Hanna Koseła-Paterczyk

Trametinib: a MEK inhibitor for management of metastatic melanoma

This review presents the current data on the efficacy and safety of the selective mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor trametinib in patients with metastatic BRAF V600-positive melanoma. The pharmacological, safety, and efficacy data come from the Phase I, II, and III studies of trametinib monotherapy, as well as those in combination with the BRAF inhibitor dabrafenib. The most common adverse effects of trametinib therapy are rash, dermatitis, diarrhea, and fatigue. The Phase III METRIC study showed significant improvement in overall survival and progression-free survival in favor of trametinib over standard dacarbazine or paclitaxel chemotherapy. Therefore, trametinib was approved by the US Food and Drug Administration and European Medicines Agency as a single agent for the treatment of patients with V600E-mutated metastatic melanoma. Progression-free survival and response rates for trametinib monotherapy were lower than those noted with BRAF inhibitors. The second step in developing trametinib was to use the combination of trametinib with the BRAF inhibitor, eg, dabrafenib, to postpone the progression on MEK or BRAF inhibitors. The recently published data showed significant improvement in overall survival and progression-free survival in favor of the combination of trametinib and dabrafenib over vemurafenib therapy or dabrafenib alone, with good tolerance. The US Food and Drug Administration has approved the combination of dabrafenib (150 mg orally twice daily) and trametinib (2 mg orally once daily) for the treatment of patients with BRAF V600E/K-mutant metastatic melanoma, and their use seems to be currently the best approach. While BRAF-MEK inhibition is a standard, molecular targeted therapy in BRAF-mutated melanomas, its future utility has to be established in the rapidly changing landscape of immunotherapeutics.

Preoperative hypofractionated radiotherapy in the treatment of localized soft tissue sarcomas

BACKGROUND The primary treatment of soft tissue sarcomas (STS) is a radical resection of the tumor with adjuvant radiotherapy. Conventional fractionation of preoperative radiotherapy is 50 Gy in fraction of 2 Gy a day. The purpose of the conducted study was to assess the efficacy and safety of hypofractionated radiotherapy in preoperative setting in STS patients. METHODS 272 patients participated in this prospective study conducted from 2006 till 2011. Tumors were localized on the extremities or trunk wall. Median tumor size was 8.5 cm, 42% of the patients had tumor larger than 10 cm, whereas 170 patients (64.6%) had high grade (G3) tumors. 167 patients (61.4%) had primary tumors. Patients were treated with preoperative radiotherapy for five consecutive days in 5 Gy per fraction, with an immediate surgery. Median follow up is 35 months. RESULTS 79 patients died at the time of the analysis, the 3-year overall survival was 72%. Local recurrences were observed in 19.1 % of the patients. Factors that had a significant adverse impact on local recurrence were tumor size of 10 cm or more and G3 grade. 114 patients (42%) had any kind of treatment toxicity, vast majority with tumors located on lower limbs. 7% (21) of the patients required surgery for treatment of the complications. CONCLUSION In this non-selected group of locally advanced STS use of hypofractionated preoperative radiotherapy was associated with similar local control (81%) when compared to previously published studies. The early toxicity is tolerable, with small rate of late complications. Presented results warrant further evaluation.

Long-term results of therapy with sunitinib in metastatic alveolar soft part sarcoma.

Background Alveolar soft part sarcoma (ASPS) is a rare, highly vascularized soft tissue sarcoma characterized by a high frequency of metastatic disease and resistance to classical chemotherapy. The purpose of our analysis was to assess long-term sunitinib activity in the treatment of metastatic ASPS. Patients and Methods Between 2009 and 2015, 15 patients were diagnosed with metastatic ASPS and received therapy with sunitinib at initial continuous daily dosing of 37.5 mg. Median age was 32 years. The primary tumor sites were lower extremities (8), trunk-retroperitoneum/pelvis (2), upper extremity (3) and other (2). All patients had unresectable disease (primary or relapse in the form of metastases to the lungs ± bones). Five patients received systemic therapy before initiating sunitinib. Median follow-up from start of sunitinib was 38 months (range 5-69 months). Results At the time of analysis 4 patients continue therapy and 9 are still alive. Six patients had RECIST partial remission as best response, 8 had stable disease, and 1 had disease progression. The median progression-free survival was 19 months, with 86% of patients being free of progression at 6 months. Median overall survival was 56 months; the 5-year overall survival rate was 49%. Five patients were treated with sunitinib longer than 2 years. All patients experienced some side effects: 8 patients (53%) had CTCAE grade 3/4 toxicity, 7 patients required dose reduction. The most common toxicities were neutropenia, thrombocytopenia, hypothyroidism, arterial hypertension, and hand-foot syndrome. Conclusions Our analysis confirms the long-term efficacy of sunitinib in patients with advanced ASPS.

