OBJECTIVE: To report the results of PADRES (Prior Axitinib as a Determinant of Outcome of Renal Surgery, NCT03438708), a study investigating neoadjuvant axitinib for tumours of high complexity with imperative indication for partial nephrectomy (PN).
METHODS: We conducted a single-arm phase II clinical trial of localized (cT1b-cT3M0) clear-cell renal cell carcinoma (RCC) patients with imperative indications for nephron preservation, where PN is a high-risk procedure due to complexity (RENAL score 10-12). Axitinib 5 mg was administered twice daily for 8 weeks with repeat imaging at completion, followed by surgery. The primary outcome was successful completion of planned PN following axitinib treatment. Secondary objectives included changes in tumour diameter, RENAL nephrometry score, renal function and Response Evaluation Criteria in Solid Tumours (RECIST) v1.1, and surgical complications.
RESULTS: Twenty-seven patients were enrolled (median age 69 years). Prior to therapy, twenty patients (74.0%) had ≥ clinical T3a staged tumours. Axitinib resulted in reductions in tumour diameter (7.5 vs 6.2 cm; P < 0.001) and RENAL score (11 vs 10; P < 0.001). Nine patients (33.3%) had partial response based on RECIST and nine (33.3%) were clinically downstaged. PN was performed in twenty patients (74.0%); twenty-five patients (96.2%) had negative margins. Six patients (22.2%) had Clavien III-IV complications. The median change in estimated glomerular filtration rate (preoperative to last follow-up) was 8.5 mL/min/1.73 m2 .
CONCLUSIONS: Neoadjuvant axitnib resulted in reductions in tumour size and complexity, enabling safe and feasible PN and functional preservation in patients with complex renal masses and imperative indication.

Cardiotoxicity is a common and under-reported side effect of tyrosine-kinase inhibitors (TKI) and immune checkpoint inhibitors (ICI). Baseline risk factors may help in risk-stratifying patients at increased risk of cardiotoxicity. This real-world study investigated the effects of baseline risk factors in cardiotoxicity on patients with non-small-cell lung cancer (NSCLC) treated with TKIs and ICIs.
This is a retrospective study carried out at The Royal Marsden Hospital, UK. Newly diagnosed patients with localized or metastatic NSCLC who received anticancer therapy with TKIs and/or ICIs were eligible. Patients who received only chemotherapy were excluded. Patients were followed up from the time of diagnosis until death or discharge. The relationship between cardiotoxicity and risk factors were tested by logistic regression.
Of 88/451 (19.5%) patients developed cardiotoxicity. Risk factors hypothesized to have a causal relationship with anticancer treatment-induced cardiotoxicity were analyzed. Cardiotoxicity risk was increased with prior diabetes mellitus (OR = 1.93, 95% CI, 1.04-3.61, P = .038), history of smoking (OR = 1.91, 95% CI, 1.13-3.22, P = .016) and presence of baseline cardiovascular disease (OR = 2.03, 95% CI, 1.13-3.64, P = .018). The risk of developing cardiotoxicity increased in patients for smokers with diabetes mellitus (OR = 3.03, 95% CI, 1.40-6.55, P < .01) and for smokers with previous cardiovascular disease (OR = 1.99, 95% CI, 1.03-3.84, P = .041).
Diabetes mellitus, smoking and baseline cardiovascular disease may synergistically contribute to cardiotoxicity when a patient is exposed to potentially cardiotoxic anticancer agents. Risk stratification at baseline may improve cardio-oncology care.

OBJECTIVE: Given the availability of TKIs with high central nervous system efficacy, the question arises as to whether upfront SRS provides additional clinical benefits. The goal of this study was to characterize the clinical outcomes of SRS as salvage therapy for TKI-uncontrolled BMs.
METHODS: This retrospective study included EGFR-mutant NSCLC patients presenting BMs at the time of primary tumor diagnosis. BMs were categorized into three subgroups, referred to as \"Nature of TKI-treated BMs\", \"TKI-controlled brain metastases ± SRS\", and \"SRS salvage therapy\". The first subgroup analysis characterized the effects of TKIs on tumor behavior. In the second subgroup, we compared outcomes of TKI-controlled BMs treated with TKI alone versus those treated with combined TKI-SRS therapy. The third subgroup characterized the outcomes of TKI-uncontrolled BMs treated with SRS as salvage therapy Clinical outcomes include local and distant tumor control.
RESULTS: This study included 106 patients with a total of 683 BMs. TKI treatment achieved control in 63% of local tumors at 24 months. Among the TKI-controlled BMs, local tumor control was significantly higher in the combined TKI-SRS group (93%) than in the TKI-alone group (65%) at 24 months (p < 0.001). No differences were observed between the two groups in terms of distant tumor control (p = 0.832). In dealing with TKI-uncontrolled BMs, salvage SRS achieved local tumor control in 58% of BMs at 24 months.
CONCLUSIONS: While upfront TKI alone proved highly effective in BM control, this study also demonstrated the outcomes of SRS when implemented concurrently with TKI or as salvage therapy for TKI-uncontrolled BMs. This study also presents a strategy of the precise timing and targeting of SRS to lesions in progression.

