Search

This study aimed to report the collective clinical characteristics of oral side effects associated with imatinib therapy according to age, sex, and clinical condition. A bibliographic review was performed using the PubMed, Web of Science, Scopus, Cochrane Library, and Embase databases. Forty-five cases of oral side effects due to imatinib therapy were identified in the literature. With the addition of five new cases seen at the authors' institution, a total of 50 cases were analysed. Of the five new cases, four with gastrointestinal stromal tumours developed oral lichenoid lesions (OLLs), and one with chronic myeloid leukaemia (CML) developed oral hyperpigmentation (OHP). Of the total 50 patients, 26 were male and 24 were female, and age ranged from 29 to 86 years. Most patients were ≥50 years old (80%); only three patients were jaw was the least common, with just five cases (10%). Among the patients with OHP, the predominant clinical condition was CML (22 cases, 91.7%). In conclusion, the possibility of oral side effects needs to be considered during the examination of patients receiving imatinib therapy. [ABSTRACT FROM AUTHOR]

In this retrospective study, among 107 mRCC patients with favorable risk receiving TKIs, those with 1 metastatic site had significantly longer overall survival and a trend of better progression-free survival compared to patients with > 1 site. Liver involvement was identified as independent poor prognostic factor for PFS. The site of metastases should be considered when choosing therapies for these patients. Background: Although in metastatic renal cell carcinoma (mRCC) patients with intermediate and poor risk the benefit of combination strategies versus tyrosine kinase inhibitor (TKI) has been ascertained, in those with favorable risk data are ambiguous. Herein, we investigated the impact of number and type of metastatic site in patients with favorable risk to contribute to the best therapeutic choice. Material and Methods: Multicenter data regarding patients with favorable risk mRCC carcinoma receiving first-line TKIs, sunitinib or pazopanib, were retrospectively collected. We divided our population into 2 groups based on the number of metastatic sites and analyzed its impact on tumor response and efficacy outcome. The Kaplan-Meier method was used to estimate efficacy outcomes and the log-rank test to examine differences between subgroups. Results: A total of 107 patients with a median age of 69 years were included in the final analysis. Patients with 1 metastatic site, compared with patients with > 1 site, had a significantly longer overall survival (OS) (not reached vs. 66 months) and a trend, although not statistically significant, of better progression-free survival (PFS) (31 vs. 17 months). In patients with 1 metastatic site, liver involvement was correlated with worse PFS and OS at the univariate analysis (P = .01) and was confirmed as independent poor prognostic factor for PFS at multivariate analysis. Conclusion: In conclusion, we reported a longer OS in favorable risk mRCC patients receiving TKI with only 1 metastatic site. Nevertheless, in patients with a single metastatic site, hepatic involvement correlated with worse PFS compared to other metastatic sites. [ABSTRACT FROM AUTHOR]

Cabozantinib is a widely used multikinase-inhibitor for the treatment of metastatic renal cell carcinoma (mRCC). This study analyzed the efficacy of cabozantinib in real world, including heavily pretreated patients. Antitumor activity was observed in various treatment lines; moreover, we observed that an alternative treatment schedule improves PFS when compared to continuous dosing. No new safety signals emerged from our analysis. Background: The multikinase-inhibitor Cabozantinib is a widely used treatment strategy in metastatic renal cell carcinoma (mRCC), either in combination with the programmed cell death protein-1 (PD-1) inhibitor nivolumab or as monotherapy. Cabozantinib is given continuously at a dose of 60 mg once daily when used as a single agent and at 40 mg when combined with nivolumab. Treatment-related adverse events (TRAE's) were shown to occur frequently. Objective: We aimed to assess the safety and efficacy of cabozantinib in patients with mRCC. Patients were treated in various lines. Furthermore, we analyzed the impact of an alternative treatment schedule in patients not able to maintain continuous dosing. Patients: This is a single center retrospective study from the Medical University of Vienna. Outcome Measurements and Statistical Analysis: Overall response rates (ORR), progression free survival (PFS) and overall survival (OS) were evaluated for the entire cohort, by treatment line and by treatment schedule. Results: Between January 2014 until April 2021, 71 patients received cabozantinib. Sixty-seven patients were eligible for full evaluation. By IMDC cr iter ia, 32.4%, 59.2%, and 8.5% were classified as favorable, intermediate and poor risk respectively. Cabozantinib was offered as a 2nd-line or 3rd-line treatment in 38.0% and 32.4% of patients, respectively. An alternative treatment schedule was offered in 39.1% of patients. Objective responses were found in 43.3% (CR 6%) of patients and the median PFS was 10.8 months (95% CI: 5.5-16.2). When compared to continuous dosing, an alternative treatment schedule was associated with longer PFS (12.2 months (95% CI: 0-25.5) vs. 6.1 months (95% CI: 0.37-11.8) (P = .014, HR 0.46 (95% CI: 0.24-0.86), respectively) and a lower frequency and severity of TRAE's. Conclusions: Safety and efficacy of cabozantinib in real world is comparable to what has been observed in the pivotal trials, irrespective of the treatment line. An alternative schedule may further improve efficacy and safety. [ABSTRACT FROM AUTHOR]

This real-world study of patients with renal cell carcinoma (RCC) compared clinical outcomes for patients treated with tyrosine kinase inhibitors (TKI), or an immunotherapy combination (IO + TKI or IO + IO). Medical record data was collected retrospectively for 498 patients across North America, Europe, and the UK. Immunotherapy (IO) combination was associated with longer progression-free survival (PFS) and time to next treatment (TTNT) than tyrosine kinase inhibitor (TKI) monotherapy. Among IO combinations, IO + TKI was associated with significantly improved progression-free survival (PFS) and TTNT compared to IO + IO. Background: Nearly 30% of new renal cell carcinoma (RCC) cases are diagnosed at an advanced or metastatic stage. Recent approvals of immunotherapies (IO) have significantly impacted patient care, but real-world outcomes of these treatments have not been widely evaluated. Methods: Eligible physicians abstracted demographic and clinical data from patient medical records for patients with advanced clear and non-clear cell RCC (aRCC) who initiated treatment between January 1, 2018, and December 31, 2020. Overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan-Meier method. A multivariate Cox regression model was developed to assess the impact of treatment category on clinical outcomes while controlling for International Metastatic RCC Database Consortium (IMDC) risk category, histology, and other patient characteristics. Results: A total of 498 patients were included (201 from US, 62 from Canada, 58 from UK, 59 from France, 58 from Germany, 60 from Spain). Of these, 250 received tyrosine kinase inhibitor (TKI) monotherapy, 197 received immunotherapy (IO) combination (119 IO + TKI, 78 IO + IO), and 32 received IO monotherapy as first-line treatment for aRCC; 19 patients received various other regimens. 16% of patients had a favorable IMDC risk score. Based on results of multivariable Cox regression, PFS (hazard ratio [HR] [95% confidence interval (CI)]: 0.50 [0.36-0.72]) (P < .001) and time to next treatment (TTNT) were significantly longer (HR [95% CI]: 0.54 [0.39-0.73]) (P < .001) for patients treated with IO combination versus TKI monotherapy. IO combination had a numerically reduced, but statistically insignificant, risk of death versus TKI monotherapy (HR: 0.66; P = .114). IO + TKI combination was associated with significantly longer PFS and reduced risk of progression (HR: 0.52; P = .04) versus IO + IO combination; similar results were observed for TTNT (HR: 0.57; P = .03). Conclusion: Our evaluation of realworld treatment outcomes in aRCC revealed that IO + TKI combination is associated with improved PFS and prolonged TTNT compared with TKI monotherapy and IO + IO combination. [ABSTRACT FROM AUTHOR]

As an effective locoregional therapy, transarterial chemoembolization (TACE) can induce vascular endothelial growth factor and PD-1/PDL-1 upregulation, accompanied by a reduction in tumor burden. The present study aimed to compare the efficacy of TACE combined with tyrosine kinase inhibitors (TKIs) plus immune checkpoint inhibitors (ICIs) (TACE-TKI-ICIs) versus TKIs plus ICIs (TKI-ICIs) in patients with unresectable hepatocellular carcinoma (HCC). The clinical data of 198 patients diagnosed with unresectable HCC who received a TKI (lenvatinib or sorafenib) plus an ICI (sintilimab or camrelizumab) with or without TACE were retrospectively reviewed between October 2019 and April 2022. Baseline characteristics of the TACE-TKI-ICI group and the TKI-ICI group were matched by propensity score matching in a 1:1 ratio. The tumor response, progression-free survival (PFS), and overall survival (OS) were evaluated and compared between the two groups. After matching, 54 patients were enrolled in each group. The objective response rate (ORR) and disease control rate (DCR) were higher in the TACE-TKI-ICI group (ORR: 63.0% vs. 29.6%, P < 0.001; DCR: 85.2% vs. 53.7%, P < 0.001). The median PFS was significantly longer in the TACE-TKI-ICI group (9.9 vs. 5.8 months; P = 0.026). The median OS between the two groups also reached a significant difference (not reached vs. 18.5 months; P = 0.003). In this retrospective study, the results indicated that the addition of TACE to TKI-ICI therapy could contribute to better tumor control, PFS, and OS benefits in patients with unresectable HCC. [ABSTRACT FROM AUTHOR]

La toxicité cutanée spécifique des inhibiteurs de la tyrosine kinase de Bruton est peu décrite. Nous rapportons un cas de vascularite systémique sévère induite par de l'ibrutinib. Une femme de 73 ans était suivie pour une leucémie lymphoïde chronique traitée par ibrutinib. Dix-huit mois après l'introduction du traitement, on notait des lésions ulcéronécrotiques, des orteils et de la langue. Une biopsie cutanée notait une vascularite des petits et moyens calibres. Le bilan biologique était négatif. Cette vascularite était réfractaire à la corticothérapie générale et à l'azathioprine. L'ibrutinib était arrêté dans l'hypothèse d'une vascularite médicamenteuse. Dès l'arrêt de l'ibrutinib, il y avait une amélioration des lésions cutanées. Le mode d'action de l'ibrutinib n'explique pas la survenue d'une vascularite liée à un possible mécanisme immuno-allergique. The specific cutaneous toxicity of Bruton's tyrosine kinase inhibitors is poorly described. We report a case of severe systemic vasculitis induced by ibrutinib. A 73-year-old woman with chronic lymphocytic leukemia was treated with ibrutinib. Eighteen months after treatment onset, ulceronecrotic lesions on toes and tongue occurred. Skin biopsy found vasculitis of small and medium vessels. Biologic tests were negative. This vasculitis was refractory to systemic corticosteroid therapy and azathioprine. Ibrutinib was stopped on the hypothesis of drug-induced vasculitis. Skin lesions improved after discontinuation of ibrutinib. The mechanism of action of ibrutinib does not explain the occurrence of vasculitis and an immunoallergic mechanism is suspected. [ABSTRACT FROM AUTHOR]

