KIT/PDGFRA inhibitors for the treatment of gastrointestinal stromal tumors: getting to the gist of the problem.

INTRODUCTION: Approximately 90% of gastrointestinal stromal tumors (GISTs) are driven by activating mutations in receptor tyrosine-kinases KIT or PDGFRA. Despite the outstanding results of first-line imatinib in advanced GIST, resistance ultimately occurs mainly through secondary mutations in KIT/PDGFRA. Other tyrosine-kinase inhibitors (TKIs) with a broader spectrum of activity against these mutations are approved after imatinib failure. However, response rates and progression-free survival are drastically lower compared to imatinib. Notably, imatinib also triggers early tolerance adaptation mechanisms, which precede the occurrence of secondary mutations. AREAS COVERED: In this review, we outline the current landscape of KIT inhibitors, discuss the novel agents, and present additional biological pathways that may be therapeutically exploitable. EXPERT OPINION: The development of broad-spectrum and highly selective TKIs able to induce a sustained KIT/PDGFRA inhibition is the pillar of preclinical and clinical investigation in GIST. However, it is now recognized that the situation is more intricate, with various factors interacting with KIT and PDGFRA, playing a crucial role in the response and resistance to treatments. Future strategies in the management of advanced GIST should integrate driver inhibition with the blockade of other molecules to enhance cell death and establish enduring responses in patients.

KIT ATP-Binding Pocket/Activation Loop Mutations in GI Stromal Tumor: Emerging Mechanisms of Kinase Inhibitor Escape.

PURPOSE: Imatinib resistance in GI stromal tumors (GISTs) is primarily caused by secondary KIT mutations, and clonal heterogeneity of these secondary mutations represents a major treatment obstacle. KIT inhibitors used after imatinib have clinical activity, albeit with limited benefit. Ripretinib is a potent inhibitor of secondary KIT mutations in the activation loop (AL). However, clinical benefit in fourth line remains limited and the molecular mechanisms of ripretinib resistance are largely unknown. PATIENTS AND METHODS: Progressing lesions of 25 patients with GISTs refractory to ripretinib were sequenced for KIT resistance mutations. Resistant genotypes were validated and characterized using novel cell line models and in silico modeling. RESULTS: GISTs progressing on ripretinib were enriched for secondary mutations in the ATP-binding pocket (AP), which frequently occur in cis with preexisting AL mutations, resulting in highly resistant AP/AL genotypes. AP/AL mutations were rarely observed in a cohort of progressing GIST samples from the preripretinib era but represented 50% of secondary KIT mutations in patients with tumors resistant to ripretinib. In GIST cell lines harboring secondary KIT AL mutations, the sole genomic escape mechanisms during ripretinib drug selection were AP/AL mutations. Ripretinib and sunitinib synergize against mixed clones with secondary AP or AL mutants but do not suppress clones with AP/AL genotypes. CONCLUSION: Our findings underscore that KIT remains the central oncogenic driver even in late lines of GIST therapy. KIT-inhibitor combinations may suppress resistance because of secondary KIT mutations. However, the emergence of KIT AP/AL mutations after ripretinib treatment calls for new strategies in the development of next-generation KIT inhibitors.

Ripretinib versus sunitinib in gastrointestinal stromal tumor: ctDNA biomarker analysis of the phase 3 INTRIGUE trial.