Dermatofibrosarcoma protuberans and gastrointestinal stromal tumor as models for targeted therapy in soft tissue sarcomas

ABSTRACT Introduction: The development of novel targeted treatment in soft tissue sarcomas (STS) is important since many sarcoma subtypes are resistant to chemotherapy and effective therapeutic options are limited. Areas covered: This review discusses the molecular background and treatment in two STS types which became a model for targeted therapy – gastrointestinal stromal tumor (GIST) and dermatofibrosarcoma protuberans (DFSP). DFSP is characterized, by chromosomal translocation which results in the formation of COL1A1-PDGFB fusion gene causing platelet-derived growth factor receptor beta(PDGFRB) signaling activation in tumor cells. The majority of GIST malignancies are associated with activating, constitutive, mutually exclusive mutations of two genes: KIT and PDGFRA (PDGF receptor-alpha). Molecular diagnostics are an essential part of GIST and DFSP management. The first effective systemic therapy in clinical practice in GIST and DFSP was imatinib – tyrosine kinase inhibitor acting on KIT and PDGFR alpha/beta. Use of the drug revolutionized treatment of inoperable and/or metastatic cases and demonstrated activity in locally advanced cases. This review summarizes the analogies of therapy and perspectives of GIST and DFSP management. Expert commentary: The next generation of kinase inhibitors are approved for use after the progression of GIST during imatinib treatment. However, little is known about treatment beyond progression in DFSP.

The use of vismodegib in the treatment of basal cell carcinoma based on case reports

Basal cell carcinoma (BCC) is the most common skin cancer, usually located on the skin of the face and neck. Locally advanced cancer is diagnosed by about 5–10% of patients, while the metastatic disease is diagnosed in 0.0028 to 0.55% of cases. The primary treatment of locally advanced disease is radical surgery, and in non-operative cases — radiotherapy. For patients not eligible for local therapy and those with metastatic disease, systemic therapies, including hedgehog inhibitor — vismodegib — is used. In the Department of Melanoma and Soft Tissue and Bone Sarcomas, Maria Sklodowska-Curie Institute — Oncology Center several patients with BCC, not eligible for local therapy, are currently systemically treated. Vismodegib is registered for the use in adults with symptomatic metastatic basal cell carcinoma or locally advanced basal cell carcinoma that does not meet the criteria for surgical treatment or radiotherapy. In this paper, we present and discuss a case of BCC cancer in a metastatic setting and a case of a patient being treated for locally advanced disease not eligible for surgery and radiotherapy. The cases presented here confirm that vismodegib treatment, currently available in the national drug access program, provides an objective response, improvement in quality of life, and probably extension of survival.

The analysis of the long-term outcomes of sorafenib therapy in routine practice in imatinib and sunitinib resistant gastrointestinal stromal tumors (GIST)*

Aim of the study was to analyze the outcome of treatment and factors predicting results of sorafenib therapy in inoperable/metastatic CD117-positive GIST patients after failure on imatinib and sunitinib. Material and methods We identified 60 consecutive patients (40 men, 20 women) with advanced inoperable/metastatic GIST after failure on at least imatinib and sunitinib treated in one sarcoma center with sorafenib at initial dose 2 × 400 mg daily in 2007–2015 (in 56 cases it was 3rd line therapy). Median follow-up time was 39 months. Results One year progression-free survival (PFS; calculated from the date of the start of sorafenib to disease progression) rate was 23% and median PFS = 7.7 months. The median overall survival (OS) was 13.5 months calculated from sorafenib start (1-year OS rate = 57%) and 7 years from imatinib start. Three patients (5%) had objective partial responses to therapy, 31 patients (52%) had stabilization of disease > 4 months. Primary tumor mutational status was known in 43 cases (73%), but we have not identified the differences in PFS between tumors carrying different KIT/PDGFRA mutations. The most common adverse events were: diarrhoea, hand and foot syndrome, fatigue, loss of weight and skin reactions; grade 3–5 toxicity occurred in 35% of patients. 23 patients required sorafenib dose reductions due to AEs. Conclusions We confirmed that many advanced GIST patients benefit from sorafenib therapy after imatinib/sunitinib failure with OS > 1 year.