Introduction: Combination of immune-checkpoint inhibitor (ICI) and vascular endothelial growth factor (VEGF) antagonist has become the first line systemic treatment for advanced hepatocellular carcinoma (HCC). However, two-thirds of patients do not respond to ICI-based treatments and biomarkers for response remain elusive. Methods: Patients with advanced HCC who received Atezolizumab/Bevacizumab combination or Nivolumab during 2016-2022 were identified in our Liver Cancer Database. Retrospective review of their clinical data was performed to investigate parameters that could be predictive of immunotherapy response. Results: 96 patients received Atezolizumab/Bevacizumab (n=60) or Nivolumab (n=36). Median age at diagnosis was 67.1 years. 70 patients had received treatment and 26 patients were treatment naïve before starting immunotherapy. Mean pre-treatment AFP was 9780.7 (±32035) ng/mL. Confirmed objective response (complete or partial) was seen in 29% of the population (n=27). Disease remained stable in 12% (n=11) and progressed in 60% (n=56). On univariate analysis, pre-treatment AFP>400 ng/mL was associated with objective response (OR=4.5, 95% CI:1.7-11.9, p=0.0015), while white race (OR=0.35, 95% CI:0.13-0.92, p=0.030) and prior radiotherapy (OR=0.14, 95% CI:0.01-1.1, p=0.033) or systemic therapy with TKIs (OR=0.25, 95% CI:0.08-0.81, p=0.017) were associated with poor response. On multivariate analysis only AFP>400 ng/mL remained associated with response (OR=3.7, 95% CI:1.3-10.5, p=0.014). Overall survival (OS) at one and three years was 86% and 43% in responders, and 45% and 29% in non-responders, respectively. Conclusion: In our institutional experience, treatment naivety and pre-treatment AFP>400 ng/mL were associated with objective response. Prospective studies aimed at identifying factors associated with response to immunotherapy will aide patient selection. [ABSTRACT FROM AUTHOR]

Chronic myeloid leukemia (CML) is a hematological malignancy characterized by the presence of BCR-ABL protein. Imatinib (IMA) is considered as the first line therapy in management of CML which particularly targets the BCR-ABL tyrosine kinase protein. However, emergence of resistance to IMA hinders its clinical efficiency. Hence, identifying novel targets for therapeutic approaches in CML treatment is of great importance. Here, we characterize a new subpopulation of highly adherent IMA-resistant CML cells that express stemness and adhesion markers compared to naive counterparts. We performed several experimental assays including FISH, flow cytometry, and gene expression assays. Additionally, bioinformatics analysis was performed by normalized web-available microarray data (GSE120932) to revalidate and introduce probable biomarkers. Protein-protein interactions (PPI) network was analyzed by the STRING database employing Cytoscape v3.8.2. Our findings demonstrated that constant exposure to 5 ​μM IMA led to development of the adherent phenotype (K562R-adh). FISH and BCR-ABL expression analysis indicated that K562R-adh cells were derived from the original cells (K562R). In order to determine the role of various genes involved in epithelial–mesenchymal transition (EMT) and stem cell characterization, up/down-regulation of various genes including cancer stem cell (CSC), adhesion and cell surface markers and integrins were observed which was similar to the findings of the GSE120932 dataset. Treating CML patients with tyrosine kinase inhibitors (TKIs) as well as targeting adhesion molecules deemed to be effective approaches in prevention of IMA resistance emergence which in turn may provide promising effects in the clinical management of CML patients. [ABSTRACT FROM AUTHOR]

Single-agent immune checkpoint inhibitors (ICIs) have been tested in patients with advanced hepatocellular carcinoma (HCC), leading to objective response rates of 15-20%, mostly without a significant overall survival (OS) benefit. Furthermore, approximately 30% of HCC exhibits intrinsic resistance to ICIs. In the absence of predictive biomarkers to identify patients likely to benefit most from immunotherapy, research has moved to exploring combinations with potential activity in broader patient populations. Basket trials, including cohorts of patients with HCC, and early phase studies tested the combination of ICIs with anti-angiogenic agents as well as the combination of two different ICIs. The promising results that were achieved provided the rationale for the following phase III trials, which tested the combination of anti-PD-1/PD-L1 antibodies with bevacizumab, or tyrosine kinase inhibitors, or anti-CTLA-4 antibodies. Positive results from the IMbrave150 trial led to the practice-changing approval of atezolizumab-bevacizumab, the first regimen to demonstrate improved survival in the front-line setting since the approval of sorafenib. More recently, the HIMALAYA trial demonstrated the superiority of durvalumab-tremelimumab (STRIDE regimen) over sorafenib, establishing a new first-line option. In contrast, inconsistent results have been achieved with combinations of ICIs and tyrosine kinase inhibitors, with only one phase III trial showing an OS benefit. The rapid evolution of the therapeutic landscape for patients with advanced HCC has left many unanswered questions that will need to be addressed by future research. These include the choice and sequencing of treatments, identification of biomarkers, combinations with locoregional therapies, and development of new immunotherapy agents. This review summarises the scientific rationale and available clinical data for combination immunotherapy in advanced HCC. [ABSTRACT FROM AUTHOR]

Data on the effectiveness of atezolizumab plus bevacizumab (atezo-bev) after failure of multikinase inhibitor (MKI) therapy in patients with advanced hepatocellular carcinoma are scarce. This retrospective multicentre study included all consecutive patients treated with atezo-bev after failing one or more MKI treatments in the setting of an early access program. The primary endpoint was the objective response rate (ORR) by investigator assessment (using Response Evaluation Criteria in Solid Tumors v1.1). Overall survival (OS) and progression-free survival (PFS) were assessed using the Kaplan‒Meier method. Fifty patients were included in this analysis. Atezo-bev was started between April 2020 and November 2021 (median follow-up, 18.21 months). The investigator-assessed ORR was 14% (95% CI 5.37–22.63%), with 7 patients displaying a tumour response, and the disease control rate was 56% (95% CI 51.21–60.8%). After starting atezo-bev, the median OS was 17.1 months (95% CI 10.58–22.01), and the median PFS was 7.99 months (95% CI 4.78–10.50). Treatment-related adverse events led to treatment discontinuation in 7 patients. Atezo-bev every three weeks showed clinical benefit for a proportion of patients previously treated with one or multiple lines of MKIs. [ABSTRACT FROM AUTHOR]

Tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) have revolutionized the treatment of metastatic renal cell carcinoma (mRCC). Emerging data suggest that these agents can result in clinically significant cardiotoxicity, compromising the care. We conducted a prospective longitudinal study to evaluate the incidence of de novo cardiac dysfunction as assessed by echocardiography and blood biomarkers in mRCC patients receiving TKI with or without ICI followed at baseline, 3-month and 6-month. We recruited consecutive newly diagnosed mRCC patients treated at our institution between 2015 and 2018 as well as patients with localized RCC not treated with systemic therapies and healthy control (HC) subjects for comparison. Twenty-eight patients were enrolled in the mRCC group (a mean age of 65.2 ± 7.5 years), 29 patients in the localized RCC group (63.6 ± 8.9 years), and 20 volunteers in the HC group (52.9 ± 9.6 years). At baseline, patients from all three groups had normal cardiac function as measured by left ventricular ejection fraction (LVEF), although patients with mRCC or localized RCC had significantly lower mean LVEF compared to HC (61.9%, 62.4%, and 68.1% respectively). Otherwise, there were no statistically significant changes in echocardiographic parameters or incidence of clinical heart failure from baseline to 6-months in patients with mRCC. Cardiac blood biomarkers including troponin I, brain natriuretic peptide, and galectin-3 remained stable over time. Our findings suggest that contemporary treatment strategies of mRCC at this single institution are well tolerated without clinically meaningful overt declines in cardiac function over time. Further studies are warranted to include a larger number of patients to better assess the overall cardiovascular safety associated with contemporary treatments of mRCC. • Contemporary treatments of metastatic renal cell carcinoma (mRCC) include tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) but their cardiovascular safety has not been well documented. • We conducted a prospective longitudinal study to evaluate the incidence of de novo cardiac dysfunction in mRCC patients receiving TKI with or without ICI. • Our findings suggest that contemporary treatment strategies of mRCC at this single institution are well tolerated without clinically meaningful overt cardiac dysfunction. • Further studies are warranted to include a larger number of patients to better assess the overall cardiovascular safety associated with contemporary treatments of mRCC. [ABSTRACT FROM AUTHOR]

