systematic review of PubMed and our internal records to retrieve patients with a PBL diagnosis with evaluable treatment outcomes. Aggressive chemotherapy was defined as more intense regimens than CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone). We compiled a meta-dataset of 173 patients. The median age at diagnosis was 48.5 years, 75% of patients were male, and stages III/IV accounted for 47% of the cohort. Of 138 patients with known response status after first-line chemotherapy, 63 (45%) achieved a complete response with a 2-year relapse-free survival of 71.6%. Sixty-nine (50%) patients received first-line CHOP. There was no significant difference in the objective response rate among the 2 most commonly used regimens, CHOP and DA-EPOCH (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) (69% vs. 79%; P = .4). The median follow-up was 9 months, and the 2-year overall survival (OS) was 47.4%. A univariate analysis identified factors associated with worse OS, including stage III/IV (hazard ratio [HR], 2.82; P < .001), human herpes virus-8-positive (HR, 3.30; P = .01), bone marrow (HR, 1.07; P = .035), and cardiorespiratory involvement (HR, 2.26; P = .015). Meanwhile, Epstein-Varr virus-encoded small RNA-positivity (HR, 0.31; P < .001) and involvement of head and neck (HR, 0.44; P = .009) were associated with better OS. Multivariate analysis showed that aggressive chemotherapy was significantly associated with better OS (HR, 0.22; P = .016). Patients with PBL with high-risk features, such as advanced stage, human herpes virus-8-positivity, bone marrow, and cardiorespiratory involvement, require more aggressive chemotherapy. Bortezomib and lenalidomide are promising add-on agents.

Pathological responses and survival outcomes in patients with locally advanced breast cancer after neoadjuvant chemotherapy: a single-institute experience.

BACKGROUND: Pathological complete response (pCR) is a surrogate for the efficacy of neoadjuvant chemotherapy (NCT) in locally advanced breast cancer (LABC). We analyzed the predictive clinical factors for pathological responses and survival outcomes in a cohort of Egyptian patients. METHODS: We evaluated the medical records of patients with breast cancer who received NCT in our academic institute. Survival curves were estimated with the Kaplan-Meier method. Cox proportional models were used for multiple regression analysis. RESULTS: Our cohort included 368 patients with a median age of 48 years (range 21-70). The median follow-up time was 3 years. The clinical tumor stage (T3-4) represented 58%, with 80% having positive axillary nodes. The luminal subgroup prevailed by 68%. The objective response rate (ORR) reached 78%, and 16% of patients achieved pCR. The clinical node stage and optimal chemotherapy were associated with higher ORR (p = 0.035 and p = 0.001, respectively). Predictors of pCR were clinical T-stage (p = 0.026), high Ki-67 index > 20 (p = 0.05), and receiving optimal chemotherapy (p = 0.014). The estimated 3-year disease free-survival (DFS) was 53%. Receptor status, achieving ORR, and pCR were associated with better DFS with hazard ratios of 0.56, p = 0.008; 0.38, p = 0.04; and 0.28, p = 0.007, respectively. CONCLUSIONS: Luminal tumors still draw benefit from neoadjuvant chemotherapy in terms of clinical response and breast conservative surgery. Treatment escalation to those who did not achieve pCR requires more investigation, given a higher recurrence rate in real-world experience.

Causes of Death Among Patients With Metastatic Prostate Cancer in the US From 2000 to 2016.

