Retrospective analysis of treatment-naive Slovenian patients with metastatic melanoma treated with pembrolizumab - real-world experience.

Background Based on recent data from clinical trials, the immune checkpoint inhibitor pembrolizumab prolongs survival and has a good toxicity profile in patients with advanced or metastatic melanoma. However, the question remains whether these results are transmitted into daily clinical practice. The aim of this study was to assess the efficacy and toxicity of pembrolizumab in treatment-naive patients with metastatic melanoma in everyday clinical practice in Slovenia and compare it to the results from clinical trials. Patients and methods This observational retrospective cohort study included 138 consecutive metastatic treatment-naive melanoma patients treated with pembrolizumab at the Institute of Oncology Ljubljana in Slovenia, from January 2016 to December 2018. Patient and treatment characteristics were retrospectively collected from hospital data base. Statistical data was obtained using the SPSS software version 22. Survival rate was calculated with the Kaplan-Meier method. Observation period took place between January 2016 and the end of June 2019. Results The estimated median overall survival (OS) was 25.1 months (95% CI, 14.6-35.6) and the median progression-free survival (PFS) was 10.7 months (95% CI, 5.9-15.4). Among all patients, 29 (21.0%) achieved complete response, 31 (22.5%) partial response and 23 (16.7%) reached stable disease. The number of organs with metastatic involvement and the level of baseline lactate dehydrogenase (LDH) concentration had significant influence on survival rates. Immune-related adverse events (irAE) were reported in 88 (63%) patients, while grade 3-4 irAE occurred in 12 (8.7%). Due to toxicity, 16 (11.6%) patients discontinued the treatment. Conclusions Our real-world data from single centre retrospective analysis of treatment-naive metastatic melanoma patients treated with pembrolizumab showed inferior median OS and similar median PFS, compared to the results from clinical trials. However, patients with normal serum levels of LDH and a small number of organs with metastatic involvement had comparable survival outcomes. Toxicity rates of pembrolizumab were quite similar. These results further support the use of pembrolizumab for metastatic treatment-naive melanoma patients.

Molecular biomarkers and histological parameters impact on survival and response to first- line systemic therapy of metastatic colorectal cancer patients.

Background Histological parameters of primary tumour and nodal metastases are prognostic factors for survival of operable colorectal (CRC) patients, but not predictive for response rate of systemic therapy. KRAS mutations in codons 12 and 13 were first recognized as a predictive factor for resistance to anti-EGFR monoclonal antibodies. Not all patients with wild-type KRAS (wtKRAS) respond to anti-EGFR antibody treatment. Additional mechanisms of resistance may activate mutations of the other main EGFR effectors pathway, such as other mutations in RAS gene, mutations in P13K and PTEN expression. Patients and methods In the prospective study prognostic and predictive impact of histological parameters of primary tumour, KRAS and BRAF mutations on overall survival (OS) and objective response (OR) rate of metastatic CRC (mCRC) patients treated with 1st line systemic therapy were analysed. We additionally retrospectively analysed other mutations in RAS genes and their impact on survival and time to progression. Results From November 2010 to December 2012, we enrolled 154 patients in the study, 95 men and 59 women. Mutations in KRAS gene and V600E BRAF gene were found in 42% and in 3% of patients, respectively. Median OS of the patients with T1, T2 and T3 tumour was 65.4 months (95% CI, 55.7-75.6) while in patients with T4 tumour, lymphangiosis, vascular and perineural invasion it has not been reached yet. Median OS of the patients with G1, G2 and G3 of tumour differentiation was 65.6 (95% CI, 53.7-77.5) and 25.3 months (95% CI, 16.6-34.1), respectively. Median OS of the patients with stage N0, N1 and N2 was 65.6 (95% CI, 56.4-74.8) and 58.0 months (95% CI, 21.9-94.2), respectively. Median OS of wtKRAS and mutated KRAS patients was 56.5 (95% CI, 48.2-64.9) and 58 months (95% CI, 52.6-63.4), respectively. Median OS of mutated codon 12 and codon 13 patients was 57 (95% CI, 50.9-64.4) and 44 months (95% CI, 40.1-48.4), respectively. Median OS of wtBRAF and of mutated BRAF patients was 59.2 (95% CI, 52.5-65.9) and 27.6 months (95% CI, 12.6-42.5), respectively. wtKRAS significantly affected the response to the first systemic therapy (p = 0.028), while other parameters did not affected it, p= 0.07. In 14 patients (17%), additional mutations in NRAS gene, codon 61 and codon 146 were found. Median OS of wtNRAS, codon 61 and 146 patients was 67.1 months (50.3-67.6) while median OS of mutated NRAS patients has not been reached yet (p = 0.072). Median time to progression of wtNRAS, codon 61 and 146 patients was 11.7 months (10.4-14.5) while median time to progression of mutated NRAS patients was 7.9 months (6.1-11.0), (p = 0.025). Conclusions Mutated BRAF, N2 and G3 of primary tumour were poor prognostic factors for OS in mCRC patients. wtKRAS significantly affected the response to the first line systemic therapy. Histological parameters included in the analysis and mutated BRAF did not affect significantly the efficacy of 1st line systemic therapy in mCRC patients.