Sorafenib is currently one of the recommended treatments for symptomatic patients with desmoid-type fibromatosis (DTF). In this study, we aim to assess the clinical efficacy and tolerability of sorafenib in DTF patients. Patients aged>18 years with a histological diagnosis of DTF and who have received sorafenib were enroled in this prospective observational study. Demographic data, clinical profile, the initial dose of sorafenib, treatment-related toxicities, dose modifications, and responses were recorded. The primary objective was to assess the objective response rate (ORR). The secondary objectives were to evaluate progression-free survival (PFS), tolerability, and adverse effects of sorafenib. Response assessment was based on response evaluation criteria in solid tumours 1.1 criteria. Adverse effects were graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 criteria. Time to event was calculated by Kaplan-Meier analysis, and survival was compared by log-rank test. Univariate and multivariable cox regression analysis were used to find independent predictors of relapse. A total of 104 patients were enroled in the study. The median age of the study population was 32 (range, 18–81) years, and 66.35% of patients were females. On response assessment, ORR was 46.1% and stable disease was observed in 31.7% patients. ORR was higher in the appendicular site (51.7%) compared to the abdominal site (27.2%). PFS at 1 and 2 years was 86.6% (79.6–92.7%) and 73.7% (62.4–82.8%), respectively. Two-thirds (66.6%) of patients had already received some form of treatment. At the time of analysis, 70 (67.3%) patients were continuing sorafenib. Only 4.8% stopped sorafenib due to progression, 10.5% due to intolerable adverse effects, and 17.3% due to other reasons. The common treatment-related toxicities were hand-foot skin reaction (HFSR) (89.4%), fatigue (79.8%), alopecia (70.1%), and diarrhoea (48.0%). In the patients with a starting dose of ≥400 mg (48.0% of patients), discontinuation was necessitated in 12% of patients, and further dose reduction was required in 58%, while only about 13% required dose reduction or discontinuation at a starting dose of 200 mg (51.9% of patients). Responses were not compromised due to lower starting doses. Sorafenib has good activity in DTF, but it is associated with significant toxicity. The adverse effect profile is distinct in Indian patients with higher HFSR and alopecia. Due to the high rate of dose reduction/discontinuation with a starting dose of 400 mg, a starting dose of 200 mg may be recommended in Indian patients. • Sorafenib is an effective drug in treatment of symptomatic desmoid-type fibromatosis. • High incidence of toxicities with current recommended dose of 400 mg daily. • Indian patients have a higher risk of hand-foot skin reaction and alopecia. • A lower dose (200 mg daily) is as effective and well tolerated in Indian patients. [ABSTRACT FROM AUTHOR]

Fixed-drug combinations have been used for the treatment of cancer. Current anticancer therapies, however, tend to induce resistance and provoke important toxicity. Therefore, there is still a need for further optimized treatments that would also take into account drug-drug interactions. Tyrosine kinase inhibitors (TKIs) and Histone deacetylase inhibitors (HDACIs) are two anticancer drug classes currently used separately in clinical practice. Those drug classes are currently being investigated in clinical trials. Several findings confirm the safety and tolerability of these treatments accompanied by clinical improvement. The activity and specificity of drug combinations can be further improved by employing appropriate drug delivery systems, such as nanocarrier systems. The different pharmacokinetic profiles of each drug may lead to a loss in synergistic effects, affecting treatment efficiency. Several combinations of either TKI or HDACI with an anticancer drug of another class co-loaded inside liposomal carriers are being investigated in vivo and show promising results in terms of efficacy and safety. In this review we discuss strategies for the delivery of synergistic drug combinations for cancer treatment. [Display omitted] [ABSTRACT FROM AUTHOR]

From the US Medicare perspective, this study compared the cost-effectiveness of tepotinib and capmatinib for treating metastatic non–small cell lung cancer with tumors harboring mesenchymal–epithelial transition factor gene exon 14 skipping. A 3-state partitioned survival model assessed outcomes over a lifetime horizon. Parametric survival analysis of the phase 2 VISION trial informed clinical inputs for tepotinib. Capmatinib inputs were captured using hazard ratios derived from an unanchored matching-adjusted indirect comparison study and published literature. National cost databases, trial data, and literature furnished drug, treatment monitoring, and disease/adverse event management expenditures (2021 US dollars) and utility inputs. Outcomes were discounted at 3% annually. In the base case, tepotinib dominated capmatinib in frontline settings (incremental discounted quality-adjusted life-years [QALYs] and costs of 0.2127 and −$47 756, respectively) while realizing an incremental cost-effectiveness ratio of $274 514/QALY in subsequent lines (incremental QALYs and costs of 0.3330 and $91 401, respectively). In a line agnostic context, tepotinib produced an incremental cost-effectiveness ratio of $105 383/QALY (incremental QALYs and costs of 0.2794 and $29 447, respectively). Sensitivity and scenarios analyses for individual lines typically supported the base case, whereas those for the line agnostic setting suggested sensitivity to drug acquisition costs and efficacy inputs. Tepotinib could be cost-effective versus capmatinib in frontline and line agnostic contexts, considering the range of willingness-to-pay thresholds recommended by the Institute for Clinical and Economic Review ($100 000-$150 000/QALY). Tepotinib could be cost-effective in subsequent lines at higher willingness-to-pay levels. These results are to be interpreted cautiously, considering uncertainty in key model inputs. • The recently approved and recommended tyrosine kinase inhibitor treatments tepotinib and capmatinib offer efficacious and tolerable treatment options for adults with metastatic non–small cell lung cancer harboring mesenchymal–epithelial transition factor gene exon 14 skipping in the United States. • This study assessed the cost-effectiveness of tepotinib versus capmatinib for this patient population in frontline, subsequent line, and any setting (overall), from a US Medicare payer perspective. • Tepotinib could be cost-effective versus capmatinib in treating adults with metastatic non–small cell lung cancer harboring mesenchymal–epithelial transition factor gene exon 14 skipping in frontline settings and overall, whereas cost-effectiveness in subsequent lines depends on willingness to pay for additional quality-adjusted life-years. [ABSTRACT FROM AUTHOR]

• MET fusions represent a promising therapeutic target. • EPHB4, THAP5, TNPO3 , and DST are novel MET fusion partners in NSCLC. • Patients with MET fusions present acquired MET D1228H/N or D1246N mutations. • Tivantinib has optimal suppression efficacy in a PDO model with MET D1228N mutation. De novo mesenchymal-to-epithelial transition (MET) gene fusions in non-small cell lung cancer (NSCLC) are a promising target for MET tyrosine kinase inhibitors (TKIs). We aimed to examine the response to targeted therapy with MET TKIs and resistance mechanisms in de novo MET fusion-positive NSCLC as these have not been comprehensively explored. We examined the MET fusions in 4,429 patients with advanced-stage NSCLC using targeted next-generation sequencing and validated the results using RT-PCR. We analyzed cellular models harboring MET fusions and established a patient-derived organoid (PDO) model. We identified 13 (0.29 %, 13/4429) patients with de novo MET fusions and found EPHB4, THAP5, TNPO3 , and DST as novel MET fusion partners. The most common concomitant gene with MET fusions was TP53 mutations. Among 12 patients receiving MET TKI treatment, two achieved stable disease, six achieved partial response, and four underwent progressive disease. An in vitro study showed that EPHB4-MET is a functional driver gene. MET inhibitors significantly inhibited the proliferation and phosphorylation of downstream STAT3, AKT, and ERK1/2 in EPHB4-MET overexpressing cells. Acquired MET D1228H/N or D1246N mutations were found in patients harboring MET fusions after acquiring resistance to MET TKIs. Tivantinib showed optimal suppression efficacy in a PDO model with an acquired MET D1228N mutation. MET fusions occur in a rare subset of patients with NSCLC and represent a promising therapeutic target. MET secondary mutations D1228H/N or D1246N present the potential resistance mechanisms of MET inhibitors in patients with de novo MET fusions. [ABSTRACT FROM AUTHOR]

• Deferred cytoreductive nephrectomy represents an appropriate management option. • Deferred cytoreductive nephrectomy demonstrates improved overall survival. • Deferred and upfront cytoreductive nephrectomy carry similar morbidity burden. Deferred cytoreductive nephrectomy (dCN) after upfront systemic therapy has been utilized in the management of select patients with metastatic renal cell carcinoma (mRCC). Herein, we sought to review the current evidence and define oncologic and perioperative outcomes associated with deferred surgical management of newly diagnosed mRCC. Our objective was to critically evaluate the role of dCN in the targeted and immunotherapy eras, comparing oncologic and perioperative outcomes between dCN and upfront CN. Medline, OVID, and Scopus databases were searched for studies evaluating patients undergoing dCN following systemic therapy (ST). PRISMA guidelines were referenced and followed. Outcomes of interest included overall survival (OS), progression free survival (PFS), percent of patients proceeding to dCN, reduction in primary tumor size, complication rates, and perioperative mortality. Random effects meta-analysis was performed comparing overall survival between dCN vs. ST alone and dCN vs. upfront CN. Nineteen studies were included to assess the primary outcomes. The percent of patients proceeding to planned dCN after planned pre-surgical ST ranged from 60.5% to 84%. The most common reason for not undergoing dCN was disease progression on upfront ST. Of patients undergoing dCN, 76% to 96% were able to resume ST postoperatively. OS and PFS ranged from 12.4 to 46 months and 4.5 to 11 months, respectively. Pooled results demonstrated significantly improved OS favoring dCN over upfront CN (hazard ratio, HR = 0.56; 95% CI 0.45–0.69) and ST alone (HR = 0.45; 95% CI 0.38–0.53). Deferred CN represents a potential treatment option in appropriately selected patients with mRCC with a favorable response to upfront systemic therapy. Future randomized trials will be needed to clarify how much this is due to the surgery vs. patient selection. [ABSTRACT FROM AUTHOR]

The landmark ADAURA study recently demonstrated a significant disease-free survival benefit of adjuvant osimertinib in patients with resected EGFR -mutated lung adenocarcinoma. However, data on prevalence rates and stage distribution of EGFR mutations in non-small cell lung cancer in Western populations are limited since upfront EGFR testing in early stage lung adenocarcinoma is not common practice. Here, we present a unique, real-world, unselected cohort of lung adenocarcinoma to aid in providing a rationale for routine testing of early stage lung cancers for EGFR mutations in the West-European population. We performed routine unbiased testing of all cases, regardless of TNM stage, with targeted next-generation sequencing on 486 lung adenocarcinoma cases between 01- January 2014 and 01 February 2020. Clinical and pathological data, including co-mutations and morphology, were collected. EGFR- mutated cases were compared to KRAS- mutated cases to investigate EGFR- specific characteristics. In total, 53 of 486 lung adenocarcinomas (11%) harboured an EGFR mutation. In early stages (stage 0-IIIA), the prevalence was 13%, versus 9% in stage IIIB-IV. Nine out of 130 (7%) stage IB-IIIA patients fit the ADAURA criteria. Early stage cases harboured more L858R mutations (p = 0.02), fewer exon 20 insertions (p = 0.048), fewer TP53 co-mutations (p = 0.007), and were more frequently never smokers (p = 0.04) compared to late stage cases with EGFR mutations. The KRAS -mutated cases were distributed more evenly across TNM stages compared to the EGFR- mutated cases. As (neo-)adjuvant targeted therapy regimes enter the field of lung cancer treatment, molecular analysis of early stage non-small cell lung cancer becomes relevant. Testing for EGFR mutations in early stage lung adenocarcinoma holds a substantial yield in our population, as our number needed to test ratio for adjuvant osimertinib was 14.4. The observed differences between early and late stage disease warrant further analysis to work towards better prognostic stratification and more personalised treatment. • EGFR mutation prevalence was 9% in early stage NSCLC in our West-European cohort. • EGFR mutation prevalence is spread unevenly across TNM stages. • Number needed to test for adjuvant osimertinib was 14.4 in our population. • Early- and late stage EGFR -mutated NSCLC differs in clinicopathological features. [ABSTRACT FROM AUTHOR]

