Why tyrosine kinase inhibitor resistance is common in advanced gastrointestinal stromal tumors

Background: Most patients with advanced gastrointestinal stromal tumors (GIST) develop drug resistance to tyrosine kinase inhibitors (TKIs) within two years of starting therapy, whereas most chronic myeloid leukemia (CML) patients in chronic phase still exhibit disease control after a decade on therapy. This article aims to explain this divergence in long term outcomes. Methods and results: By combining clinical and experimental observations with mathematical formulas we estimate that, in advanced GIST, the genetic changes responsible for resistance are generally already present at disease detection. Conclusion: This result has relevant clinical implications by providing support for the exploration of combination therapies

Phase I dose-escalation and pharmacokinetic study of dasatinib in patients with advanced solid tumors

PURPOSE: To determine the maximum tolerated dose, dose-limiting toxicity (DLT), and recommended phase II dose of dasatinib in metastatic solid tumors refractory to standard therapies or for which no effective standard therapy exists. <br></br> EXPERIMENTAL DESIGN: In this phase I, open-label, dose-escalation study, patients received 35 to 160 mg of dasatinib twice daily in 28-day cycles either every 12 hours for 5 consecutive days followed by 2 nontreatment days every week (5D2) or as continuous, twice-daily (CDD) dosing. <br></br> RESULTS: Sixty-seven patients were treated (5D2, n = 33; CDD, n = 34). The maximum tolerated doses were 120 mg twice daily 5D2 and 70 mg twice daily CDD. DLTs with 160 mg 5D2 were recurrent grade 2 rash, grade 3 lethargy, and one patient with both grade 3 prolonged bleeding time and grade 3 hypocalcemia; DLTs with 120 mg twice daily CDD were grade 3 nausea, grade 3 fatigue, and one patient with both grade 3 rash and grade 2 proteinuria. The most frequent treatment-related toxicities across all doses were nausea, fatigue, lethargy, anorexia, proteinuria, and diarrhea, with infrequent hematologic toxicities. Pharmacokinetic data indicated rapid absorption, dose proportionality, and lack of drug accumulation. Although no objective tumor responses were seen, durable stable disease was observed in 16% of patients.<br></br> CONCLUSION: Dasatinib was well tolerated in this population, with a safety profile similar to that observed previously in leukemia patients, although with much less hematologic toxicity. Limited, although encouraging, preliminary evidence of clinical activity was observed. Doses of 120 mg twice daily (5D2) or 70 mg twice daily (CDD) are recommended for further studies in patients with solid tumors.<br></br&gt

Use of Erythropoietin in Cancer Patients: Assessment of Oncologists’ Practice Patterns in the United States and Other Countries

PURPOSE: To assess physician use of erythropoietin in cancer patients before publication of the American Society of Clinical Oncology/American Society of Hematology guidelines. METHODS: Questionnaires about erythropoietin use in practice and 12 hypothetical clinical scenarios involving patients with cancer were mailed to 2000 oncologists/hematologists in the United States and 19 other countries. Response rates were 30% in the United States and 25% internationally. Data on erythropoietin use for ovarian cancer were obtained from one clinical trial. Multivariate regression models assessed predictors of erythropoietin prescription. RESULTS: Most physicians selected a hemoglobin level ≤10 g/dL as an upper threshold for erythropoietin use (36% to 51% of U.S. physicians and 21% to 32% of foreign physicians). Frequent erythropoietin use (defined as use in at least 10% of cancer patients) was higher in the United States than elsewhere (adjusted odds ratio [OR]=5.8; 95% confidence interval [CI]: 2.5 to 13.4). Among U.S. physicians, those who said they used erythropoietin frequently were more likely to be in fee-for-service than managed care settings (OR=2.2; 95% CI: 1.3 to 3.7). Those who reported never using erythropoietin practiced in countries that had lower annual per capita health care expenditures, lower proportions of privately funded health care, and a national health service (P \u3c0.05 for all comparisons). Of 235 ovarian cancer patients who received topotecan, 38% (45/118) of U.S. patients and 2% (2/117) of European patients who developed grade 1 anemia (hemoglobin level between 10 and 12 g/dL) were treated with erythropoietin (P\u3c0.01). CONCLUSION: Financial considerations and a hemoglobin level \u3c10 g/dL appear to influence erythropoietin use in the United States, whereas financial considerations alone determine erythropoietin use abroad

