Optimal Avapritinib Treatment Strategies for Patients with Metastatic or Unresectable Gastrointestinal Stromal Tumors.

BACKGROUND: Avapritinib, a novel inhibitor of KIT/PDGFRA, is approved in the U.S. for the treatment of adults with PDGFRA exon 18-mutant unresectable or metastatic gastrointestinal stromal tumors (U/M GISTs). We assessed the safety of avapritinib and provide evidence-based guidance on management of avapritinib-associated adverse events (AEs), including cognitive effects and intracranial bleeding. MATERIALS AND METHODS: We performed a post hoc analysis of data from a two-part, single-arm dose escalation/expansion phase I study (NAVIGATOR; NCT02508532) in patients with U/M GISTs treated with oral avapritinib 30-600 mg once daily. The primary endpoints were safety and tolerability; the impact of dose modification (interruption and/or reduction) on progression-free survival (PFS) was a secondary endpoint. Efficacy analyses were limited to patients who started avapritinib at 300 mg (approved dose). RESULTS: Of 250 patients enrolled in the study, 74.0% presented with KIT mutation and 24.8% presented with PDGFRA exon 18-mutation; 66.8% started avapritinib at 300 mg. The most common treatment-related AEs (any grade) were nausea (59.2%), fatigue (50.0%), periorbital edema (42.0%), anemia (39.2%), diarrhea (36.0%), vomiting (36.0%), and increased lacrimation (30.8%). No treatment-related deaths occurred. Among 167 patients starting on 300 mg avapritinib, all-cause cognitive effects rate (grade 1-2) was 37.0% in all patients and 52.0% in patients ≥65 years. Cognitive effects improved to a lower grade more quickly with dose modification (1.3-3.1 weeks) than without (4.9-7.6 weeks). Median PFS was 11.4 months with dose modification and 7.2 months without. CONCLUSION: Tolerability-guided dose modification of avapritinib is an effective strategy for managing AEs in patients with GISTs. IMPLICATIONS FOR PRACTICE: Early recognition of adverse events and tailored dose modification appear to be effective approaches for managing treatment-related adverse events and maintaining patients on avapritinib. Dose reduction does not appear to result in reduced efficacy. Patients' cognitive function should be assessed at baseline and monitored carefully throughout treatment with avapritinib for the onset of cognitive adverse events. Dose interruption is recommended at the first sign of any cognitive effect, including grade 1 events.

Immunotherapy with single agent nivolumab for advanced leiomyosarcoma of the uterus: Results of a phase 2 study.

BACKGROUND: Immunotherapy has changed the therapeutic landscape in oncology. Advanced uterine leiomyosarcoma (ULMS) remains an incurable disease in most cases, and despite new drug approvals, improvements in overall survival have been modest at best. The goal of this study was to evaluate programmed-death 1 (PD-1) inhibition with nivolumab in this patient population. METHODS: This single-center phase 2 trial completed enrollment between May and October 2015. Patients received 3 mg/kg of intravenous nivolumab on day 1 of each 2-week cycle until disease progression or unacceptable toxicity. The primary endpoint was objective response rate. We assessed PD-1, PD-ligand 1 (PD-L1), and PD-L2 expression in archival tumor samples and variations in immune-phenotyping of circulating immune cells during treatment. RESULTS: Twelve patients were enrolled in the first stage of the 2-stage design. A median of 5 (range, 2-6) 2-week cycles of nivolumab were administered. Of the 12 patients, none responded to treatment. The overall median progression-free survival was 1.8 months (95% confidence interval, 0.8-unknown). The study did not open the second stage due to lack of benefit as defined by the statistical plan. Archival samples were available for 83% of patients. PD-1 (>3% of cells), PD-L1, and PD-L2 (>5% and >10% of tumor cells, respectively) expression were observed in 20%, 20%, and 90% of samples, respectively. No significant differences were observed between pre- and posttreatment cell phenotypes. CONCLUSION: Single-agent nivolumab did not demonstrate a benefit in this cohort of previously treated advanced ULMS patients. Further biomarker-driven approaches and studies evaluating combined immune checkpoint-modulators should be considered. Cancer 2017;123:3285-90. © 2017 American Cancer Society.

Management of Patients With Advanced Gastrointestinal Stromal Tumor: Emphasis on Fourth-Line Treatment With Ripretinib.