Although recent advances in cancer treatment improve cancer prognosis, cancer therapeutics-related cardiovascular dysfunction (CTRCD) significantly contributes to the global burden of cardiovascular disease. CTRCD causes two crucial issues: first, premature treatment interruption or discontinuation of chemotherapy; second, the development of congestive heart failure during and after cancer treatment. Thus, early detection and prompt treatment of CTRCD may improve the prognosis in cancer patients. This review covers representative anticancer drugs, including anthracyclines, human epidermal growth factor 2 inhibitors, tyrosine kinase inhibitors, proteasome inhibitors, and immune checkpoint inhibitors. We focus on the molecular mechanisms of CTRCD and various approaches to diagnosis, prevention, monitoring, and treatment. [Display omitted] • CTRCD significantly contributes to the global burden of cardiovascular disease. • Comprehensive cardiac monitoring may be useful during and after cardiotoxic chemotherapy. • Echocardiography and cardiac biomarkers play pivotal roles to detect CTRCD. • Early detection and prompt treatment of CTRCD may improve the prognosis in cancer patients. • Close collaboration between oncologists and cardiologists is becoming more and more important. [ABSTRACT FROM AUTHOR]

Targeted therapy and precision oncology aim to improve efficacy and minimize side effects by targeting specific molecules involved in cancer growth and spread. With the advancements in genomics, proteomics, and transcriptomics with the accessible modalities such as next-generation sequencing, circulating tumor cells, and tumor Deoxyribonucleic Acid (DNA), more number of patients are being offered the targeted therapy in form of monoclonal antibodies and various intracellular targets, specific for their tumor. The harnessing of host immunity against the cancer cells by utilizing immune-oncology agents and chimeric antigen receptor T-cell therapy has further revolutionized the management of various cancers. These agents, however, have the challenge of managing the adverse effects that are peculiar to the class of drugs and very different from the conventional chemotherapy. This review article discusses the molecular basis, diagnostics, and use of targeted therapy in oncology. [ABSTRACT FROM AUTHOR]

To determine the incidence of ALK translocations in patients with advanced/metastatic NSCLC in Spain, to describe the clinical characteristics of these patients, and to evaluate the effectiveness and safety of treatment with crizotinib in a real-world setting. This is an observational prospective and retrospective cohort study to determine the incidence of ALK translocations and to analyze the effectiveness and safety of crizotinib in a real-world setting. Patient characteristics, treatment patterns, time to best overall response, duration of treatment, objective response rates (ORR), rates of adverse events (AE), progression free survival (PFS) and overall survival (OS) were evaluated in the ALK study cohort of patients treated with crizotinib (prospective and retrospective). ALK incidence and quality of life (QoL) questionnaires were measured from patients included in the prospective cohort. The incidence of ALK translocations was 5.5 % (31 of 559 patients). Compared with ALK -negative patients, ALK -positive patients were significantly younger, predominantly female, and non-smokers. In the crizotinib effectiveness and safety study, 91 patients (42 prospective, 49 retrospective) with ALK -positive NSCLC (43.9 % in first-line, 56.1 % in second or more lines) were included. The ORR was 59.3 % and the median duration of response was 13.5 months (IQR, 5.3–26.2). The median PFS was 15.8 months (95 % CI, 11.8–22.3) and the median OS was 46.5 months, with 53 patients (58.2 %) still alive at data cut-off date. Frequently reported AEs included elevated transaminases, gastrointestinal disorders, and asthenia. Most patients (76.5 %) reported improved or stable scores for global QoL during treatment. The observed incidence of ALK translocations in NSCLC patients is aligned with published reports. This analysis of the real-world clinical experience in Spain confirms the therapeutic benefit and safety of crizotinib in advanced/metastatic ALK -positive NSCLC. Clinicaltrials.gov : NCT02679170. [ABSTRACT FROM AUTHOR]

• This is the largest studies for EGFR E709-T710delinsX in lung cancer. • EGFR E709-T710delinsX accounts for 0.44% of EGFR mutant NSCLC patients and 0.17% in NSCLC patients. • Afatinib might exert superior antitumor activity in EGFR E709-T710delinsX mutant patients. Currently, whether patients with rare epidermal growth factor receptor (EGFR) mutations could benefit from EGFR tyrosine kinase inhibitors (TKIs) demands further studies. Limited clinical data are available regarding the molecular characteristics and clinical response in non-small-cell lung cancer (NSCLC) patients harboring EGFR E709-T710delinsX mutations, a rare mutation type in exon 18 of EGFR. In this study, we aimed to explore the molecular distribution and clinical outcome of EGFR E709-T710delinsX mutated Chinese patients. Next-generation sequencing (NGS) tests were performed in 15,078 NSCLC patients. A multicenter retrospective cohort involving 17 advanced lung cancer patients with EGFR E709-T710delinsX was collected to evaluate clinical responses to diverse therapies. In silico protein structure modeling was conducted to predict drug response. 5905 EGFR mutant patients (39.2%, 5905/15078) were identified, with 26 cases (0.44%, 26/5905) harbored EGFR E709-T710delinsD. Afatinib showed a better overall objective response rate (ORR) compared with the first-generation (1G) EGFR TKIs and chemotherapy with significant difference. Superior progression free survival (PFS) was also observed in patients treated with afatinib (afatinib 10.85 m vs 1G EGFR TKIs 4.0 m vs chemotherapy 2.8 m, p = 0.0007). In silico protein structure modeling predicts better binding of afatinib with EGFR E709-T710delinsD compared with other EGFR TKIs. This is the largest studies for EGFR E709-T710delinsX, with 26 cases with EGFR E709-T710delinsX being identified (0.44% in EGFR mutant NSCLC, 0.17% in NSCLC patients). This study also firstly revealed that afatinib might exert superior antitumor activity to the 1G EGFR TKIs and chemotherapy in EGFR E709-T710delinsX mutant patients. [ABSTRACT FROM AUTHOR]

Anaplastic lymphoma kinase (ALK) fusions identify a limited subset of non–small cell lung cancer (NSCLC) patients, whose therapeutic approach have been radically changed in recent years. However, diagnostic procedures and clinical-radiological responses to specific targeted therapies remain heterogeneous and intrinsically resistant or poor responder patients exist. A total of 290 patients with advanced NSCLC defined as ALK+ by immunohistochemistry (IHC) and/or fluorescent in situ hybridisation (FISH) test and treated with single or sequential multiple ALK inhibitors (ALKi) from 2011 to 2017 have been retrospectively retrieved from a multicentre Italian cancer network database. In 55 patients with enough leftover tumour tissue, specimens were analysed with both targeted and customised next generation sequencing panels. Identified fusion variants have been correlated with clinical outcomes. Of the 55 patients, 24 received crizotinib as first-line therapy, 1 received ceritinib, while 30 received chemotherapy. Most of the patients (64%) received ALKi in sequence. An ALK fusion variant was identified in 73% of the cases, being V3 variant (E6A20) the most frequent, followed by V1 (E13A20) and more rare ones (e.g. E6A19). In three specimens, four new EML4-ALK fusion breakpoints have been reported. Neither fusion variants nor brain metastases were significantly associated with overall survival (OS), while it was predictably longer in patients receiving a sequence of ALKi. The presence of V1 variant was associated with progression-free survival (PFS) improvement when crizotinib was used (p = 0.0073), while it did not affect cumulative PFS to multiple ALKi. Outcomes to sequential ALKi administration were not influenced by fusion variants. Nevertheless, in V1+ patients a prolonged clinical benefit was observed. Fusion variant identification by NGS technology may add relevant information about rare chromosomal events that could be potentially correlated to worse outcomes. • NGS platforms add relevant information to refine diagnosis of ALK+ NSCLC patients. • RNA-based technologies allow the identification of rare/unknown EML4-ALK fusions. • Fusion variants correlate with clinical outcomes to single/sequential ALKi. • Molecular stratification of ALK+ patients may inform clinical strategies. [ABSTRACT FROM AUTHOR]

• The TAPT-DBTA-SPME-ESI-MS platform was constructed. • The TAPT-DBTA-SPME probe was fabricated by layer-by-layer synthesis strategy. • The developed analytical method was reproducible, rapid, and efficient. • The method can selectively enrich TKIs in biological samples. • The method enabled the detection of TKIs metabolism in mouse. Sunitinib, N-desmethyl imatinib, dasatinib, imatinib, and bosutinib are tyrosine kinase inhibitors (TKIs) that are commonly employed in the treatment of a multitude of cancers. However, the inappropriate concentrations of TKIs can result in ineffective treatment or the emergence of multiple adverse effects. Consequently, the development of a rapid and sensitive analytical method for TKIs is of paramount importance for the safe administration of drugs. In this work, solid-phase microextraction (SPME) probe combined with an electrospray ionization mass spectrometry (ESI-MS) coupling platform was constructed for rapid and sensitive determination of TKIs. The covalent organic frameworks (COFs) coated SPME probe was made of 2,4,6-tris(4-aminophenyl)-1,3,5-triazine (TAPT) and 2,5-dibutoxyterephthalaldehyde (DBTA) by in-situ layer-by-layer chemical bonding synthesis strategy. The TAPT-DBTA-SPME probe exhibited several advantageous properties which rendered it suitable for the enrichment of TKIs. Under the optimal conditions, the developed analytical method demonstrated a broad linear range (0.05–500.00 µg/L), a low limit of detection (0.02 µg/L) and a high enrichment factor (51–203) for TKIs. The developed analytical method was successfully applied to a pharmacokinetic study of TKIs in mouse plasma and tissue matrix, demonstrating that the proposed analytical method has promise for clinical applications and metabolic monitoring. [ABSTRACT FROM AUTHOR]