INTRIGUE was an open-label, phase 3 study in adult patients with advanced gastrointestinal stromal tumor who had disease progression on or intolerance to imatinib and who were randomized to once-daily ripretinib 150 mg or sunitinib 50 mg. In the primary analysis, progression-free survival (PFS) with ripretinib was not superior to sunitinib. In clinical and nonclinical studies, ripretinib and sunitinib have demonstrated differential activity based on the exon location of KIT mutations. Therefore, we hypothesized that mutational analysis using circulating tumor DNA (ctDNA) might provide further insight. In this exploratory analysis (N = 362), baseline peripheral whole blood was analyzed by a 74-gene ctDNA next-generation sequencing-based assay. ctDNA was detected in 280/362 (77%) samples with KIT mutations in 213/362 patients (59%). Imatinib-resistant mutations were found in the KIT ATP-binding pocket (exons 13/14) and activation loop (exons 17/18). Mutational subgroup assessment showed 2 mutually exclusive populations with differential treatment effects. Patients with only KIT exon 11 + 13/14 mutations (ripretinib, n = 21; sunitinib, n = 20) had better PFS with sunitinib versus ripretinib (median, 15.0 versus 4.0 months). Patients with only KIT exon 11 + 17/18 mutations (ripretinib, n = 27; sunitinib, n = 25) had better PFS with ripretinib versus sunitinib (median, 14.2 versus 1.5 months). The results of this exploratory analysis suggest ctDNA sequencing may improve the prediction of the efficacy of single-drug therapies and support further evaluation of ripretinib in patients with KIT exon 11 + 17/18 mutations. ClinicalTrials.gov identifier: NCT03673501.

Hyperammonemic encephalopathy after tyrosine kinase inhibitors: A literature review and a case example.

OBJECTIVE: To review the evidence of uncommon but fatal adverse event of hyperammonemic encephalopathy by tyrosine kinase inhibitors (TKI) and the possible mechanisms underlying this condition and to describe the case of a patient that developed drug-induced hyperammonemic encephalopathy related to TKI. DATA SOURCES: Literature search of different databases was performed for studies published from 1 January 1992 to 7 May 2023. The search terms utilized were hyperammonemic encephalopathy, TKI, apatinib, pazopanib, sunitinib, imatinib, sorafenib, regorafenib, trametinib, urea cycle regulation, sorafenib, carbamoyl-phosphate synthetase 1, ornithine transcarbamylase, argininosuccinate synthetase, argininosuccinate lyase, arginase 1, Mitogen activated protein kinases (MAPK) pathway and mTOR pathway, were used individually search or combined. DATA SUMMARY: Thirty-seven articles were included. The articles primarily focused in hyperammonemic encephalopathy case reports, management of hyperammonemic encephalopathy, urea cycle regulation, autophagy, mTOR and MAPK pathways, and TKI. CONCLUSION: Eighteen cases of hyperammonemic encephalopathy were reported in the literature from various multitargeted TKI. The mechanism of this event is not well-understood but some authors have hypothesized vascular causes since some of TKI are antiangiogenic, however our literature review shows a possible relationship between the urea cycle and the molecular inhibition exerted by TKI. More preclinical evidence is required to unveil the biochemical mechanisms responsible involved in this process and clinical studies are necessary to shed light on the prevalence, risk factors, management and prevention of this adverse event. It is important to monitor neurological symptoms and to measure ammonia levels when manifestations are detected.

Clinical Benefit of Avapritinib in KIT-Mutant Gastrointestinal Stromal Tumors: A Post Hoc Analysis of the Phase I NAVIGATOR and Phase I/II CS3007-001 Studies.