Importance: Owing to improved survival among US patients with prostate cancer (PC), patients tend to live long enough after a PC diagnosis for non-cancer-related comorbidities to be associated with their overall survival. Although studies have investigated causes of death among patients with localized PC, data are lacking regarding causes of death among patients with metastatic PC. Objective: To assess causes of death among US patients with metastatic PC from 2000 to 2016. Design, Setting, and Participants: This retrospective cohort study used data from the Surveillance, Epidemiology, and End Results Program database to analyze a sample of 26 168 US men who received a diagnosis of metastatic PC from January 1, 2000, to December 31, 2016. Data were analyzed from February 2 to July 28, 2020. Exposure: Diagnosis of metastatic PC. Main Outcomes and Measures: Standardized mortality ratios (SMRs) for different causes of death were calculated by dividing the observed number of deaths from each cause of death by the expected number of deaths in the age-matched US male population for the same period, adjusting for age and race/ethnicity. Results: Of 26 168 patients with metastatic PC included in the analysis, 48.9% were aged 50 to 70 years (mean age at diagnosis, 70.83 years); 74.5% were White individuals, and 72.7% received a diagnosis of stage M1b metastatic PC. A total of 16 732 patients (63.9%) died during the follow-up period. The mean age at death was 74.13 years. Most deaths (59.0%) occurred within the latency period of 2 years after diagnosis of metastatic PC, whereas 31.6% occurred 2 to 5 years after diagnosis and 9.4% occurred more than 5 years after diagnosis. Of the total deaths, 13 011 (77.8%) were from PC, 924 (5.5%) were from other cancers, and 2797 (16.7%) were from noncancer causes. During all latency periods, the most common noncancer causes of death were cardiovascular diseases (SMR, 1.34; 95% CI, 1.26-1.42), chronic obstructive pulmonary disease (SMR, 1.19; 95% CI, 1.03-1.36), and cerebrovascular diseases (SMR, 1.31; 95% CI, 1.13-1.50). Conclusions and Relevance: In this cohort study, deaths from noncancer causes, including cardiovascular disease, constituted a substantial number of deaths among men with metastatic PC. Therapy and follow-up should be tailored to the needs of each patient with metastatic PC, and counseling regarding future health risks should be provided.

Functional comparison of exome capture-based methods for transcriptomic profiling of formalin-fixed paraffin-embedded tumors.

The availability of fresh frozen (FF) tissue is a barrier for implementing RNA sequencing (RNA-seq) in the clinic. The majority of clinical samples are stored as formalin-fixed, paraffin-embedded (FFPE) tissues. Exome capture platforms have been developed for RNA-seq from FFPE samples. However, these methods have not been systematically compared. We performed transcriptomic analysis of 32 FFPE tumor samples from 11 patients using three exome capture-based methods: Agilent SureSelect V6, TWIST NGS Exome, and IDT XGen Exome Research Panel. We compared these methods to the TruSeq RNA-seq of fresh frozen (FF-TruSeq) tumor samples from the same patients. We assessed the recovery of clinically relevant biological features. The Spearman's correlation coefficients between the global expression profiles of the three capture-based methods from FFPE and matched FF-TruSeq were high (rho = 0.72-0.9, p < 0.05). A significant correlation between the expression of key immune genes between individual capture-based methods and FF-TruSeq (rho = 0.76-0.88, p < 0.05) was observed. All exome capture-based methods reliably detected outlier expression of actionable gene transcripts, including ERBB2, MET, NTRK1, and PPARG. In urothelial cancer samples, the Agilent assay was associated with the highest molecular subtype concordance with FF-TruSeq (Cohen's k = 0.7, p < 0.01). The Agilent and IDT assays detected all the clinically relevant fusions that were initially identified in FF-TruSeq. All FFPE exome capture-based methods had comparable performance and concordance with FF-TruSeq. Our findings will enable the implementation of RNA-seq in the clinic to guide precision oncology approaches.

Adjuvant ovarian function suppression and tamoxifen in premenopausal breast cancer patients: A meta-analysis.

BACKGROUND: The benefit of adding ovarian function suppression (OFS) to tamoxifen in the adjuvant treatment of premenopausal women with breast cancer is uncertain. We conducted a meta-analysis of randomized controlled trials that addressed this question. METHODS: Systematic search of PubMed, the web of science, and the meeting library of ASCO, ESMO, and SABCS was conducted using the following keywords: tamoxifen, ovarian suppression, and breast cancer. Eligible studies were those recruiting patients with breast cancer randomized to receive adjuvant tamoxifen and OFS versus tamoxifen alone. Pooled hazard ratio [HR]) for disease-free (DFS) and overall survival (OS) with 95% confidence interval (CI) were calculated using the fixed effect model. RESULTS: We searched a total of 845 records, of which 5 clinical trials, including 7557 patients, were eligible for our analysis. Adding OFS to tamoxifen improved DFS with pooled HR: 0.88 (95% CI: 0.80-0.96, P= 0.004) and OS (pooled HR: 0.87 {95% CI: 0.77-0.98, P= 0.02}) compared to tamoxifen alone. The benefit of the addition of OFS to tamoxifen was mostly observed in patients younger than 40 years where the pooled HRs of DFS was 0.76 (95% CI: 0.63-0.91; P= 0.004), and in those who received adjuvant chemotherapy with pooled HRs of DFS 0.80 (95% CI: 0.65-0.99, P= 0.042). There was an increase in the incidence of all grade musculoskeletal symptoms and high-grade hot flushes with the addition of OFS with risk ratios of 1.12 (95% CI: 1.07-1.17, P< 0.001) and 2.14 (95% CI: 1.01-4.51, P= 0.047) respectively. CONCLUSION: Our analysis indicates that the addition of OFS to tamoxifen improves DFS and OS. This strategy could be considered in patients in which tamoxifen alone is not deemed sufficient or in case of poor tolerance to OFS with aromatase inhibitors.

