A multicenter, dose-finding, phase 1b study of imatinib in combination with alpelisib as third-line treatment in patients with advanced gastrointestinal stromal tumor

Background: Acquired resistance to approved tyrosine kinase inhibitors limits their clinical use in patients with gastrointestinal stromal tumor (GIST). This study investigated the safety, tolerability and efficacy of alpelisib, a phosphatidylinositol 3-kinase inhibitor, used in combination with imatinib in patients with advanced GIST who had failed prior therapy with both imatinib and sunitinib. Methods: This phase 1b, multicenter, open-label study consisted of 2 phases: dose escalation and dose expansion. Dose escalation involved 200 mg once daily (QD) alpelisib, initially, followed by 250 and 350 mg. These were combined with 400 mg QD imatinib until maximum tolerated dose (MTD) and/or a recommended phase 2 dose (RP2D) of alpelisib in combination with imatinib was determined. This MTD/RP2D dose was tested to evaluate the clinical activity of this combination in dose expansion. Results: Fifty-six patients were enrolled, 21 and 35 in the dose escalation and expansion phases, respectively. The MTD of alpelisib given with imatinib was determined as 350 mg QD. Combination treatment showed partial response in 1 (2.9%) and stable disease in 15 (42.9%) patients. Median progression-free survival was 2 months (95% CI 1.8–4.6). Overall, 92.9% patients had adverse events (AEs) while 46.4% had grade 3/4 AEs, hyperglycemia being the most common (23.2%). Conclusions: The MTD of alpelisib was estimated as 350 mg QD when used in combination with imatinib 400 mg QD after oral administration in patients with advanced GIST. The safety and tolerability profile of this combination was acceptable; however, the combination did not demonstrate sufficient clinical activity to justify additional clinical testing

Docetaxel plus cisplatin is effective for patients with metastatic breast cancer resistant to previous anthracycline treatment: a phase II clinical trial

BACKGROUND: Patients with metastatic breast cancer (MBC) are frequently exposed to high cumulative doses of anthracyclines and are at risk of resistance and cardiotoxicity. This phase II trial evaluated the efficacy and toxicity of docetaxel plus cisplatin, as salvage chemotherapy in patients with MBC resistant to prior anthracyclines. METHODS: Patients with MBC that had progressed after at least one prior chemotherapy regimen containing anthracyclines received docetaxel 75 mg/m(2 )followed by cisplatin 60 mg/m(2 )every 3 weeks for a maximum of 6 cycles or until disease progression. RESULTS: Between Jan 2000 and May 2002, 24 patients with tumors primary resistant and 15 with secondary resistant disease were accrued. All 39 patients were evaluable for safety and 36 for efficacy. The objective response rate was 31% (95% CI, 16–45%) with 3 complete responses. The median time to disease progression was 7 months, and the median overall survival was 23 months (median follow-up of 41 months). Neutropenia was the most frequently observed severe hematologic toxicity (39% of patients), whereas asthenia and nausea were the most common non-hematologic toxicities. No treatment-related death was observed. CONCLUSION: In conclusion, we found docetaxel plus cisplatin to be an active and safe chemotherapy regimen for patients with MBC resistant to anthracyclines

Avapritinib versus regorafenib in locally advanced unresectable or metastatic GI stromal tumor: A randomized, open-label phase III study

PURPOSE Primary or secondary mutations in KIT or platelet-derived growth factor receptor alpha (PDGFRA) underlie tyrosine kinase inhibitor resistance in most GI stromal tumors (GISTs). Avapritinib selectively and potently inhibits KIT- and PDGFRA-mutant kinases. In the phase I NAVIGATOR study (NCT02508532), avapritinib showed clinical activity against PDGFRA D842V–mutant and later-line KIT-mutant GIST. VOYAGER (NCT03465722), a phase III study, evaluated efficacy and safety of avapritinib versus regorafenib as third-line or later treatment in patients with unresectable or metastatic GIST. PATIENTS AND METHODS VOYAGER randomly assigned patients 1:1 to avapritinib 300 mg once daily (4 weeks continuously) or regorafenib 160 mg once daily (3 weeks on and 1 week off). Primary end point was progression-free survival (PFS) by central radiology per RECIST version 1.1 modified for GIST. Secondary end points included objective response rate, overall survival, safety, disease control rate, and duration of response. Regorafenib to avapritinib crossover was permitted upon centrally confirmed disease progression. RESULTS Four hundred seventy-six patients were randomly assigned (avapritinib, n 5 240; regorafenib, n 5 236). Median PFS was not statistically different between avapritinib and regorafenib (hazard ratio, 1.25; 95% CI, 0.99 to 1.57; 4.2 v 5.6 months; P 5 .055). Overall survival data were immature at cutoff. Objective response rates were 17.1% and 7.2%, with durations of responses of 7.6 and 9.4 months for avapritinib and regorafenib; disease control rates were 41.7% (95% CI, 35.4 to 48.2) and 46.2% (95% CI, 39.7 to 52.8). Treatment-related adverse events (any grade, grade $ 3) were similar for avapritinib (92.5% and 55.2%) and regorafenib (96.2% and 57.7%). CONCLUSION Primary end point was not met. There was no significant difference in median PFS between avapritinib and regorafenib in patients with molecularly unselected, late-line GIST