Empagliflozin (EMPA), a selective sodium-glucose cotransporter type 2 (SGLT2) inhibitor, has been shown to reduce major adverse cardiovascular events in patients with heart failure of different etiologies, although the underlying mechanism still remains unclear. Ponatinib (PON) is a multi-tyrosine kinase inhibitor successfully used against myeloid leukemia and other human malignancies, but its cardiotoxicity remains worrisome. Cardiac connexins (Cxs) are both substrates and regulators of autophagy and responsible for proper heart function. Alteration in connexin expression and localization have been described in patients with heart failure. To assess whether EMPA can mitigate PON-induced cardiac dysfunction by restoring the connexin 43-autophagy pathway. Male C57BL/6 mice, randomized into four treatment groups (CNTRL, PON, EMPA, PON+EMPA) for 28 days, showed increased autophagy, decreased Cx43 expression as well as Cx43 lateralization, and attenuated systo-diastolic cardiac dysfunction after treatment with EMPA and PON compared with PON alone. Compared with CNTRL (DMSO), cardiomyocyte-differentiated H9c2 (dH9c2) cells treated with PON showed significantly reduced cell viability to approximately 20 %, decreased autophagy, increased cell senescence and reduced DNA binding activity of serum response factor (SRF) to serum response elements (SRE), which were paralleled by reduction in cardiac actin expression. Moreover, PON induced a significant increase of Cx43 protein and its S368-phosphorylated form (pS368-Cx43), as well as their displacement from the plasma membrane to the perinuclear and nuclear cellular region. All these effects were reverted by EMPA. EMPA attenuates PON-induced cardiotoxicity by reducing senescence, enhancing the SRE-SRF binding and restoring the connexin 43-autophagy pathway. This effect may pave the way to use of SGLT2 inhibitors in attenuating tyrosine-kinase inhibitor cardiotoxicity. [Display omitted] • Empagliflozin prevented ponatinib-induced cardiotoxicity in vivo and in vitro. • Cx43-autophagy pathway is involved in the empagliflozin's cardiac protective effect. • Empagliflozin restored the SRF-SRE binding and cardiac actin expression. • Gliflozin's effects on cardiotoxicity are worthy of clinical studies. [ABSTRACT FROM AUTHOR]

[Display omitted] • Cancer patients are polymedicated and are at risk of drug interactions. • Proton pump inhibitors decrease absorption of many TKIs and CDK 4/6 inhibitors. • They decrease the diversity in microbiome, decreasing efficacy of immunotherapies. • The Precautionary Principle is of interest until we have new contradictory data. • PPIs may be replaced in most cases by antacids or H2 blockers. Proton pump inhibitors (PPIs) are widely used in cancer patients despite accumulating data showing that they can impact the efficacy of major anticancer drugs. This is particularly important with tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (CPIs). Most TKIs require gastric acidity for their absorption and some retrospective series demonstrated that coprescription decreases the survival benefit of some TKI use (erlotinib, gefitinib and pazopanib). Relations between microbiota, the immune system, and the efficacy of immunotherapy are now obvious, just as modifications to gut flora after PPIs use are well-known. Many retrospective articles, including articles based on individual-participant data from randomized studies, demonstrated that patients treated with CPIs have a poorer outcome (overall survival, progression-free survival and response rate) when they received PPIs concomitantly, while there was no impact of such coprescription among patients in control arms, not treated with immunotherapies. Similar data were also observed in patients treated with palbociclib. For these interactions, it is very important to use the precautionary principle and warn patients and physicians about this. In patients who require acid suppression because of severe symptoms, using antacids or H2 blockers could be recommended. [ABSTRACT FROM AUTHOR]

We studied the short- and long-term effects of imatinib in hospitalized COVID-19 patients. Participants were randomized to receive standard of care (SoC) or SoC with imatinib. Imatinib dosage was 400 mg daily until discharge (max 14 days). Primary outcomes were mortality at 30 days and 1 year. Secondary outcomes included recovery, quality of life and long COVID symptoms at 1 year. We also performed a systematic review and meta-analysis of randomized trials studying imatinib for 30-day mortality in hospitalized COVID-19 patients. We randomized 156 patients (73 in SoC and 83 in imatinib). Among patients on imatinib, 7.2% had died at 30 days and 13.3% at 1 year, and in SoC, 4.1% and 8.2% (adjusted HR 1.35, 95% CI 0.47–3.90). At 1 year, self-reported recovery occurred in 79.0% in imatinib and in 88.5% in SoC (RR 0.91, 0.78–1.06). We found no convincing difference in quality of life or symptoms. Fatigue (24%) and sleep issues (20%) frequently bothered patients at one year. In the meta-analysis, imatinib was associated with a mortality risk ratio of 0.73 (0.32–1.63; low certainty evidence). The evidence raises doubts regarding benefit of imatinib in reducing mortality, improving recovery and preventing long COVID symptoms in hospitalized COVID-19 patients. • We found no short or long-term benefit from imatinib in hospitalized COVID-19. • Pooled evidence raises doubts regarding benefit of imatinib in reducing mortality. • Fatigue and sleeping problems common at 1 year after hospitalized COVID-19. [ABSTRACT FROM AUTHOR]

[Display omitted] • BUVs interact with the extracellular domain of the human EGFR. • The halogenated BUVs UV-326 and UV-327 inhibit the activation of EGFR by polypeptide growth factors. • BUVs interfere with EGFR ligand-induced signal transduction and DNA synthesis in human keratinocytes. Phenolic benzotriazole UV stabilizers (BUV) are commonly used additives in synthetic polymeric products, which constantly leak into the environment. They are persistent and bioaccumulative, and have been detected not only in fish, birds, and sea mammals, but also in humans, including breast milk samples. Several authorities including the European Chemical Agency already consider some BUVs as Substances of Very High Concern in need of further information, e.g. mechanistical studies and biomonitoring. In this study, we are addressing this need by investigating the effect of several BUVs on the activity of the human epidermal growth factor receptor (EGFR), an important regulator of cellular processes that has recently been identified as a cell-surface receptor for environmental organic chemicals. By combining in silico docking, mutant analyses, receptor binding and internalization assays, we demonstrate that BUVs, particularly the chlorinated variants, bind to the extracellular domain of EGFR and thereby prevent the binding of growth factors. Accordingly, BUVs can inhibit EGFR downstream events, such as ERK1/2 phosphorylation and DNA synthesis, in human keratinocytes. Our data establish EGFR as a plasma membrane receptor for BUVs, offering novel mechanistic insights into the biological effects induced by these widespread and persistent chemicals. The findings of this study may not only improve hazard assessment for BUVs, but also contribute to the development of novel EGFR-targeting drugs. [ABSTRACT FROM AUTHOR]

A multitude of TKI has been developed and approved targeting various oncogenetic alterations. While these have provided improvements in efficacy compared with conventional chemotherapies, resistance to targeted therapies occurs. Mutations in the kinase domain result in the inability of TKI to inactivate the protein kinase. Also, gene amplification, increased protein expression and downstream activation or bypassing of signalling pathways are commonly reported mechanisms of resistance. Improved understanding of mechanisms involved in TKI resistance has resulted in the development of new generations of targeted agents. In a race against time, the search for new, more potent and efficient drugs, and/or combinations of drugs, remains necessary as new resistance mechanisms to the latest generation of TKI emerge. This review examines the various generations of TKI approved to date and their common mechanisms of resistance, focusing on TKI targeting BCR-ABL, epidermal growth factor receptor, anaplastic lymphoma kinase and BRAF/MEK tyrosine kinases. [Display omitted] • BCR-ABL, EGFR, ALK and BRAF/MEK tyrosine kinases are implicated in various cancers • Mechanisms of resistance to targeted TKI include kinase domain mutations and downstream signal pathway activation • New-generation TKIs are effective against TK mutant and can overcome resistance involving other pathways [ABSTRACT FROM AUTHOR]

Secondary hematologic malignancies, such as B-cell acute lymphoblastic leukemia/lymphoma (B-ALL), have been reported following multiple myeloma. Tyrosine kinase inhibitors have improved clinical outcomes of patients with Philadelphia-positive (Ph+) B-ALL. Therefore, recognition of the Ph chromosome in B-ALL patients is important for both prognosis and therapies. We present a case of a secondary Ph+ B-ALL following multiple myeloma that highlights a BCR::ABL1 fusion by a gene fusion assay to reveal a cryptic Ph chromosome, which may otherwise be missed by conventional cytogenetics and typical interphase fluorescence in situ hybridization. [ABSTRACT FROM AUTHOR]

• EML4-ALK patient derived cell lines showed differential sensitivity towards ALK TKIs. • WGS and RNA-seq analyses identified several common genetic lesions such as TP53 and CDKN2A/B. • The RRM2 gene showed an overall response to ALK TKI treatment and is a downstream target of EML4-ALK fusions. • 3-AP showed mild synergy with lorlatinib in EML4-ALK patient derived cell lines. Echinoderm microtubule-associated protein-like 4 (EML4)-Anaplastic Lymphoma Kinase (ALK) rearrangements occur in 3% to 7% of lung adenocarcinomas and are targets for treatment with tyrosine kinase inhibitors (TKIs). Here we have developed three novel EML4-ALK-positive patient–derived Non-Small-Cell-Lung-Cancer (NSCLC) cancer cell lines, CUTO8 (variant 1), CUTO9 (variant 1) and CUTO29 (variant 3) and included a fourth ALK-positive cell line YU1077 (variant 3) to study ALK-positive signaling and responses. Variants 1 and 3 are the most common EML4-ALK variants expressed in ALK-positive NSCLC, and currently cell lines representing these EML4-ALK variants are limited. Resazurin assay was performed to evaluate cell viability. Protein levels were determined using western blotting. RNA sequencing was performed in all four cell lines to identify differentially expressed genes. Whole-genome sequencing was performed to determine the presence of EML4-ALK fusion and ALK tyrosine kinase inhibitor resistance mutations. In this study, we have confirmed expression of the corresponding ALK fusion protein and assessed their sensitivity to a range of ALK tyrosine kinase inhibitors. These patient derived cell lines exhibit differential sensitivity to lorlatinib, brigatinib and alectinib, with EML4-ALK variant 3 containing cell lines exhibiting increased sensitivity to lorlatinib and brigatinib as compared to alectinib. These cell lines were further characterized by whole genome sequencing and RNA-seq analysis that identified the ribonucleotide reductase regulatory subunit 2 (RRM2) as a downstream and potential therapeutic target in ALK-positive NSCLC. We provide a characterization of four novel EML4-ALK-positive NSCLC cell lines, highlighting genomic heterogeneity and differential responses to ALK TKI treatment. The RNA-Seq characterization of ALK-positive NSCLC CUTO8, CUTO9, CUTO29 and YU1077 cell lines reported here, has been compiled in an interactive ShinyApp resource for public data exploration (https://ccgg.ugent.be/shiny/nsclc_rrm2_2022/). [ABSTRACT FROM AUTHOR]