Cutaneous adverse effects (AE) related to tyrosine-kinase inhibitor (TKI) drugs have been mainly described as case reports. We have characterized their appearance and correlation with patient\'s photoexposition habits and, further, with treatment response, in 61 patients with chronic myelogenous leukemia (CML) treated with TKI drugs. We have found hypopigmentation in 49.2% of the cases and a statistically significant association with interferon (IFN) intake. Eyelid edema\'s frequency was 45.4%. Mean photo-exposure was 1.95 h/day and only 8.3% of the patients used sunscreen daily. 44.3% of the patients reported a lighter skin color with the treatment and a statistically significant relationship with conjunctival hemorrhage was also found. Concordance between patients and dermatologist was moderate (kappa index 0.41). We found xerosis (21.3%), eczematous eruptions (21.3%), melasma (4.9%) and other isolated skin problems (ie, granulomatous panniculitis) in up to 16.4% of cases. Appearance of hypopigmented macules is associated to vascular conjunctival fragility and these patients need a slightly longer time to reach a complete molecular response, but without additional changes in survival or relapse frequency. We have stablished a specific dermatologic diagnosis in all the cases and we have not found the previously published as maculopapular rashes. Hypopigmentation, the more frequent AE, was not perceived as a relevant side effect. Photosensitivity, in our cases, was not reported, although imatinib-treated patients avoided sun-exposure. In addition, we identified some nonpreviously described dermatologic conditions in patients taking TKI drugs, like granulomatous panniculitis tufted folliculitis or oral spindle cell lipoma.

Tyrosine kinase inhibitors are considered for use in patients with hepatocellular carcinoma (HCC) refractory to transarterial chemoembolization (TACE). The aim of the present retrospective study was to identify factors associated with progression-free survival (PFS) and to evaluate the indications for lenvatinib treatment in patients with intermediate-stage HCC refractory to TACE using a data-mining analysis. A total of 171 patients with intermediate-stage HCC refractory to TACE were included. All patients were classified into three groups according to their HCC treatment: Lenvatinib (n=45), sorafenib (n=53) and TACE (n=73) groups. PFS time was calculated using the Kaplan-Meier method and analyzed using a log-rank test. Factors associated with PFS time were evaluated using multivariate and decision-tree analyses. The median PFS time was 5.8, 3.2 and 2.4 months in the lenvatinib, sorafenib and TACE groups, respectively (P<0.001). In the Cox regression analysis, lenvatinib treatment and being within the up-to-seven criteria were identified as independent factors for PFS (lenvatinib, P<0.0001; within up-to-seven, P=0.001). The decision-tree analysis revealed that patients beyond the up-to-seven criteria, treated with lenvatinib and with albumin-bilirubin (ALBI) grade 1 had a longer PFS time (245.2±107.9 days) than patients beyond the up-to-seven criteria, treated with lenvatinib and with ALBI grade 2 (147.1±78.6 days). Additionally, lenvatinib was independently associated with longer PFS time in patients with intermediate-stage HCC refractory to TACE. Therefore, lenvatinib may be recommended for patients who have intermediate-stage HCC refractory to TACE, ALBI grade 1 and who are within the up-to-seven criteria.

This observational, prospective study assessed, in a daily clinical practice, the molecular response, safety, quality of life (QoL) and treatment adherence in 183 patients with chronic myeloid leukaemia in chronic phase (CML-CP), receiving nilotinib as first-line treatment. Premature study termination before 24 months of follow-up occurred in 61 patients (33·3%), and was essentially due to nilotinib treatment discontinuation (n = 53; 29%), motivated by treatment intolerance (n = 29; 15·8%) and inefficacy (n = 19; 10·4%). After 24 months of treatment, 112/122 patients (91·8%) had a molecular assessment, 95·5% of whom achieved a major molecular response (MMR), 32·1% achieved uMR4 , defined as an undetectable molecular disease with 4-log molecular response sensitivity (≥10 000 ABL1 transcripts). The Morisky Green Levine Medication Adherence Scale was completed by 94/122 patients (77·0%), and 89·4% of these patients obtained a satisfactory level of treatment adherence, defined as a score ≥3. Patients\' QoL was good at baseline and stable during the follow-up period. The two most common nilotinib-related adverse events (AEs) were pruritus (14·8%) and asthenia (13·7%). Seven patients (3·8%) experienced at least one cardiovascular ischaemic AE. This French nationwide cohort study provides relevant information in daily clinical practice indicating that nilotinib is a valuable first-line treatment option for CML-CP patients.