Microenvironmental Influence on Pre-Clinical Activity of Polo-Like Kinase Inhibition in Multiple Myeloma: Implications for Clinical Translation

Polo-like kinases (PLKs) play an important role in cell cycle progression, checkpoint control and mitosis. The high mitotic index and chromosomal instability of advanced cancers suggest that PLK inhibitors may be an attractive therapeutic option for presently incurable advanced neoplasias with systemic involvement, such as multiple myeloma (MM). We studied the PLK 1, 2, 3 inhibitor BI 2536 and observed potent (IC50<40 nM) and rapid (commitment to cell death <24 hrs) in vitro activity against MM cells in isolation, as well as in vivo activity against a traditional subcutaneous xenograft mouse model. Tumor cells in MM patients, however, don't exist in isolation, but reside in and interact with the bone microenvironment. Therefore conventional in vitro and in vivo preclinical assays don't take into account how interactions between MM cells and the bone microenvironment can potentially confer drug resistance. To probe this question, we performed tumor cell compartment-specific bioluminescence imaging assays to compare the preclinical anti-MM activity of BI 2536 in vitro in the presence vs. absence of stromal cells or osteoclasts. We observed that the presence of these bone marrow non-malignant cells led to decreased anti-MM activity of BI 2536. We further validated these results in an orthotopic in vivo mouse model of diffuse MM bone lesions where tumor cells interact with non-malignant cells of the bone microenvironment. We again observed that BI 2536 had decreased activity in this in vivo model of tumor-bone microenvironment interactions highlighting that, despite BI 2536's promising activity in conventional assays, its lack of activity in microenvironmental models raises concerns for its clinical development for MM. More broadly, preclinical drug testing in the absence of relevant tumor microenvironment interactions may overestimate potential clinical activity, thus explaining at least in part the gap between preclinical vs. clinical efficacy in MM and other cancers

Effects of preset sequential administrations of sunitinib and everolimus on tumour differentiation in Caki-1 renal cell carcinoma.

BACKGROUND: Sunitinib (VEGFR/PDGFR inhibitor) and everolimus (mTOR inhibitor) are both approved for advanced renal cell carcinoma (RCC) as first-line and second-line therapy, respectively. In the clinics, sunitinib treatment is limited by the emergence of acquired resistance, leading to a switch to second-line treatment at progression, often based on everolimus. No data have been yet generated on programmed alternating sequential strategies combining alternative use of sunitinib and everolimus before progression. Such strategy is expected to delay the emergence of acquired resistance and improve tumour control. The aim of our study was to assess the changes in tumours induced by three different sequences administration of sunitinib and everolimus. METHODS: In human Caki-1 RCC xenograft model, sunitinib was alternated with everolimus every week, every 2 weeks, or every 3 weeks. Effects on necrosis, hypoxia, angiogenesis, and EMT status were assessed by immunohisochemistry and immunofluorescence. RESULTS: Sunitinib and everolimus programmed sequential regimens before progression yielded longer median time to tumour progression than sunitinib and everolimus monotherapies. In each group of treatment, tumour growth control was associated with inhibition of mTOR pathway and changes from a mesenchymal towards an epithelial phenotype, with a decrease in vimentin and an increase in E-cadherin expression. The sequential combinations of these two agents in a RCC mouse clinical trial induced antiangiogenic effects, leading to tumour necrosis. CONCLUSIONS: In summary, our study showed that alternate sequence of sunitinib and everolimus mitigated the development of mesenchymal phenotype compared with sunitinib as single agent

Diagnosis and management of tropomyosin receptor kinase (TRK) fusion sarcomas : expert recommendations from the World Sarcoma Network

Sarcomas are a heterogeneous group of malignancies with mesenchymal lineage differentiation. The discovery of neurotrophic tyrosine receptor kinase (NTRK) gene fusions as tissue-agnostic oncogenic drivers has led to new personalized therapies for a subset of patients with sarcoma in the form of tropomyosin receptor kinase (TRK) inhibitors. NTRK gene rearrangements and fusion transcripts can be detected with different molecular pathology techniques, while TRK protein expression can be demonstrated with immunohistochemistry. The rarity and diagnostic complexity of NTRK gene fusions raise a number of questions and challenges for clinicians. To address these challenges, the World Sarcoma Network convened two meetings of expert adult oncologists and pathologists and subsequently developed this article to provide practical guidance on the management of patients with sarcoma harboring NTRK gene fusions. We propose a diagnostic strategy that considers disease stage and histologic and molecular subtypes to facilitate routine testing for TRK expression and subsequent testing for NTRK gene fusions.Peer reviewe

Population screening for hereditary haemochromatosis in Australia: Construction and validation of a state-transition cost-effectiveness model