The activity of pembrolizumab in therapy of pretreated metastatic melanomas — two centres’ experience

Introduction. Pembrolizumab [programmed death 1 (PD-1) checkpoint inhibitor] mediates durable responses and prolongs survival in patients with advanced melanomas. We assessed the efficacy and safety of pembrolizumab in pretreated metastatic melanoma patients outside clinical trials. Methods. Fifty-four patients (median age 57 years; range 18–77) after progression on previous therapy (at least ipilimumab) in metastatic setting were administered pembrolizumab at a registered dose 2 mg/kg every three weeks and were observed for progression-free survival (PFS), overall survival (OS), responses, and toxicity. Median follow-up time for survivors was 8.5 months. Results. In all except six cases pembrolizumab was given in at least third line of systemic therapy. All patients (except two patients with ocular melanomas) had cutaneous origin of the primary; 16 were BRAF -positive (30%), 42 patients were in M1c stage (78%); and 27 patients had increased initial LDH level (50%). The clinical benefit of pembrolizumab therapy was 50% with one complete remission, seven partial remissions, and 19 stable diseases. Thirty-six patients received more than four doses of the drug; 13 patients still remain on treatment. Median OS was not reached. The estimated one-year OS was 48%. We observed no differences in OS between BRAF -positive and BRAF -negative cases. Poorer OS was found in patients with initially increased LDH level (p = 0.04), and slightly worse results were seen for patients treated with more than three lines of therapy and in M1c stage. Median PFS was 5.6 months, estimated one-year PFS rate was 40%, and better PFS was observed for patients with initially normal LDH (7.5 vs . 4.5 months; p = 0.02). The treatment was well tolerated with adverse events (AE) occurring in 14 patients (26%), but in only three cases grade 3 AEs were observed (6%): diarrhoea, diabetes mellitus, pneumonitis. Conclusions. Pembrolizumab confirmed its activity and safety outside clinical trials in therapy of pretreated metastatic melanomas. Anti-PD-1 inhibitors are the preferred treatment option in advanced melanoma management.

The efficacy and safety of trabectedin in patients with advanced liposarcomas and leiomyosarcomas (L-sarcomas)

Wstep . Trabektedyna jest lekiem zarejestrowanym do leczenia chorych z rozpoznaniem zaawansowanych miesakow tkanek miekkich. Badania wykazaly jej skutecznośc w leczeniu paliatywnym, zwlaszcza w tluszczakomiesakach (LPS — liposarcoma ) i mieśniakomiesaku gladkokomorkowym (LMS — leiomyosarcoma ). Celem badania byla analiza wynikow leczenia trabektedyną pacjentow leczonych w jednym ośrodku. Materialy i metody . Od kwietnia 2008 roku do października 2013 roku leczono trabektedyną 50 pacjentow (23 kobiety, 27 mezczyzn) z rozpoznaniem miejscowo zaawansowanych przerzutowych miesakow tkanek miekkich (20 — LMS, 30 — LPS, w tym 13 myxoid LPS — MLPS). Mediana wieku w momencie leczenia wyniosla 51 lat. Prawie wszyscy chorzy (49/50) otrzymali wcześniejsze leczenie systemowe oparte na doksorubicynie. 14 (28%) pacjentow otrzymywalo trabektedyne w 2. linii leczenia, 23 (46%) w 3. linii, 13 (26%) w > 3. linii. Odpowiedź na leczenie wedlug kryteriow RECIST oceniano co 3 miesiące za pomocą badania tomografii komputerowej (CT). Wyniki . Mediana liczby podanych cykli leczenia wynosila 5 (zakres 2–40); 18 chorych (36%) otrzymalo ≥ 10 cykli. U 4 pacjentow (8%) stwierdzono cześciową odpowiedź, u 23 (46%) stabilizacje choroby (przez minimum 3 miesiące), u 23 (46%) — progresje choroby. Po pol roku leczenia 47% pacjentow bylo wolnych od progresji choroby (PFS — progression-free survival ), wiecej w grupie chorych z rozpoznaniem LPS — 66% w porownaniu z 27% w grupie LMS (p = 0,023). PFS byl istotnie dluzszy u pacjentow otrzymujących trabektedyne w 2. lub 3. linii leczenia (mediana 7 miesiecy) niz > 3. linii leczenia (mediana 2 miesiące) p = 0,038. Mediana przezycia calkowitego (OS — overall survival ) wynosila 13 miesiecy. Stezenie hemoglobiny oraz aktywnośc LDH przy rozpoczeciu leczenia nie mialo wplywu na wyniki terapii. 34 pacjentow otrzymalo kolejne linie leczenia po niepowodzeniu leczenia trabektedyną. W momencie analizy 37 chorych zmarlo. Podtyp histologiczny mial wplyw na OS (p = 0,008), prawie 70% pacjentow z rozpoznaniem MLPS zylo dluzej niz rok. Toksycznośc terapii byla umiarkowana. Nie obserwowano zgonow spowodowanych leczeniem. 30 (60%) pacjentow doznalo jakiejkolwiek toksyczności leczenia, w wiekszości w stopniu 1. i 2. Trzech pacjentow wymagalo redukcji dawki leku. Wnioski . Przeprowadzona analiza potwierdza skutecznośc stosowania trabektedyny w paliatywnym leczeniu u chorych na L-miesaki. Zastosowanie leku pozwala na uzyskanie dlugotrwalej kontroli choroby przy dobrej tolerancji leczenia. Najdluzszy czas calkowitego przezycia stwierdzono w grupie chorych z rozpoznaniem MLPS.