PURPOSE: The efficacy of the selective KIT/PDGFRA inhibitor avapritinib (300 mg once daily) was explored in patients with non-PDGFRA-mutant gastrointestinal stromal tumors (GISTs) from the phase I NAVIGATOR and phase I/II CS3007-001 trials. PATIENTS AND METHODS: Adults with unresectable/metastatic, KIT-only-mutant GISTs and progression following ≥1 tyrosine kinase inhibitors (TKIs) were included in this post hoc analysis. Baseline mutational status was identified in tumor and plasma. Primary endpoints were objective response rate (ORR) and progression-free survival (PFS) by blinded independent radiology review per modified RECIST v1.1 in patients harboring KIT activation-loop mutations (KIT exons 17 or 18) without ATP binding-pocket mutations (KIT exons 13 or 14; ALposABPneg), and other KIT mutations (OTHERS). RESULTS: Sixty KIT ALposABPneg and 100 KIT OTHERS predominantly heavily pretreated patients (61.3% with ≥3 prior TKIs) were included. ORR was significantly higher in KIT ALposABPneg than KIT OTHERS patients (unadjusted: 26.7% vs. 12.0%; P = 0.0852; adjusted: 31.4% vs. 12.1%; P = 0.0047). Median PFS (mPFS) was significantly longer in KIT ALposABPneg patients compared with KIT OTHERS patients (unadjusted: 9.1 vs. 3.5 months; P = 0.0002; adjusted: 9.1 vs. 3.4 months; P < 0.0001), and longer in second- versus later-line settings (19.3 vs. 5.6-10.6 months). Benefit with avapritinib was observed in patients with KIT exon 9 mutations in the ≥4 line settings (mPFS: 5.6 and 3.7 months for 4 line and >4 line, respectively). CONCLUSIONS: Avapritinib showed greater antitumor activity in patients with GISTs harboring KIT ALposABPneg mutations versus KIT OTHERS, and may be considered in the former subpopulation. Patients with KIT exon 9 mutations may also benefit in ≥4 line settings.

Cost Evaluation Analysis of Genetic Testing and Tailored Adjuvant Imatinib in Patients With Resected High-Risk GI Stromal Tumors: The Brazilian Perspective.

PURPOSE: Mutations of the KIT gene are the molecular hallmark of most GI stromal tumors (GISTs). Imatinib has revolutionized GIST treatment. Adjuvant imatinib for 3 years is the standard of care for high-risk resected GIST. However, the GIST molecular biologic profile has found different responses to this approach. Despite this, genetic testing at diagnosis is not a routine and empirical adjuvant imatinib remains the rule. Barriers to genetic profiling include concerns about the cost and utility of testing. This analysis aims to determine whether targeted genetic testing reduces costs as an ancillary tool for a limited-resource scenario instead of adjuvant empirical imatinib in patients with resected high-risk GIST. METHODS: The cost evaluation analysis of molecular testing for GIST was based on the Cost of Preventing an Event (COPE), considering the Number Needed to Treat and the costs of each test compared with the cost of 3-year empirical adjuvant imatinib and real treatment costs (median number of cycles) from the public and private Brazilian Healthcare System's perspective. The analysis compared the costs of the molecular tests (broad next-generation sequencing [NGS], GS Infinity DNA/RNA assay, and targeted NGS: GS Focus GIST and the Fleury GIST Tumor DNA sequencing panel), costs of drug acquisition, considering discounts (imatinib mesylate and Glivec), and the costs of supportive care. RESULTS: In both scenarios, public and private, regardless of the use of imatinib or Glivec, tailoring adjuvant treatment reduced costs, irrespective of the number of cycles. The only exception was the combination of the broad NGS test and imatinib in the Public Healthcare System. CONCLUSION: The molecularly tailored adjuvant imatinib reduced costs considering the COPE of available NGS tests for both the public and private Brazilian health care systems.

2023 GEIS Guidelines for gastrointestinal stromal tumors.

Gastrointestinal stromal tumor (GIST) is the most common malignant neoplasm of mesenchymal origin. GIST spans a wide clinical spectrum that ranges from tumors with essentially no metastatic potential to malignant and life-threatening spread diseases. Gain-of-function mutations in KIT or PDGFRA receptor tyrosine kinases are the crucial drivers of most GISTs, responsible for tumor initiation and evolution throughout the entire course of the disease. The introduction of tyrosine kinase inhibitors targeting these receptors has substantially improved the outcomes in this formerly chemoresistant cancer. As of today, five agents hold regulatory approval for the treatment of GIST: imatinib, sunitinib, regorafenib, ripretinib, and avapritinib. This, in turn, represents a success for a rare neoplasm. During the past two decades, GIST has become a paradigmatic model in cancer for multidisciplinary work, given the disease-specific particularities regarding tumor biology and tumor evolution. Herein, we review currently available evidence for the management of GIST. This clinical practice guideline has been developed by a multidisciplinary expert panel (oncologist, pathologist, surgeon, molecular biologist, radiologist, and representative of patients' advocacy groups) from the Spanish Group for Sarcoma Research, and it is conceived to provide, from a critical perspective, the standard approach for diagnosis, treatment, and follow-up.