Effect of gastrointestinal resection on sunitinib exposure in patients with GIST

Background: GIST patients often undergo GI-surgery. Previous studies have shown that imatinib and nilotinib exposures were decreased in GIST patients with prior major gastrectomy. We investigated whether major gastrectomy influences the exposure to sunitinib and its active metabolite SU12662. Methods: Pharmacokinetic data from 305 GIST patients included in 4 phase I-III trials were analyzed. Patients were subdivided into 6 groups according to their prior GI-surgery. Apparent clearance (CL/F) and dose-corrected steady-state plasma exposures (AUC24,ss) of sunitinib and SU12662 were estimated using a population PK approach. ANCOVA was performed to test for differences in AUC24,ss and CL/F between each surgery subgroup and controls. Results: Major gastrectomy did not influence sunitinib or SU12662 exposure. The geometric mean of sunitinib and SU12662 AUC24,ss was decreased by 21% and 28% in patients with both gastrectomy and small bowel resection (n = 8) compared to controls (n = 63) for sunitinib (931 ng*hr/mL (95%-CI; 676–1283) versus 1177 ng*hr/mL (95%-CI; 1097–1263); p < 0.05) and SU12662 (354 ng*hr/mL (95%-CI; 174–720) versus 492 ng*hr/mL (95%-CI; 435–555); p < 0.05). No significant differences in exposure were observed in each of the other subgroups versus controls. Conclusion: In contrast to previous results for imatinib and nilotinib, gastrectomy alone does not influence sunitinib or SU12662 exposure. This should be taken into account for the treatment of gastrectomized GIST patients with TKIs. In patients who had undergone both gastrectomy and small bowel resection, sunitinib and SU12662 exposures are significantly, although clinically not relevantly, decreased

Phase II study of olaparib in patients with refractory Ewing sarcoma following failure of standard chemotherapy

Background: Preclinical studies have documented antitumor activity of PARP inhibition both in vitro and in vivo, against Ewing sarcoma cells. This study aimed to translate that observation into a clinical trial to assess the efficacy and tolerability of olaparib, a PARP inhibitor, in patients with advanced Ewing sarcoma (EWS) progressing after prior chemotherapy. Methods: In this nonrandomized phase II trial, adult participants with radiographically measureable metastatic EWS received olaparib tablets, 400 mg orally twice daily, until disease progression or drug intolerance. Tumor measurements were determined by CT or MRI at 6 and 12 weeks after starting olaparib administration, and then every 8 weeks thereafter. Tumor response determinations were made according to RECIST 1.1, and adverse event determinations were made according to CTCAE, version 4.0. A total of 22 participants were planned to be enrolled using a conventional 2-step phase II study design. If no objective responses were observed after 12 participants had been followed for at least 3 months, further accrual would be stopped. Results: 12 participants were enrolled, and all were evaluable. There were no objective responses (PR/CR), 4 SD (duration 10.9, 11.4, 11.9, and 17.9 wks), and 8 PD as best response. Of the SD, 2 had minor responses (−9% and −11.7% by RECIST 1.1). The median time to disease progression was 5.7 weeks. Further enrollment was therefore discontinued. No significant or unexpected toxicities were observed with olaparib, with only a single case each of grade 3 anemia and grade 3 thrombocytopenia observed. Conclusions: This study is the first report of a prospective phase II trial to evaluate the safety and efficacy of a PARP inhibitor in patients with advanced Ewing sarcoma after failure of standard chemotherapy. Olaparib administration was safe and well tolerated when administered to this small heavily pre-treated cohort at the 400 mg BID dose, although the median duration of dosing was for only 5.7 weeks. No significant responses or durable disease control was seen, and the short average interval to disease progression underscores the aggressiveness of this disease. Other studies to combine cytotoxic chemotherapy with PARP inhibition in EWS are actively ongoing. Trial registration ClinicalTrials.gov Identifier: NCT0158354

Dose-escalation study of a second-generation non-ansamycin HSP90 inhibitor, onalespib (AT13387), in combination with imatinib in patients with metastatic gastrointestinal stromal tumour

AbstractBackgroundGastrointestinal stromal tumours (GIST) treated with the tyrosine kinase inhibitor (TKI) imatinib can become resistant when additional mutations in the receptor tyrosine kinases KIT or PDGFRA block imatinib activity. Mutated KIT requires the molecular chaperone heat-shock protein 90 (HSP90) to maintain stability and activity. Onalespib (AT13387) is a potent non-ansamycin HSP90 inhibitor. We hypothesised that the combination of onalespib and imatinib may be safe and effective in managing TKI-resistant GIST.Patients and methodsIn this dose-escalation study, we evaluated the safety and efficacy of combination once-weekly intravenous onalespib for 3 weeks and daily oral imatinib in 28-d cycles. Twenty-six patients with TKI-resistant GIST were enrolled into four sequential dose cohorts of onalespib (dose range, 150–220 mg/m2) and imatinib 400 mg. The relationship between tumour mutational status (KIT/PDGFRA) and efficacy of treatment was explored.ResultsCommon onalespib-related adverse events were diarrhoea (58%), nausea (50%), injection site events (46%), vomiting (39%), fatigue (27%), and muscle spasms (23%). Overall, 81% of patients reported more than one onalespib-related gastrointestinal disorder. Nine patients (35%) had a best response of stable disease, including two patients who had KIT mutations known to be associated with resistance to imatinib and sunitinib. Disease control at 4 months was achieved in five patients (19%), and median progression-free survival was 112 d (95% confidence interval 43–165). One patient with PDGFRA-mutant GIST had a partial response for more than 376 d.ConclusionThe combination of onalespib plus imatinib was well tolerated but exhibited limited antitumour activity as dosed in this TKI-resistant GIST patient population.Trial registration ID: clinicaltrials.gov: NCT0129420