Results for advanced melanoma therapy with vemurafenib in a Polish drug programme

Introduction. Melanoma is a heterogeneous group of tumours with poor prognosis if the disease is metastatic. More than half of patients with melanoma of the skin have detectable mutations in the BRAF gene. Vemurafenib is the BRAF kinase inhibitor used in the treatment of patients with advanced melanoma with the BRAF mutation. This improves time to progression-free survival and overall survival in patients with this diagnosis. The aim of the study was to analyse the results of treatment and safety of vemurafenib in patients treated during the Polish drug programme. Materials and methods .Between October 2013 and April 2015 a total of 189 patients were treated, 90 women and 99 men, who had previously been diagnosed with unresectable/metastatic melanoma with BRAF V600 mutation. Patients received vemurafenib in 960 mg dose twice per day. The estimated progression-free survival, overall survival and adverse events were assessed. For the survival analysis the Kaplan-Meier method and log-rank test (log-rank) for multi-factor analysis were used. Results. In the first evaluation of the effectiveness of treatment, 8 patients (4.3%) had a complete response, 75 patients (39.7%) partial response, 62 patients (32.8%) had stable disease, and 44 patients (23.2%) had progression of the disease. The disease was controlled in 76.7% of patients. After progression during the therapy with vemurafenib 27% of the patients received subsequent lines of systemic therapy. Twenty-eight patients received chemotherapy and 22 patients immunotherapy with ipilimumab. During the last analysis dated 5 September 2015, the median observation time for still living patients was 8 months (range 3–26). Median progression-free survival was 6.7 months. The median overall survival was 12 months. 146 patients (77%) had adverse events, mostly in the form of dermal toxicity of Grades 1 and 2. Thirty-two patients (17%) presented with side effects of the 3rd and 4th grades of toxicity. Two patients had to stop the treatment due to the toxicity. There were no deaths reported due to the toxicity of treatment. Conclusions. The multicentre analysis confirmed the efficacy and safety of vemurafenib in routine clinical practice in a heterogeneous group of advanced melanomas with BRAF mutation. We confirmed the importance of the known prognostic factors for overall survival in this group of patients, such as lactate dehydogenaze activity (LDH) and ECOG performance status. The current survival of patients with the metastatic melanomas with BRAF mutations are longer than those observed in historical groups.

The outcomes of Polish patients with advanced BRAF-positive melanoma treated with vemurafenib in a safety clinical trial.

Aim of the study The BRAF inhibitor vemurafenib has improved progression-free survival and overall survival in patients with BRAFV600-mutation-positive metastatic melanoma. Here we present the results of an open-label safety study with vemurafenib in patients with metastatic melanoma enrolled in Polish oncological centres. Material and methods Patients with untreated or previously treated Stage IIIC/IV BRAFV600 mutation-positive melanoma were treated with oral vemurafenib in an initial dose of 960 mg twice daily. Assessments for safety and efficacy were made every 28 days. For the survival analysis the Kaplan-Meier estimator was used with the log-rank tests for bivariate comparisons. Results In total, 75 Polish patients were enrolled in the safety study across four centres. At data cut-off, 28 patients died (37%), mainly (26) due to disease progression; 33 (44%) patients continued vemurafenib after disease progression. The objective response rate was 46%, including two patients with a complete response and 29 with a partial response. Median progression-free survival was 7.4 months. The one-year overall survival rate was 61.9% (median overall survival was not reached). Seventy-three (97.3%) patients reported adverse events (AEs), and grade 3–5 toxicity was reported in 49.4% (37) patients. The most common AEs were: skin lesions (including rash and photosensitivity), arthralgia, and fatigue. Conclusions The overall safety profile and response rate of vemurafenib were comparable to those reported in previous studies of this drug. Our study confirmed the value of well-established prognostic features for overall survival, such as initial LDH (lactate dehydrogenase) level and AJCC staging.