SEOM-GEIS clinical guideline for gastrointestinal stromal tumors (2022)

Gastrointestinal stromal tumor (GIST) is the most common malignant neoplasm of mesenchymal origin, and a paradigmatic model for a successful rational development of targeted therapies in cancer. The introduction of tyrosine kinase inhibitors with activity against KIT/PDGFRA in both localized and advanced stages has remarkably improved the survival in a disease formerly deemed resistant to all systemic therapies. These guidelines are elaborated by the conjoint effort of the Spanish Society of Medical Oncology (SEOM) and the Spanish Sarcoma Research Group (GEIS) and provide a multidisciplinary and updated consensus for the diagnosis and treatment of GIST patients. We strongly encourage that the managing of these patients should be performed within multidisciplinary teams in reference centers (AU)

Patient-reported outcomes and tolerability in patients receiving ripretinib versus sunitinib after treatment with imatinib in INTRIGUE, a phase 3, open-label study.

PURPOSE: In the INTRIGUE trial, ripretinib showed no significant difference versus sunitinib in progression-free survival for patients with advanced gastrointestinal stromal tumour (GIST) previously treated with imatinib. We compared the impact of these treatments on health-related quality of life (HRQoL). PATIENTS AND METHODS: Patients were randomised 1:1 to once-daily ripretinib 150 mg or once-daily sunitinib 50 mg (4 weeks on/2 weeks off). Patient-reported outcomes were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire for Cancer-30 (EORTC QLQ-C30) questionnaire at day (D)1, and D29 of all cycles until treatment discontinuation. Change from baseline was calculated. Time without symptoms or toxicity (TWiST) was estimated as the mean number of days without progression, death, or grade ≥3 treatment-emergent adverse events per patient over 1 year of follow-up. RESULTS: Questionnaire completion at baseline was 88.1% (199/226) for ripretinib and 87.7% (199/227) for sunitinib and remained high for enrolled patients throughout treatment. Patients receiving sunitinib demonstrated within-cycle variation in self-reported HRQoL, corresponding to the on/off dosing regimen. Patients receiving ripretinib reported better HRQoL at D29 assessments than patients receiving sunitinib on all scales except constipation. HRQoL was similar between treatments at D1 assessments, following 2 weeks without treatment for sunitinib patients. TWiST was greater for ripretinib patients (173 versus 126 days). CONCLUSION: Patients receiving ripretinib experienced better HRQoL than patients receiving sunitinib during the dosing period and similar HRQoL to patients who had not received sunitinib for 2 weeks for all QLQ-C30 domains except constipation. Ripretinib may provide clinically meaningful benefit to patients with advanced GIST previously treated with imatinib.

REGISTRI: Regorafenib in first-line of KIT/PDGFRA wild type metastatic GIST: a collaborative Spanish (GEIS), Italian (ISG) and French Sarcoma Group (FSG) phase II trial.

BACKGROUND: Approximately 15% of adult GIST patients harbor tumors that are wild-type for KIT and PDGFRα genes (KP-wtGIST). These tumors usually have SDH deficiencies, exhibit a more indolent behavior and are resistant to imatinib. Underlying oncogenic mechanisms in KP-wtGIST include overexpression of HIF1α high IGFR signaling through the MAPK pathway or BRAF activating mutation, among others. As regorafenib inhibits these signaling pathways, it was hypothesized that it could be more active as upfront therapy in advanced KP-wtGIST. METHODS: Adult patients with advanced KP-wtGIST after central confirmation by NGS, naïve of systemic treatment for advanced disease, were included in this international phase II trial. Eligible patients received regorafenib 160 mg per day for 21 days every 28 days. The primary endpoint was disease control rate (DCR), according to RECIST 1.1 at 12 weeks by central radiological assessment. RESULTS: From May 2016 to October 2020, 30 patients were identified as KP-wtGIST by Sanger sequencing and 16 were confirmed by central molecular screening with NGS. Finally, 15 were enrolled and received regorafenib. The study was prematurely closed due to the low accrual worsened by COVID outbreak. The DCR at 12 weeks was 86.7% by central assessment. A subset of 60% experienced some tumor shrinkage, with partial responses and stabilization observed in 13% and 87% respectively, by central assessment. SDH-deficient GIST showed better clinical outcome than other KP-wtGIST. CONCLUSIONS: Regorafenib activity in KP-wtGIST compares favorably with other tyrosine kinase inhibitors, especially in the SDH-deficient GIST subset and it should be taken into consideration as upfront therapy of advanced KP-wtGIST. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02638766.

