Exceptional responses with sequential metronomic temozolomide after pembrolizumab failure in patients with metastatic melanoma.

Pembrolizumab is an effective therapy for patients with metastatic melanoma. However, not all patients derive benefit. It is postulated that an increase in regulatory T cells in melanoma patients can impair the response to immunotherapies. Continuous low-dose temozolomide has shown to cause immunomodulatory effects resulting in CD4 + lymphopenia due to which Treg population can also decrease significantly. Herein, we present a case series of three patients with metastatic melanoma who after progression on pembrolizumab showed a radiological response after just one cycle of metronomic temozolomide (75 mg/m daily for 6 weeks on 8-week cycle). This suggests that temozolomide may be a useful alternative for patients with metastatic melanoma after disease progression on pembrolizumab. Further studies with biomarkers are warranted to elucidate which patients will derive benefit from this strategy.

Targeting epigenetics for treatment of BRAF mutated metastatic melanoma with decitabine in combination with vemurafenib: A phase lb study.

INTRODUCTION: Epigenetic modifications play an important role in progression and development of resistance in V600EBRAF positive metastatic melanoma. Therefore, we hypothesized that the action of vemurafenib (BRAF inhibitor) can be made more effective by combining with low dose decitabine (a DNA methyltransferase inhibitor). The primary objective of this phase lb study was to determine the dose limiting toxicity and maximum tolerated dose of combination of subcutaneous decitabine with oral vemurafenib in patients with V600EBRAF positive metastatic melanoma with or without any prior treatment. EXPERIMENTAL DESIGN: The study employed 3+3 dose escalation combining subcutaneous decitabine at different doses and schedules (4 cohorts) with the standard oral dose of vemurafenib 960 mg twice daily. Preclinical assessment and further analysis were also performed in A375 melanoma cell line. RESULTS: Fourteen patients received study treatment. No dose limiting toxicity was encountered and maximum tolerated dose was not reached. Important toxicities included fatigue, increased creatinine, neutropenia, leucopenia, hypophosphatemia, rash and hyperuricemia. Three patients achieved complete response, three had partial response and five had stable disease. Preclinical assessment demonstrated action of the combination which delayed the development of acquired resistance and improved duration of treatment sensitivity. CONCLUSIONS: The combination of oral vemurafenib with subcutaneous decitabine is safe and showed activity in V600EBRAF positive metastatic melanoma. Since most responses were seen in cohort 1, which utilized low-dose, long-term decitabine, future studies of this combination treatment should utilize longer duration of decitabine, at the lowest dose of 0.1 mg/kg.

The effect of weight-based chemotherapy dosing in a cohort of gynecologic oncology patients.

OBJECTIVE: Many clinicians limit chemotherapy doses based on a maximum body surface area (BSA) of 2m(2). We sought to determine how chemotherapy-related toxicities compared between groups of patients that varied with respect to BSA. We hypothesized that obese patients receiving weight-based (WB) dosing would not have significantly higher chemotherapy-related toxicities than control groups. METHODS: We performed a retrospective review of patients with BSA≥2m(2) who received WB chemotherapy for a gynecologic cancer between January and August 2013. Subjects were matched with two controls: patients with BSA<2m(2) who received WB dosing, and patients with BSA≥2m(2) who received capped dosing at BSA=2m(2). Groups were matched for medical co-morbidities and prior cancer treatment. Demographic and clinical information was extracted and analyzed via ANOVA and Fisher's exact test. RESULTS: A total of 75 patients were included. The three groups were similar in their medical co-morbidities and prior cancer treatment. When comparing pre- and post-treatment laboratory values, there was no difference in hematologic toxicities. There was no difference between groups with regard to treatment delays, unplanned admissions, transfusions, or dose reductions for toxicity. CONCLUSIONS: Gynecologic cancer patients with BSA≥2m(2) treated with WB chemotherapy had no increase in hematologic or non-hematologic toxicities when compared to controls. Consideration should be given to using WB dosing in obese patients with gynecologic malignancies. Further investigation is required to determine the effect of WB dosing on progression-free and overall survival in obese gynecologic cancer patients.