The aim of the article was to study relationships between the axitinib steady-state trough concentration (C trough) and treatment efficacy and toxicity. There was a statistically significant differences between measured axitinib C trough value and treatment response, median progression-free survival, and toxicity in the group of 35 patients. The data collected may be used to determine indications for axitinib therapy monitoring based on C trough measurements. Introduction: There are known correlations between axitinib exposure and treatment response. The aim of the article was to study relationships between the axitinib steady-state trough concentration and the treatment efficacy and toxicity. Patients and methods: 35 patients (24 men and 11 women), treated or initiating treatment with axitinib, were included in the study over the period 2016-2019. Blood samples were collected following 2 weeks of treatment (in patients who initiated the therapy) and at the end of Cycles 1, 2, and 3 thereafter (in the entire study population). For concentration measurements, high-performance liquid chromatography - mass spectrometry (HPLC-MS) was applied. Treatment efficacy was assessed according to the RECIST 1.1 cr iter ia. Therapy toxicity was evaluated according to the CTCAE cr iter ia. Results: A statistically significant relationship between the first measured axitinib trough concentration (C trough first) value and treatment response (P = .004) as well as the median progression-free survival (mPFS) (P = .003) was observed. The association between axitinib C trough first and the median overall survival (mOS) was not statistically significant (P = .142). A statistically significant relationship was observed between the mean trough concentration from 3-month observation (C trough 1-3m) and treatment response (P = .008) as well as mPFS (P = .001), without a significant relationship for mOS (P = .097). At least grade 3 adverse reactions were meaningfully associated with C trough first (P = .012) and C trough 1-3m (P = .003). Conclusion: There are significant relationships between axitinib C trough and treatment response, PFS, and grade = 3 toxicity. The data collected may be used to determine indications for axitinib therapy monitoring based on C trough measurements. [ABSTRACT FROM AUTHOR]

• Resistance to therapy is a common and complex feature of non-small cell lung cancer. • New treatment options are needed for patients with tumors that fail prior therapies. • Resistance mechanisms include EGFR-dependent and EGFR-independent gene mutations and amplifications. • Several novel agents are emerging to address these resistance mechanisms. • MET-, HER2-, and HER3-directed therapies are promising treatments in development. Tyrosine kinase inhibitors (TKIs) are the standard of care for patients with non-small cell lung cancer (NSCLC) that harbor mutations of the epidermal growth factor receptor (EGFR) gene. First-line therapy for these patients is often osimertinib, a third-generation EGFR TKI. Erlotinib, gefitinib, afatinib, and dacomitinib are first- and second-generation TKIs that are also available. However, almost all patients eventually develop disease progression due to TKI-acquired resistance. The mechanisms of resistance after TKI exposure often involve EGFR or its downstream pathways. While a frequently utilized strategy for combating acquired resistance to EGFR TKIs remains standard platinum-based chemotherapy, clinical investigation of promising novel agents targeting common resistance mechanisms such as MET, HER2, and HER3 is of increased interest. In this review, we discuss the mechanisms of resistance to TKIs in EGFR-mutant NSCLC, examine current treatment standards, and discuss novel developing therapies. Both EGFR-dependent (involving secondary mutations in EGFR) and EGFR-independent (mutations that bypass EGFR signaling and histologic transformation) resistance mechanisms are considered. Several novel treatment strategies are emerging to overcome these resistance mechanisms, as the understanding and identification of specific EGFR-TKI resistance mechanisms continues to improve. The treatments in development aim to target or bypass the mechanisms of resistance, including MET-, HER2-, and HER3-directed therapies. In patients with acquired TKI resistance, molecular profiling at the time of initial progression may help identify relevant mechanisms of resistance. Clinical trial participation is vital to continued investigation for EGFR-mutant NSCLC. [ABSTRACT FROM AUTHOR]

• Osimertinib 160 mg showed modest antitumor activity in EGFR exon 20 mutated NSCLC. • Confirmed overall response was 28%. • The median duration of response was 5.3 months. • Osimertinib 160 mg can be beneficial, particularly if CNS disease is present. • Approved and newer drugs in clinical trials should be considered first for this patient group. Patients with life-threatening advanced non-small cell lung cancer (NSCLC) who harbor an exon 20 deletion and/or insertion mutation (EGFRex20 +) have limited effective treatment options. The high dose 3rd generation tyrosine kinase inhibitor (TKI) osimertinib shows promising in vitro activity in EGFRex20 + NSCLC tumors. The POSITION20 is a single arm phase II, multicenter study investigating 160 mg osimertinib in patients with EGFRex20+, T790M negative NSCLC. We allowed patients to be treatment naïve and to have asymptomatic brain metastases. The primary endpoint was overall response rate (ORR). Secondary outcomes were duration of response (DoR), progression free survival (PFS), overall survival (OS), and treatment related adverse events (trAEs). From June 2018 to October 2021, 25 patients were enrolled across five centers in the Netherlands. The median age was 70 years (range, 47–87), 20 patients (80%) were women, and the median number of previous lines of therapy was 1 (range, 0–3). The exon 20 mutations were clustered between A763 and L777. The most common exon 20 mutations were p.(N771_H773dup) (n = 3) and p.(A767_V769dup) (n = 3). The ORR was 28% (95% CI, 12–49%), including seven partial responses, with a median DoR of 5.3 months (range, 2.7–27.6). The median PFS was 6.8 months (95% CI, 4.6–9.1) and the median OS was 15.2 months (95% CI, 14.3–16.0). The most common trAEs were diarrhea (72%), dry skin (44%), and fatigue (44%). The primary reason for discontinuation was progressive disease in 14 patients (56%). The POSITION20 study showed modest antitumor activity in patients with EGFRex20 + NSCLC treated with 160 mg osimertinib, with a confirmed ORR of 28% and acceptable toxicity. [ABSTRACT FROM AUTHOR]

Cardiotoxicity by tyrosine kinase inhibitors remains an important concern. Nilotinib and vandetanib clinically carry high proarrhythmic risk and the exact mechanism underlying arrhythmogenesis is not fully understood. In this study, we investigated the effects of nilotinib and vandetanib on the abundance of human ether-á-go-go-related gene (hERG) K+ channel and assessed the potential role of acute hERG blockage versus chronic effects in arrhythmogenesis. We found that both nilotinib and vandetanib prolonged the field potential duration reflecting the repolarisation process and induced cellrythmias of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in a time-and concentration-dependent manner after, after chronic exposure. Patch-clamp recordings revealed significant reductions of hERG current densities by nilotinib or vandetanib after chronic incubation with hERG-HEK293 cells in addition to the acute inhibition. Western blot analysis showed that nilotinib and vandetanib decreased mature hERG protein (155-kDa) expression, in a greater extent than that of the immature form (135-kDa). A serum and glucocorticoid kinase 1 (SGK1) activator, C 4 -ceramide, prevented the nilotinib-and vandetanib-induced hERG protein downregulation and thus the incidence of cellrrhythmias. Taken together, our data demonstrated that the downregulation of hERG channel abundance on the cellular membrane predominantly contributed to the proarrhythmic effect of nilotinib and vandetanib. • Nilotinib and vandetanib impact hERG channel protein abundance. • Nilotinib and vandetanib induced cellrythmias after chronic exposure in hiPSC-CMs. • Nilotinib and vandetanib downregulated hERG protein levels in heterologous system. • SGK1 activator protected against hERG downregulation and arrhythmogenesis. [ABSTRACT FROM AUTHOR]

Indolent systemic mastocytosis (ISM) is the most prevalent form of systemic mastocytosis. Many patients with ISM suffer from mast cell (MC) mediator-related symptoms. In a small number of patients, hematologic progression is seen in the follow-up. In some patients with ISM, symptoms arising from MC-derived mediators including gastrointestinal symptoms, anaphylaxis, and neuropsychiatric symptoms are kept under control with conventional mediator-targeting drugs or MC-stabilizing agents. However, in a substantial number of patients, the symptoms are refractory to such conventional therapy. For these patients, novel drugs and targeted approaches are considered. One reasonable approach may be to apply tyrosine kinase inhibitors directed against KIT and other key kinase targets expressed in neoplastic MCs in ISM. Because MCs in more than 90% of all patients with typical ISM display the KIT D816V mutant receptor, clinically effective KIT-targeting drugs have to be active against this mutant form of KIT. The 2 such most effective and well-studied agents currently available are midostaurin and avapritinib. Other KIT-targeting drugs, such as imatinib or masitinib, are less effective or even noneffective against KIT D816V and are thus recommended for use only in patients with other KIT mutant forms (noncodon 816 mutations) or with wild-type KIT. In the present article, we review the current state in the treatment of ISM with tyrosine kinase inhibitors, with special emphasis on treatment responses and potential adverse effects. In fact, all of these agents also have unique and common adverse effects, and their use to treat patients with ISM should be balanced against their toxicity and short- and long-term safety. [ABSTRACT FROM AUTHOR]

The number of effective systemic therapies for the treatment of advanced hepatocellular carcinoma (HCC) is rapidly increasing, and the advent of immunotherapy has changed the treatment paradigm for these patients, leading to significantly improved survival outcomes. However, many patients with HCC will continue to receive tyrosine kinase inhibitors, partly because of contraindications to immune checkpoint inhibitors. Currently, the best sequential first- and second-line systemic treatment remains elusive. Maintenance of optimal liver function is crucial, it is likely to impinge on temporary or permanent treatment discontinuation, and should also be considered when defining the treatment sequence. Hepatic decompensation, which does not always coincide with disease progression, is part of this complex dynamically evolving system, and must be promptly recognized and adequately managed to allow the patient to continue in the therapeutic course. The purpose of this review is to highlight and summarize the evidence on the efficacy and safety of systemic agents, with a focus on the impact of underlying cirrhosis, and to suggest new clinical outcomes for randomized controlled trials for advanced HCC to better assess the net health benefit in this specific setting. [ABSTRACT FROM AUTHOR]