Vatalanib for metastatic gastrointestinal stromal tumour (GIST) resistant to imatinib: final results of a phase II study

BACKGROUND: Vatalanib (PTK787/ZK 222584) inhibits a few tyrosine kinases including KIT, platelet-derived growth factor receptors (PDGFRs) and vascular endothelial growth factor receptors (VEGFRs). We report efficacy and safety results of vatalanib in advanced gastrointestinal stromal tumour (GIST) resistant to imatinib or both imatinib and sunitinib. PATIENTS AND METHODS: Forty-five patients whose metastatic GIST had progressed on imatinib were enrolled. Nineteen (42.2%) patients had received also prior sunitinib. Vatalanib 1250 mg was administered orally daily. RESULTS: Eighteen patients (40.0%; 95% confidence interval (CI), 25.7-54.3%) had clinical benefit including 2 (4.4%) confirmed partial remissions (PR; duration, 9.6 and 39.4 months) and 16 (35.6%) stabilised diseases (SDs; median duration, 12.5 months; range, 6.0-35.6+ months). Twelve (46.2%) out of the 26 patients who had received prior imatinib only achieved either PR or SD compared with 6 (31.6%, all SDs) out of the 19 patients who had received prior imatinib and sunitinib (P = 0.324). The median time to progression was 5.8 months (95% CI, 2.9-9.5 months) in the subset without prior sunitinib and 3.2 (95% CI, 2.1-6.0) months among those with prior imatinib and sunitinib (P = 0.992). Vatalanib was generally well tolerated. CONCLUSION: Vatalanib is active despite its narrow kinome interaction spectrum in patients diagnosed with imatinib-resistant GIST or with imatinib and sunitinib-resistant GIST

E3 ubiquitin ligase Atrogin-1 mediates adaptive resistance to KIT-targeted inhibition in gastrointestinal stromal tumor

KIT/PDGFRA oncogenic tyrosine kinase signaling is the central oncogenic event in most gastrointestinal stromal tumors (GIST), which are human malignant mesenchymal neoplasms that often feature myogenic differentiation. Although targeted inhibition of KIT/PDGFRA provides substantial clinical benefit, GIST cells adapt to KIT/PDGFRA driver suppression and eventually develop resistance. The specific molecular events leading to adaptive resistance in GIST remain unclear. By using clinically representative in vitro and in vivo GIST models and GIST patients’ samples, we found that the E3 ubiquitin ligase Atrogin-1 (FBXO32)—the main effector of muscular atrophy in cachexia—resulted in the most critical gene derepressed in response to KIT inhibition, regardless the type of KIT primary or secondary mutation. Atrogin-1 in GISTs is transcriptionally controlled by the KIT-FOXO3a axis, thus indicating overlap with Atrogin-1 regulation mechanisms in nonneoplastic muscle cells. Further, Atrogin-1 overexpression was a GIST-cell-specific pro-survival mechanism that enabled the adaptation to KIT-targeted inhibition by apoptosis evasion through cell quiescence. Buttressed on these findings, we established in vitro and in vivo the preclinical proof-of-concept for co-targeting KIT and the ubiquitin pathway to maximize the therapeutic response to first-line imatinib treatment.This project was funded by the 2014 SARC International Career Development Award (SARC Sarcoma Spore 1U54CA168512–01), Fundación Mari Paz Jiménez Casado, FERO Foundation, Spanish Society of Medical Oncology (SEOM), PERIS SLT006/17/221, ISCIII PI16/01371 and PI19/01271, all to C.S. ISCIII FI20/00275 (to DG-P), and a Ph.D. fellowship from the National Secretary for Higher Education, Science, Technology and Innovation of Ecuador (SENESCYT) (to DFP-J). AE-C is funded by ISCIII PT17/0009/0019 and co-funded by FEDER