The multifaceted landscape behind imatinib resistance in gastrointestinal stromal tumors (GISTs): A lesson from ripretinib.

Gastrointestinal stromal tumors (GISTs) are rare mesenchymal sarcomas and the gold-standard treatment is represented by tyrosine kinase inhibitors (TKIs). Unfortunately, first-line treatment with the TKI imatinib usually promotes partial response or stable disease rather than a complete response, and resistance appears in most patients. Adaptive mechanisms are immediately relevant at the beginning of imatinib therapy, and they may represent the reason behind the low complete response rates observed in GISTs. Concurrently, resistant subclones can silently continue to grow or emerge de novo, becoming the most representative populations. Therefore, a slow evolution of the primary tumor gradually occurs during imatinib treatment, enriching heterogeneous imatinib resistant clonal subpopulations. The identification of secondary KIT/PDGFRA mutations in resistant GISTs prompted the development of novel multi-targeted TKIs, leading to the approval of sunitinib, regorafenib, and ripretinib. Although ripretinib has broad anti-KIT and -PDGFRA activity, it failed to overcome sunitinib as second-line treatment, suggesting that imatinib resistance is more multifaceted than initially thought. The present review summarizes several biological aspects suggesting that heterogeneous adaptive and resistance mechanisms can also be driven by KIT or PDGFRA downstream mediators, alternative kinases, as well as non-coding RNAs, which are not targeted by any TKI, including ripretinib. This may explain the modest effect observed with ripretinib and all anti-GIST agents in patients.

SEOM-GEIS clinical guideline for gastrointestinal stromal tumors (2022).

Gastrointestinal stromal tumor (GIST) is the most common malignant neoplasm of mesenchymal origin, and a paradigmatic model for a successful rational development of targeted therapies in cancer. The introduction of tyrosine kinase inhibitors with activity against KIT/PDGFRA in both localized and advanced stages has remarkably improved the survival in a disease formerly deemed resistant to all systemic therapies. These guidelines are elaborated by the conjoint effort of the Spanish Society of Medical Oncology (SEOM) and the Spanish Sarcoma Research Group (GEIS) and provide a multidisciplinary and updated consensus for the diagnosis and treatment of GIST patients. We strongly encourage that the managing of these patients should be performed within multidisciplinary teams in reference centers.

LIX1 Controls MAPK Signaling Reactivation and Contributes to GIST-T1 Cell Resistance to Imatinib.

Gastrointestinal stromal tumor (GIST), the most common sarcoma, is mainly caused by an oncogenic mutation in the KIT receptor tyrosine kinase. Targeting KIT using tyrosine kinase inhibitors, such as imatinib and sunitinib, provides substantial benefit; however, in most patients, the disease will eventually progress due to KIT secondary mutations leading to treatment failure. Understanding how GIST cells initially adapt to KIT inhibition should guide the selection of appropriate therapies to overcome the emergence of resistance. Several mechanisms have been broadly implicated in the resistance to imatinib anti-tumoral effects, including the reactivation of MAPK signaling upon KIT/PDGFRA targeted inhibition. This study provides evidence that LImb eXpression 1 (LIX1), a protein we identified as a regulator of the Hippo transducers YAP1 and TAZ, is upregulated upon imatinib or sunitinib treatment. LIX1 silencing in GIST-T1 cells impaired imatinib-induced MAPK signaling reactivation and enhanced imatinib anti-tumor effect. Our findings identified LIX1 as a key regulator of the early adaptative response of GIST cells to targeted therapies.