Gastrointestinal stromal tumors (GISTs) are considered rare, yet they represent the most common sarcomas of the gastrointestinal tract. The development of tyrosine kinase inhibitors (TKI) for the treatment of GISTs changed the way we treat patients and has greatly impacted outcomes. However, most patients who initially benefit from TKIs eventually develop disease progression and require subsequent therapies. Ripretinib is a switch-control TKI approved for the treatment of adult patients with advanced GIST who received prior treatment with three or more TKIs, including imatinib. Our objective was to review existing treatment options for patients with advanced GIST, focusing on management optimization for heavily pretreated patients receiving ripretinib. With the integration of ripretinib as a fourth-line therapy, the GIST treatment landscape continues to evolve. As the treatment paradigm becomes increasingly complex, successful management of adverse events and individualized supportive care remain crucial to maintaining effective treatment and patient quality of life. Additionally, we present a detailed case study of a heavily pretreated patient with advanced GIST who received ripretinib as fourth-line therapy. The information provided here should help inform advanced practitioners on the effective management of patients with GIST who have progressed on multiple therapies. Advanced practitioners are well positioned to provide the necessary supportive care to achieve optimal outcomes and drug compliance.

Supporting patients in the transition to the revised pexidartinib dosing regimen: perspectives from the multidisciplinary clinical and allied health professional team.

Pexidartinib is a colony-stimulating factor-1 receptor inhibitor approved in the United States for treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and not amenable to improvement with surgery. Because of the risk of severe and potentially fatal hepatotoxicity, pexidartinib is only available through a Risk Evaluation and Mitigation Strategy (REMS) program. Pexidartinib pharmacokinetics are influenced by the fat content of meals: compared with the fasted state, consuming a high-fat meal with pexidartinib increases pexidartinib absorption by 100%; a low-fat meal increases absorption by approximately 60%. Pexidartinib was initially authorized to be taken at 800 mg/day on an empty stomach; therefore, if this same dose of pexidartinib is taken with food, there is a risk of overexposure and potential toxicity. To reduce the risk of hepatotoxicity and improve patient compliance, pexidartinib has undergone a revised dosing regimen, from 800 mg/day (400 mg twice daily) fasted to 500 mg/day (250 mg twice daily) with a low-fat meal (approximately 11-14 g of total fat). The objective of this report is to educate clinical and allied health professionals on the revised dosing regimen and the importance of patient compliance with a low-fat meal. Healthcare professionals need to understand the rationale for the switch from pexidartinib dosing on an empty stomach to dosing with a low-fat meal and how meal composition and timing influence pharmacokinetics. Finally, we provide guidance for the healthcare team of prescribing providers, nurses, pharmacists, and dietitians who are caring for patients with TGCT on pexidartinib. It is important for healthcare providers to deliver consistent messaging on the low-fat meal requirement and help patients fit pexidartinib into their regular meal schedules. Consulting a dietitian may be helpful for patients, especially those with complex dietary needs. We provide an overview of the roles and responsibilities of each healthcare professional and outline steps to best support patients, including key questions and answers related to the revised dosing regimen. This report provides the information necessary to guide the multidisciplinary team caring for patients with TGCT and to support them through the pexidartinib dosing regimen change.

Managing stomatitis in patients treated with Mammalian target of rapamycin inhibitors.

Mammalian target of rapamycin (mTOR) inhibitors are a class of targeted cancer therapeutic agents with clinical benefit for multiple tumor types. Oral ulcerations are a common side effect of mTOR inhibitors; however, the clinical findings resemble aphthous stomatitis rather than the mucositis seen with chemotherapy. Consequently, the appearance of aphthous-like oral ulcerations has been referred to as mTOR inhibitor-associated stomatitis (mIAS). The severity of mIAS can be minimized by following common preventive steps and initiating treatment at the first sign of mouth discomfort, thereby reducing the likelihood of treatment discontinuation. mIAS can be managed through prophylactic measures, such as patient education in oral hygiene and avoidance of triggers. Patients who develop mIAS may be treated topically using rinses or other local therapies, including corticosteroids. In severe cases, dose modifications may be required. Oncology nurses have an important role in the management of patients with cancer and are well positioned to offer strategies for minimizing the occurrence and impact of mIAS.

Gemcitabine and vinorelbine combination chemotherapy for patients with advanced soft tissue sarcomas: results of a phase II trial.

BACKGROUND: Single-agent gemcitabine and vinorelbine have activity in treatment of patients with soft-tissue sarcomas. The combination of gemcitabine plus vinorelbine has activity against several forms of metastatic carcinoma with acceptable toxicity. This study evaluated the efficacy and tolerability of gemcitabine plus vinorelbine in advanced soft-tissue sarcoma. METHODS: A single academic center performed this phase II trial. Eligible patients had unresectable or metastatic soft-tissue sarcomas, Eastern Cooperative Group performance status of 0-2, adequate organ function, and 4 months. There has been 1 CR lasting >1 year in a patient with high-grade pleomorphic spindle-cell sarcoma. CONCLUSIONS: Gemcitabine given by a fixed-dose rate of infusion combined with vinorelbine was associated with clinically meaningful rates of disease control in patients with advanced soft-tissue sarcoma. Toxicity was acceptable. This study contributed to data that have supported the administration of fixed-dose rate gemcitabine-based drug regimens in soft-tissue sarcomas.