INTRODUCTION: HFE-associated haemochromatosis, the most common monogenic disorder amongst populations of northern European ancestry, is characterised by iron overload. Excess iron is stored in parenchymal tissues, leading to morbidity and mortality. Population screening programmes are likely to improve early diagnosis, thereby decreasing associated disease. Our aim was to develop and validate a health economics model of screening using utilities and costs from a haemochromatosis cohort. METHODS: A state-transition model was developed with Markov states based on disease severity. Australian males (aged 30 years) and females (aged 45 years) of northern European ancestry were the target populations. The screening strategy was the status quo approach in Australia; the model was run over a lifetime horizon. Costs were estimated from the government perspective and reported in 2015 Australian dollars ($A); costs and quality-adjusted life-years (QALYs) were discounted at 5$A22,737 (3670-85,793) for males and $A13,840 (1335-67,377) for females. Sensitivity analyses revealed discount rates and prevalence had the greatest impacts on outcomes. CONCLUSION: We have developed a transparent, validated health economics model of C282Y homozygote haemochromatosis. The model will be useful to decision makers to identify cost-effective screening strategies

Immunostaining of thymidylate synthase and p53 for predicting chemoresistance to S-1/cisplatin in gastric cancer

High expression of thymidylate synthase (TS) and inactivation of p53 are allegedly associated with chemoresistance. The authors evaluated TS and p53 expression in gastric cancer treated with neoadjuvant S-1/cisplatin chemotherapy. Paraffin sections of pretreatment biopsy and surgical specimens from 41 gastric cancers were immunostained for TS and p53 protein after appropriate antigen retrieval. Fifty-one cases without neoadjuvant chemotherapy were also studied. In the pretreatment biopsies, high expression of TS was seen in 8% of the histologic responders, in 28% of the nonresponders and in 31% of the controls. High expression of p53 was observed in 56% of the nonresponders, but in 8% of the responders and in 29% of the controls (P<0.01 and P<0.05, respectively). The TS- and/or p53-high phenotype was seen in 76% of the nonresponders and in 54% of the controls, but in 8% of the responders (P<0.0001 and P<0.005, respectively). The data of the surgical specimens were consistent with those of the pretreatment biopsies. These results suggest that immunostaining for TS and p53 protein is useful for pretreatment selection of gastric cancer patients unresponsive to S-1/cisplatin chemotherapy

Fungal infection-related mortality versus total mortality as an outcome in trials of antifungal agents

BACKGROUND: Disease specific mortality is often used as outcome rather than total mortality in clinical trials. This approach assumes that the classification of cause of death is unbiased. We explored whether use of fungal infection-related mortality as outcome rather than total mortality leads to bias in trials of antifungal agents in cancer patients. METHODS: As an estimate of bias we used relative risk of death in those patients the authors considered had not died from fungal infection. Our sample consisted of 69 trials included in four systematic reviews of prophylactic or empirical antifungal treatment in patients with cancer and neutropenia we have published previously. RESULTS: Thirty trials met the inclusion criteria. The trials comprised 6130 patients and 869 deaths, 220 (25%) of which were ascribed to fungal infection. The relative risk of death was 0.85 (95% CI 0.75–0.96) for total mortality, 0.57 (95% CI 0.44–0.74) for fungal mortality, and 0.95 (95% CI 0.82–1.09) for mortality among those who did not die from fungal infection. CONCLUSION: We could not support the hypothesis that use of disease specific mortality introduces bias in antifungal trials on cancer patients as our estimate of the relative risk for mortality in those who survived the fungal infection was not increased. We conclude that it seems to be reliable to use fungal mortality as the primary outcome in trials of antifungal agents. Data on total mortality should be reported as well, however, to guard against the possible introduction of harmful treatments

Enithelioid hemangioendothelioma, an ultra-rare cancer : a consensus paper from the community of experts

Epithelioid hemangioendothelioma (EHE) is an ultra-rare, translocated, vascular sarcoma. EHE clinical behavior is variable, ranging from that of a low-grade malignancy to that of a high-grade sarcoma and it is marked by a high propensity for systemic involvement. No active systemic agents are currently approved specifically for EHE, which is typically refractory to the antitumor drugs used in sarcomas. The degree of uncertainty in selecting the most appropriate therapy for EHE patients and the lack of guidelines on the clinical management of the disease make the adoption of new treatments inconsistent across the world, resulting in suboptimal outcomes for many EHE patients. To address the shortcoming, a global consensus meeting was organized in December 2020 under the umbrella of the European Society for Medical Oncology (ESMO) involving >80 experts from several disciplines from Europe, North America and Asia, together with a patient representative from the EHE Group, a global, disease-specific patient advocacy group, and Sarcoma Patient EuroNet (SPAEN). The meeting was aimed at defining, by consensus, evidence-based best practices for the optimal approach to primary and metastatic EHE. The consensus achieved during that meeting is the subject of the present publication.Peer reviewe