Co-targeting of ACK1 and KIT triggers additive anti-proliferative and -migration effects in imatinib-resistant gastrointestinal stromal tumors.

Most gastrointestinal stromal tumors (GIST) harbor mutated receptor tyrosine kinase (RTK) KIT/PDGFRA, which provides an attractive therapeutic target. However, a majority of GISTs ultimately develop resistance to KIT/PDGFRA inhibitor imatinib, multiple therapeutic targets will be identified as a reasonable strategy in imatinib-resistant GISTs. Biological mechanisms of non-RTK activated CDC42 associated kinase 1 (ACK1) are still unclear, which has been found to be activated in GISTs. In the current report, ACK1 overexpression is demonstrated in GIST cell lines and biopsies. RNA-seq analysis and immunoblotting show that ACK1 expression is dependent on imatinib treatment time in GIST-T1 cell line. The colocalization/complex of KIT and ACK1 in GIST cells are observed, and ACK1 activation is in a partially KIT and CDC42 dependent manner. Treatment with a specific ACK1 inhibitor AIM-100 or ACK1 siRNA, mildly suppresses cell viability, but markedly inhibits cell migration in imatinib sensitive and in imatinib resistant GIST cell lines, which is associated with inactivation of PI3K/AKT/mTOR and RAF/MAPK signaling pathways, and inhibition of epithelial-mesenchymal transition, evidencing upregulation of E-cadherin and downregulation of ZEB1, N-cadherin, vimentin, snail, and/or ß-catenin after treatment with AIM-100 or ACK1/CDC42 shRNAs. Combination inhibition of ACK1 and KIT results in additive effects of anti-proliferation and pro-apoptosis as well as cell cycle arrest, and inhibition of invasiveness and migration in vitro and in vivo, compared to either intervention alone through dephosphorylation of KIT downstream intermediates (AKT, S6, and MAPK). Our data suggest that co-targeting of ACK1 and KIT might be a novel therapeutic strategy in imatinib-resistant GIST.

The microphthalmia-associated transcription factor is involved in gastrointestinal stromal tumor growth.

Gastrointestinal stromal tumors (GISTs) are the most common neoplasms of mesenchymal origin, and most of them emerge due to the oncogenic activation of KIT or PDGFRA receptors. Despite their relevance in GIST oncogenesis, critical intermediates mediating the KIT/PDGFRA transforming program remain mostly unknown. Previously, we found that the adaptor molecule SH3BP2 was involved in GIST cell survival, likely due to the co-regulation of the expression of KIT and Microphthalmia-associated transcription factor (MITF). Remarkably, MITF reconstitution restored KIT expression levels in SH3BP2 silenced cells and restored cell viability. This study aimed to analyze MITF as a novel driver of KIT transforming program in GIST. Firstly, MITF isoforms were characterized in GIST cell lines and GIST patients' samples. MITF silencing decreases cell viability and increases apoptosis in GIST cell lines irrespective of the type of KIT primary or secondary mutation. Additionally, MITF silencing leads to cell cycle arrest and impaired tumor growth in vivo. Interestingly, MITF silencing also affects ETV1 expression, a linage survival factor in GIST that promotes tumorigenesis and is directly regulated by KIT signaling. Altogether, these results point to MITF as a key target of KIT/PDGFRA oncogenic signaling for GIST survival and tumor growth.

Microfluidic-based dynamic BH3 profiling predicts anticancer treatment efficacy.