Human epidermal growth factor receptor 2 (HER2) is a transmembrane receptor-like protein with tyrosine kinase activity that plays a vital role in processes such as cell proliferation, differentiation, and angiogenesis. The degree of malignancy of different cancers, notably breast cancer, is strongly associated with HER2 amplification, overexpression, and mutation. Currently, widely used clinical HER2 tyrosine kinase inhibitors (TKIs), such as lapatinib and neratinib, have several drawbacks, including susceptibility to drug resistance caused by HER2 mutations and adverse effects from insufficient HER2 selectivity. To address these issues, it is essential to create innovative HER2 TKIs with enhanced safety, effectiveness against mutations, and high selectivity. Typically, SPH5030 has advanced to phase I clinical trials for its strong suppression of four HER2 mutations. This review discusses the latest research progress in HER2 TKIs, with a focus on the structural optimization process and structure-activity relationship analysis. In particular, this study highlights promising design strategies to address these challenges, providing insightful information and inspiration for future development in this field. [Display omitted] • Comprehensive summary of HER2 structure, function, and clinical drugs. • Overview of the latest advancements in HER2 tyrosine kinase inhibitors (TKIs). • Detailed SAR analysis and design strategies for HER2 TKIs. • Discussion on the challenges and future directions for HER2 TKIs. [ABSTRACT FROM AUTHOR]

Pheochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumors derived from chromaffin cells in the autonomic nervous system. Depending on their location, these tumors are capable of excessive catecholamine production, which may lead to uncontrolled hypertension and other life-threatening complications. They are associated with a significant risk of metastatic disease and are often caused by an inherited germline mutation. Although surgery can cure localized disease and lead to remission, treatments for metastatic PPGL (mPPGL)—including chemotherapy, radiopharmaceutical agents, multikinase inhibitors, and immunotherapy used alone or in combination— aim to control tumor growth and limit organ damage. Substantial advances have been made in understanding hereditary and somatic molecular signaling pathways that play a role in tumor growth and metastasis. Treatment options for metastatic disease are rapidly evolving, and this paper aims to provide a brief overview of the management of mPPGL with a focus on therapy options. [ABSTRACT FROM AUTHOR]

Medullary thyroid carcinoma (MTC) is a rare primary neuroendocrine thyroid carcinoma that is distinct from other thyroid or neuroendocrine cancers. Most cases of MTC are sporadic, although MTC exhibits a high degree of heritability as part of the multiple endocrine neoplasia syndromes. RE arranged during T ransfection (RET) mutations are the primary oncogenic drivers and advances in molecular profiling have revealed that MTC is enriched in druggable alterations. Surgery at an early stage is the only chance for cure, but many patients present with or develop metastases. C-cell-specific calcitonin trajectory and structural doubling times are critical biomarkers to inform prognosis, extent of surgery, likelihood of residual disease, and need for additional therapy. Recent advances in the role of active surveillance, regionally directed therapies for localized disease, and systemic therapy with multi-kinase and RET-specific inhibitors for progressive/metastatic disease have significantly improved outcomes for patients with MTC. [ABSTRACT FROM AUTHOR]

Protein kinases play pivotal roles in various biological functions, influencing cell differentiation, promoting survival, and regulating the cell cycle. The disruption of protein kinase activity is intricately linked to pathways in tumor development. This manuscript explores the transformative impact of protein kinase inhibitors on cancer therapy, particularly their efficacy in cases driven by targeted mutations. Focusing on key tyrosine kinase inhibitors (TKIs) like Bcr-Abl, Epidermal Growth Factor Receptor (EGFR), and Vascular Endothelial Growth Factor Receptor (VEGFR), it targets critical kinase families in cancer progression. Clinical trial details of these TKIs offer insights into their therapeutic potentials. Learning from FDA-approved kinase inhibitors, the review dissects trends in kinase drug development since imatinib's paradigm-shifting approval in 2001. TKIs have evolved into pivotal drugs, extending beyond oncology. Ongoing clinical trials explore novel kinase targets, revealing the vast potential within the human kinome. The manuscript provides a detailed analysis of advancements until 2022, discussing the roles of specific oncogenic protein kinases in cancer development and carcinogenesis. Our exploration on PubMed for relevant and significant TKIs undergoing pre-FDA approval phase III clinical trials enriches the discussion with valuable findings. While kinase inhibitors exhibit lower toxicity than traditional chemotherapy in cancer treatment, challenges like resistance and side effects emphasize the necessity of understanding resistance mechanisms, prompting the development of novel inhibitors like osimertinib targeting specific mutant proteins. The review advocates thorough research on effective combination therapies, highlighting the future development of more selective RTKIs to optimize patient-specific cancer treatment and reduce adverse events. [Display omitted] • Tyrosine kinases (TKIs) are targeted therapies that inhibit enzymes that are essential for cancer cell growth and proliferation. • FDA-approved TKIs have demonstrated significant efficacy in treating various types of cancers. • Several FDA-approved TKIs including Imatinib (Gleevec), Erlotinib (Tarceva), etc. are discussed in the paper. • Disruption of protein kinase activity is associated with multiple pathways involved in tumor development. [ABSTRACT FROM AUTHOR]

• Lorlatinib is a TKI indicated for the treatment ALK -positive metastatic NSCLC. • The lorlatinib safety profile is distinct from other ALK TKIs. • In clinical trials, lorlatinib AEs were mostly managed with dose modifications. • There is a need for pragmatic clinical recommendations for managing lorlatinib AEs. • These recommendations follow the framework of "prepare, monitor, manage, reassess" Lorlatinib is a brain-penetrant, third-generation tyrosine kinase inhibitor (TKI) indicated for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC). In clinical trials, lorlatinib has shown durable efficacy and a manageable safety profile in treatment-naive patients and in those who have experienced progression while receiving first- and/or second-generation ALK TKIs. Lorlatinib has a distinct safety profile from other ALK TKIs, including hyperlipidemia and central nervous system effects. Clinical trial data showed that most adverse events (AEs) can be managed effectively or reversed with dose modifications (such as dose interruptions or reductions) or with concomitant medications without compromising clinical efficacy or quality of life for patients. A pragmatic approach to managing AEs related to lorlatinib is required. We present patient-focused recommendations for the evaluation and management of select AEs associated with lorlatinib developed by clinicians and nurses with extensive lorlatinib expertise in routine clinical practice. The recommendations follow the general framework of "prepare, monitor, manage, reassess" to streamline AE management and assist in practical, actionable, and personalized patient care. [ABSTRACT FROM AUTHOR]

Despite the success of Tyrosine kinase inhibitors (TKIs) in treating chronic myeloid leukemia (CML), leukemic stem cells (LSCs) persist, contributing to relapse and resistance. CML Mesenchymal Stromal Cells (MSCs) help in LSC maintenance and protection from TKIs. However, the limited passage and self-differentiation abilities of primary CML MSCs hinder extensive research. To overcome this, we generated and characterized an immortalised CML patient-derived MSC (iCML MSC) line and assessed its role in LSC maintenance. We also compared the immunophenotype and differentiation potential between primary CML MSCs at diagnosis, post-treatment, and with normal bone marrow MSCs. Notably, CML MSCs exhibited enhanced chondrogenic differentiation potential compared to normal MSCs. The iCML MSC line retained the trilineage differentiation potential and was genetically stable, enabling long-term investigations. Functional studies demonstrated that iCML MSCs protected CML CD34+ cells from imatinib-induced apoptosis, recapitulating the bone marrow microenvironment-mediated resistance observed in patients. iCML MSC-conditioned media enabled CML CD34+ and AML blast cells to proliferate rapidly, with no impact on healthy donor CD34+ cells. Gene expression profiling revealed dysregulated genes associated with calcium metabolism in CML CD34+ cells cocultured with iCML MSCs, providing insights into potential therapeutic targets. Further, cytokine profiling revealed that the primary CML MSC lines abundantly secreted 25 cytokines involved in immune regulation, supporting the hypothesis that CML MSCs create an immune modulatory microenvironment that promotes growth and protects against TKIs. Our study establishes the utility of iCML MSCs as a valuable model to investigate leukemic-stromal interactions and study candidate genes involved in mediating TKI resistance in CML LSCs. [ABSTRACT FROM AUTHOR]

The BYOND study evaluated the efficacy and safety of bosutinib 500 mg once daily in patients with chronic myeloid leukemia (CML) resistant/intolerant to prior tyrosine kinase inhibitors (TKIs). These post-hoc analyses assessed the efficacy and safety of bosutinib by resistance or intolerance to prior TKIs (imatinib-resistant vs dasatinib/nilotinib-resistant vs TKI-intolerant), and cross-intolerance between bosutinib and prior TKIs (imatinib, dasatinib, nilotinib), in patients with Philadelphia chromosome–positive chronic phase CML. Data are reported after ≥3 years' follow-up. Of 156 patients with Philadelphia chromosome–positive chronic phase CML, 53 were imatinib-resistant, 29 dasatinib/nilotinib-resistant, and 74 intolerant to all prior TKIs; cumulative complete cytogenetic response rates at any time were 83.7%, 61.5%, and 86.8%, and cumulative major molecular response rates at any time were 72.9%, 40.7%, and 82.4%, respectively. Of 141, 95, and 79 patients who received prior imatinib, dasatinib, and nilotinib, 64 (45.4%), 71 (74.7%), and 60 (75.9%) discontinued the respective TKI due to intolerance; of these, 2 (3.1%), 5 (7.0%), and 0 had cross-intolerance with bosutinib. The response rates observed in TKI-resistant and TKI-intolerant patients, and low cross-intolerance between bosutinib and prior TKIs, further support bosutinib use for patients with Philadelphia chromosome–positive chronic phase CML resistant/intolerant to prior TKIs. ClinicalTrials.gov: NCT02228382 • Bosutinib was assessed in Ph+ CP CML patients resistant or intolerant to prior TKIs. • Response rates were high in imatinib-resistant and TKI-intolerant patients. • Rates were lower but responses durable in dasatinib/nilotinib-resistant patients. • Cross-intolerance between bosutinib and prior TKIs was low. • Bosutinib is a viable option after resistance or intolerance to prior TKIs. [ABSTRACT FROM AUTHOR]