Purpose: Apatinib has shown effectiveness in treating sarcoma. This study aimed to assess the safety and efficacy of apatinib and doxorubicin combination therapy in metastatic soft tissue sarcomas (STS) and to compare the therapeutic effects of two treatments (apatinib after doxorubicin vs apatinib plus doxorubicin) on STS. Patients and methods: A total of 76 patients with metastatic STS who received apatinib and doxorubicin between May 2016 and June 2017 were retrospectively reviewed. Patients were divided into either the apatinib after doxorubicin group (in which apatinib was used after six cycles of doxorubicin chemotherapy) or the apatinib plus doxorubicin group (in which apatinib was used in combination with doxorubicin chemotherapy). Results: There were 55 patients in the apatinib after doxorubicin group and 21 patients in the apatinib plus doxorubicin group. There were significant differences between the apatinib plus doxorubicin group and the apatinib after doxorubicin group in the objective response rate (57.14% vs 25.45%, respectively, p=0.016) and average change from baseline in the target lesion size (-41.71±43.75% vs -1.89±51.61%, respectively, p=0.03). There were no significant differences in disease control rate (85.71% vs 63.64%, p=0.093) and median progression-free survival (8.8 months vs 10.3 months, p=1). Grade 3-4 adverse events were more common with apatinib plus doxorubicin than with apatinib after doxorubicin, and these included leukopenia (5.45% vs 38.1%, respectively, p=0.001), anemia (7.27% vs 28.57%, respectively, p=0.023), oral mucositis (3.64% vs 19.05%, respectively, p=0.046), transaminase increases (0% vs 14.29%, respectively, p=0.011). Conclusion: Our results do not support the use of apatinib plus doxorubicin for metastatic STS unless the specific objective is tumor shrinkage.

This trial compared the sequential therapy with the multikinase inhibitor sorafenib (So) followed by pazopanib (Pa) or vice versa in advanced/metastatic renal cell carcinoma (mRCC) patients.
This multicenter, randomized phase 3 study assessed the sequential use of So-Pa versus Pa-So in patients with mRCC without prior systemic therapy. Pts were randomized to So 2 × 400 mg/day followed by Pa 1 × 800 mg/day in case of progression or intolerable toxicity or vice versa. Primary endpoint was total PFS (tPFS), defined as time from randomization to progression, or death during second-line therapy. Key secondary endpoints included overall survival (OS), first-line PFS, disease control rate (DCR) and safety.
A total of 377 pts were randomized (So-Pa, n = 189; Pa-So, n = 188). Recruitment of a total 544 pts was calculated, but actual accrual rate turned out to be lower than expected. The primary endpoint median tPFS was 8.6 mo (95% CI 7.7-10.2) for So-Pa and 12.9 mo (95% CI 10.8-15.2) for Pa-So with a hazard ratio (HR) of 1.36 (upper limit of one-sided 95% CI 1.68), which exceeded a predefined HR <1.225 as a one-sided 95% confidence interval. Non-inferiority of So-Pa regarding tPFS was not met. Secondary endpoints displayed marked statistical differences in favor of Pa-So in first-line PFS and DCR but not for OS and 2nd-line PFS. Side effect profiles were consistent with known toxicities of the respective multikinase-inhibitor including diarrhea, fatigue, hand-foot skin reaction and hypertension.
Non-inferiority of the primary endpoint tPFS could not be demonstrated for So-Pa. The results for first-line PFS and DCR favored the Pa-So sequence.
NCT01613846, www.clinicaltrials.gov.

OBJECTIVE: More tolerable treatment options are needed for the large number of elderly patients with non-small-cell lung cancer (NSCLC). An analysis of the phase IV POLARSTAR surveillance study examined the safety and efficacy of erlotinib in elderly Japanese patients with previously treated NSCLC.
METHODS: From December 2007 to October 2009, all erlotinib-treated patients with unresectable, recurrent/advanced NSCLC in Japan were enrolled. Efficacy and safety data were stratified by age (<75 years, 75-84 years, ≥85 years). Kaplan-Meier methodology was used to estimate median progression-free survival (PFS). Safety data were collected with a focus on interstitial lung disease (ILD).
RESULTS: A total of 9907 patients were eligible for safety assessment (<75 years, n=7848; 75-84 years, n=1911; ≥85 years, n=148) and 9651 for efficacy assessment (<75 years, n=7701; 75-84 years, n=1815; ≥85 years, n=135). Other baseline characteristics were balanced. The incidence of ILD (all grades) was 4.2% (<75 years), 5.1% (75-84 years), and 3.4% (≥85 years). The mortality rate due to ILD was ≤1.7% in all age groups. Other toxicities (including rash) were similar between age groups. The median PFS was 65 days (95% confidence interval [CI], 62-68) for patients aged <75 years, 74 days (95% CI, 69-82) for patients aged 75-84 years, and 72 days (95% CI, 56-93) for patients aged ≥85 years.
CONCLUSIONS: Efficacy and tolerability of erlotinib for elderly patients was not numerically inferior to that reported in younger patients. Erlotinib could be considered for elderly patients with recurrent/advanced NSCLC.