Common germline-somatic variant interactions in advanced urothelial cancer.

The prevalence and biological consequences of deleterious germline variants in urothelial cancer (UC) are not fully characterized. We performed whole-exome sequencing (WES) of germline DNA and 157 primary and metastatic tumors from 80 UC patients. We developed a computational framework for identifying putative deleterious germline variants (pDGVs) from WES data. Here, we show that UC patients harbor a high prevalence of pDGVs that truncate tumor suppressor proteins. Deepening somatic loss of heterozygosity in serial tumor samples is observed, suggesting a critical role for these pDGVs in tumor progression. Significant intra-patient heterogeneity in germline-somatic variant interactions results in divergent biological pathway alterations between primary and metastatic tumors. Our results characterize the spectrum of germline variants in UC and highlight their roles in shaping the natural history of the disease. These findings could have broad clinical implications for cancer patients.

MicroRNA as a diagnostic biomarker in childhood acute lymphoblastic leukemia; systematic review, meta-analysis and recommendations.

Several studies detected abnormal mi-RNAs expression levels in childhood Acute Lymphoblastic Leukemia (ALL) with potential diagnostic value. We conducted a systematic search on certain microRNAs in childhood ALL. We included 17 studies with a total of 928 ALL children and 307 controls. Ten studies provided miRNAs expression levels and seven provided frequency data. Sensitivity and specificity of a single miRNA ranged from 46.55% to 100% and from 71.8% to 100%, respectively. The highest diagnostic odds ratio (DOR) was for the diagnostic panel (miR-128a and miR-223) reaching 546 [95% CI: 73.768-4041.282]. Also, miR-128a, miR-128b, miR-223, let-7b, miR-155 and miR-24 can be used as diagnostic discriminatory biomarkers between ALL and AML. Further large cohort studies are needed to confirm our results.

Safety issues with the ALK inhibitors in the treatment of NSCLC: A systematic review.

INTRODUCTION: Oral tyrosine kinase inhibitors targeting the chromosomal rearrangements of the anaplastic lymphoma kinase gene (ALK) in non-small cell lung cancer (NSCLC) were associated with superior clinical outcome. Tyrosine Kinase inhibitors (TKIs) are known to have peculiar toxicity profile, hence, increasing awareness to the safety profile of ALK inhibitors is essential. METHODS: A comprehensive systematic review of literature has been conducted to include prospective trials that used the ALK inhibitors Crizotinib, Ceritinib, Alectinib, Brigatinib and Lorlatinib in patients with advanced NSCLC and have available efficacy and toxicity results. RESULTS: A total of 14 studies including 2793 patients were considered eligible for our review and included two phase IB, seven phase II and five phase III studies. The most common adverse events (AEs) observed with ALK inhibitors were gastrointestinal (GI) toxicities as nausea (up to 83%), vomiting (up to 67%) and diarrhea (up to 86%), elevation of liver enzymes occurred in up to 60% and fatigue (up to 43%). There were differences in the toxicity patterns between the different ALK inhibitors with more GI and hepatic toxicities with Ceritinib, more visual disorders with Crizotinib, more dysgeusia with crizotinib and Alectinib and possibly more respiratory complications with Brigatinib. Most of the AEs were low grade and treatment-related deaths were associated with ALK inhibitors in 0-1% of patients. CONCLUSION: Most of adverse effects of ALKi can be managed efficiently via dose modifications or interruptions. Timely identification of each ALKi pattern of toxicity can prevent treatment-related morbidity and mortality in this palliative setting.