[Display omitted] • Approvals of ICI-TKI combinations in RCC, endometrial and hepatocellular carcinoma. • Data from phase I-III trials from many different advanced solid tumor types. • Immunomodulatory and synergistic antitumor effects of ICI-TKI combinations. • Efficient but toxic treatment combinations. Immune checkpoint inhibitors (ICI) and tyrosine kinase inhibitors (TKI) have gained therapeutical significance in cancer therapy over the last years. Due to the high efficacy of each substance group, additive or complementary effects are considered, and combinations are the subject of multiple prospective trials in different tumor entities. The majority of available data results from clinical phase I and II trials. Although regarded as well-tolerated therapies ICI-TKI combinations have higher toxicities compared to monotherapies of one of the substance classes and some combinations were shown to be excessively toxic leading to discontinuation of trials. So far, ICI-TKI combinations with nivolumab + cabozantinib, pembrolizumab + axitinib, avelumab + axitinib, pembrolizumab + lenvatinib have been approved in advanced renal cell (RCC), with pembrolizumab + lenvatinib in endometrial carcinoma and with camrelizumab + rivoceranib in hepatocellular carcinoma (HCC). Several ICI-TKI combinations are currently investigated in phase I to III trials in various other cancer entities. Further, the optimal sequence of ICI-TKI combinations is an important subject of investigation, as cross-resistances between the substance classes were observed. This review reports on clinical trials with ICI-TKI combinations in different cancer entities, their efficacy and toxicity. [ABSTRACT FROM AUTHOR]

Patients with metastatic renal cell carcinoma (mRCC) who may benefit most from axitinib still need to be identified. AXILONG study confirms long-term benefits in a selected population in which age at axitinib initiation and haemoglobin baseline levels were significantly associated although further validation may be required. First-line sunitinib outcomes were also correlated with prolonged response. These results might be helpful in real-life management of mRCC patients. Background: Axitinib monotherapy obtained approval in pre-treated mRCC patients and recently in combination with pembrolizumab or avelumab in the first-line setting. However, patient profiles that may obtain increased benefit from this drug and its combinations still need to be identified. Patients and Methods: Retrospective multicentre analysis describing clinical characteristics associated with axitinib long-responder (LR) population by comparing two extremeresponse sub-groups (progression-free survival [PFS] =9 months vs. disease progression/refractory patients [RP]). A multivariate logistic-regression model was used to analyse clinical factors. Efficacy and safety were also analysed. Results: In total, 157 patients who received axitinib in second or subsequent line were evaluated (91 LR and 66 RP). Older age at start of axitinib and haemoglobin levels > LLN were independent predictive factors for LR in multivariate analyses. In LR patients, median (m) PFS was 18.1 months, median overall survival was 36.0 months and objective response rate (ORR) was 45.5%. In 59 LR patients receiving axitinib in second-line, mPFS was 18.7 months, mOS was 44.8 months and ORR was 43.9%. mOS was significantly longer in second line compared to subsequent lines (44.8 vs. 26.5 months; P = .009). In LR vs. RP, mPFS with sunitinib in first-line was correlated with mPFS with axitinib in second-line (27.2 vs. 10.9 months P < .001). The safety profile was manageable and consistent with known data. Conclusions: This study confirms the long-term benefits of axitinib in a selected population, helping clinicians to select the best sequential approach and patients who could obtain a greater benefit from axitinib. [ABSTRACT FROM AUTHOR]

The Metastatic Renal Cell Carcinoma Registry provides prospective data on real-world treatment patterns and outcomes in patients with metastatic renal cell carcinoma (mRCC). A total of 376 patients with mRCC and no prior systemic therapy were included in this study. This report describes initial real-world treatment patterns. Physician emphasis on efficacy over quality of life and toxicity suggests more data and education are needed. Introduction: The Metastatic Renal Cell Carcinoma (MaRCC) Registry provides prospective data on real-world treatment patterns and outcomes in patients with metastatic renal cell carcinoma (mRCC). Methods and Materials: Patients with mRCC and no prior systemic therapy were enrolled at academic and community sites. End of study data collection was in March 2019. Outcomes included overall sur vival (OS). A sur vey of treating physicians assessed reasons for treatment initiations and discontinuations. Results: Overall, 376 patients with mRCC initiated first-line therapy; 171 (45.5%) received pazopanib, 75 (19.9%) sunitinib, and 74 (19.7%) participated in a clinical trial. Median (95% confidence interval) OS was longest in the clinical trial group (50.3 [35.8-not reached] months) versus pazopanib (39.0 [29.7-50.9] months) and sunitinib 26.2 [19.9-61.5] months). Non-clear cell RCC (21.5% of patients) was associated with worse median OS than clear cell RCC (18.0 vs. 47.3 months). Differences in baseline characteristics, treatment starting dose, and relative dose exposure among treatment groups suggest selection bias. Survey results revealed a de-emphasis on quality of life, toxicity, and patient preference compared with efficacy in treatment selection. Conclusion: The MaRCC Registry gives insights into real-world first-line treatment selection, outcomes, and physician rationale regarding initial treatment selection prior to the immunotherapy era. Differences in outcomes between clinical trial and off-study patients reflect the difficulty in translating trial results to real-world patients, and emphasize the need to broaden clinical trial eligibility. Physician emphasis on efficacy over quality of life and toxicity suggests more data and education are needed regarding these endpoints. [ABSTRACT FROM AUTHOR]

This study aimed to fill a gap in knowledge of clinical outcomes among patients with advanced/metastatic renal cell carcinoma treated with lenvatinib/everolimus as second line or greater after 1 prior antiangiogenic therapy. From chart review data abstraction, 79 patients had a median overall survival from lenvatinib/everolimus index date of 14.8 (CI, 10.2-23.9) months. Results showed real-world effectiveness in clinical practice for a heavily pretreated advanced/metastatic renal cell carcinoma patient population. Introduction: Few studies have evaluated real-world effectiveness of lenvatinib (Len)/everolimus (Eve) for advanced/metastatic renal cell carcinoma (a/mRCC). This study evaluated patient profiles and clinical outcomes of second- and subsequent-line (= 2L) Len/Eve for a/mRCC. Patients and Methods: A longitudinal retrospective study examined adult patients initiating = 2L Len/Eve for a/mRCC from May 13, 2016, to July 31, 2019. Len/Eve clinical trial participants or those treated for other primary tumors were excluded. Outcomes included objective response rate, duration of response, progression-free survival (PFS), time to treatment discontinuation, and overall survival. Timeto- event outcomes were estimated using Kaplan-Meier methods. Results: Seventy-nine patients were assessed: the median age was 64.8 years, 78.5% were Caucasian, 73.4% were male, 78.5% had an Eastern Cooperative Oncology Group performance status score of 0/1, 29.1% received 2L/3L Len/Eve, and the median number of prior lines of therapy was 3 (range, 1-8). At initial diagnosis, 55.7% had stage IV disease, 65.8% had International Metastatic risk scores of intermediate/poor, 19.0% favorable, and 15.2% with missing score. Thirty-one (39.2%) patients received immuno-oncology-based regimens, and 50.6% received tyrosine kinase inhibitors directly before Len/Eve initiation. The median time to treatment discontinuation was 5.7 months (95% CI, 3.3-6.9). The physician-assessed objective response rate was 55.7% (1.6% complete response and 54.1% with some degree of tumor shrinkage). The median duration of response was 9.7 months (95% CI, 5.8-17.1). The median PFS was 6.1 months (95% CI, 4.4-9.0). The median PFS for patients receiving Len/Eve post-immuno-oncology was 6.4 months (95% CI, 4.1-10.8) and for post-tyrosine kinase inhibitor 5.7 months (95% CI, 4.1-10.5). Median overall survival was 14.8 months (95% CI, 10.2-23.9). Conclusion: In this longitudinal retrospective study, Len/Eve showed real-world effectiveness in clinical practice in a heavily pretreated a/mRCC patient population. [ABSTRACT FROM AUTHOR]

• Our study is the first to evaluate the effect of early thoracic surgery on patients with unresectable stage IIIB–IV EGFR-mutant lung adenocarcinoma who received and responded to EGFR-TKIs. • Thoracic surgery reduced the incidence of death in patients with unresectable stage IIIB–IV EGFR-mutant lung adenocarcinoma who received and responded to EGFR-TKIs. • Thoracic surgery appeared to be more beneficial for OS in older patients (aged ≥65 years) patients receiving and responding to TKIs compared with younger patients. No large-scale, prospective, randomized study has evaluated the effect of thoracic surgery on patients with unresectable stage IIIB–IV epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma who received and responded to EGFR tyrosine kinase inhibitor (TKI) treatment. Therefore, we designed a propensity-score-matched, nationwide, population-based, cohort study to investigate the effects of thoracic surgery on patients with EGFR-mutant lung adenocarcinoma. We included patients with unresectable stage IIIB–IV EGFR-mutant lung adenocarcinoma and categorized them into two groups according to their treatment modalities and compared their outcomes: the case group consisted of patients who underwent thoracic surgery for lung tumors after receiving and responding to EGFR-TKI treatment and the comparison group consisted of patients who received EGFR-TKI treatment alone until tumor progression. Patients in both groups were matched at a ratio of 1:4. The matching process yielded a final cohort of 1395 patients (279 and 1,116 in the case and comparison groups, respectively) who were eligible for further analysis. According to multivariable Cox regression analyses, the adjusted hazard ratio (aHR; 95% confidence interval [CI]) for thoracic surgery for lung tumors after EGFR-TKI use and tumor response (group 2) compared with EGFR-TKI treatment alone (group 1) was 0.445 (0.351–0.564). Thoracic surgery prolonged overall survival in patients with unresectable stage IIIB–IV EGFR-mutant lung adenocarcinoma who received and responded to EGFR-TKI treatment. [ABSTRACT FROM AUTHOR]