Precision medicine is starting to incorporate functional assays to evaluate anticancer agents on patient-isolated tissues or cells to select for the most effective. Among these new technologies, dynamic BH3 profiling (DBP) has emerged and extensively been used to predict treatment efficacy in different types of cancer. DBP uses synthetic BH3 peptides to measure early apoptotic events ('priming') and anticipate therapy-induced cell death leading to tumor elimination. This predictive functional assay presents multiple advantages but a critical limitation: the cell number requirement, that limits drug screening on patient samples, especially in solid tumors. To solve this problem, we developed an innovative microfluidic-based DBP (µDBP) device that overcomes tissue limitations on primary samples. We used microfluidic chips to generate a gradient of BIM BH3 peptide, compared it with the standard flow cytometry based DBP, and tested different anticancer treatments. We first examined this new technology's predictive capacity using gastrointestinal stromal tumor (GIST) cell lines, by comparing imatinib sensitive and resistant cells, and we could detect differences in apoptotic priming and anticipate cytotoxicity. We then validated µDBP on a refractory GIST patient sample and identified that the combination of dactolisib and venetoclax increased apoptotic priming. In summary, this new technology could represent an important advance for precision medicine by providing a fast, easy-to-use and scalable microfluidic device to perform DBP in situ as a routine assay to identify the best treatment for cancer patients.

Patient-reported outcomes in individuals with advanced gastrointestinal stromal tumor treated with ripretinib in the fourth-line setting: analysis from the phase 3 INVICTUS trial.

BACKGROUND: Ripretinib is a novel switch-control kinase inhibitor that inhibits KIT and PDGFRA signaling. In the INVICTUS phase 3 trial, ripretinib increased median progression-free survival and prolonged overall survival vs. placebo in ≥ fourth-line advanced GIST. Here, we report prespecified analysis of quality of life (QoL) as assessed by patient-reported outcome (PRO) measures and an exploratory analysis evaluating the impact of alopecia on QoL. METHODS: In the INVICTUS trial (NCT03353753), QoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30; physical function, role function, overall health, and overall QoL) and the EuroQoL 5-Dimension 5-Level (EQ-5D-5 L; visual analogue scale). Analysis of covariance (ANCOVA) models compared changes in scores from baseline to treatment cycle 2, day 1 within and between ripretinib and placebo. Within the ripretinib arm, repeated measures models assessed the impact of alopecia on QoL. RESULTS: Patients receiving ripretinib maintained QoL (as assessed by the EORTC QLQ-C30 and EQ-5D-5 L PRO measures) from baseline to cycle 2, day 1 whereas QoL declined with placebo, resulting in clinically significant differences between treatments (nominal P < 0.01). The most common treatment-emergent adverse event with ripretinib was alopecia; however, QoL was similarly maintained out to treatment cycle 10, day 1 in patients receiving ripretinib who developed alopecia and those who did not. CONCLUSION: PRO assessments in the INVICTUS trial suggest that patients on ripretinib maintain their QoL out to C2D1, unlike patients receiving placebo. Longitudinal QoL was maintained for patients receiving ripretinib out to cycle 10, day 1 (approximately 8 months; past the point of median progression-free survival with ripretinib [6.3 months]), even if the patients developed alopecia. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03353753 ; first posted: November 27, 2017.

Uncommon Cause of Hemoptysis in a 15-Year-Old Boy.

CASE PRESENTATION: A 15-year-old boy presented with three acute episodes of self-limited hemoptysis. He was being followed by the pediatric pulmonology department for necrotizing pneumonia and a right upper lobe lung abscess with residual pneumatocele 5 years earlier. He had also experienced recurrent perianal abscesses and more than 15 acute suppurative otitis media throughout his life, even after myringotomy and transtympanic drainage; methicillin-sensitive Staphyloccocus aureus was found in a culture of otic exudate. He had no known allergies and was not taking any drugs. The patient's father had presented with more than 20 skin abscesses and was carrier of methicillin-resistant S aureus. After necrotizing pneumonia and along with his family history, the patient had undergone a neutrophil oxidative burst test excluding chronic granulomatous disease; immunoglobulin levels and lymphocyte populations were within normal range.