Prevalence of BRAF, NRAS and c-KIT mutations in Slovenian patients with advanced melanoma.

Background BRAF, NRAS and c-KIT mutations are characteristics of tumour tissues that influence on treatment decisions in metastatic melanoma patients. Mutation frequency and their correlation with histological characteristics in Slovenian population have not been investigated yet. Patients and methods In our retrospective analysis we analysed mutational status of BRAF, NRAS and c-KIT in 230 pathological samples of patients who were intended to be treated with systemic therapy due to metastatic disease at the Institute of Oncology Ljubljana between 2013 and 2016. We collected also histological characteristics of primary tumours and clinical data of patients and correlated them with mutational status of tumour samples. Results The study population consisted of 230 patients with a mean age 59 years (range 25-85). 141 (61.3%) were males and 89 (38.7%) females. BRAF mutations were identified in 129 (56.1%), NRAS in 31 (13.5%) and c-KIT in 3 (1.3%) tissue samples. Among the 129 patients with BRAF mutations, 114 (88.4%) patients had V600E mutation and 15 (11.6%) had V600K mutation. Patients with BRAF mutations tended to be younger at diagnosis (52 vs. 59 years, p < 0.05), patients with NRAS mutations older (61 vs. 55 years, p < 0.05). Number of c-KIT mutations were too low for any statistical correlation, but there was one out of 3 melanoma located in mucus membranes. Conclusions The analysis detected high rate of BRAF mutations, low NRAS mutations and low c-KIT mutations compared to previously published studies in Europe and North America. One of the main reasons for this observation is specific characteristics of study population.

Bevacizumab plus chemotherapy in elderly patients with previously untreated metastatic colorectal cancer: single center experience.

BACKGROUND: Metastatic colorectal cancer (mCRC) is mainly a disease of elderly, however, geriatric population is underrepresented in clinical trials. Patient registries represent a tool to assess and follow treatment outcomes in this patient population. The aim of the study was with the help of the patients' register to determine the safety and efficacy of bevacizumab plus chemotherapy in elderly patients who had previously untreated metastatic colorectal cancer. PATIENTS AND METHODS: The registry of patients with mCRC was designed to prospectively evaluate the safety and efficacy of bevacizumab-containing chemotherapy as well as selection of patients in routine clinical practice. Patient baseline clinical characteristics, pre-specified bevacizumab-related adverse events, and efficacy data were collected, evaluated and compared according to the age categories. RESULTS: Between January 2008 and December 2010, 210 patients with mCRC (median age 63, male 61.4%) started bevacizumab-containing therapy in the 1(st) line setting. Majority of the 210 patients received irinotecan-based chemotherapy (68%) as 1(st) line treatment and 105 patients (50%) received bevacizumab maintenance therapy. Elderly (≥ 70 years) patients presented 22.9% of all patients and they had worse performance status (PS 1/2, 62.4%) than patients in < 70 years group (PS 1/2, 35.8%). Difference in disease control rate was mainly due to inability to assess response in elderly group (64.6% in elderly and 77.8% in < 70 years group, p = 0.066). The median progression free survival was 10.2 (95% CI, 6.7-16.2) and 11.3 (95% CI, 10.2-12.6) months in elderly and < 70 years group, respectively (p = 0.58). The median overall survival was 18.5 (95% CI, 12.4-28.9) and 27.4 (95% CI, 22.7-31.9) months for elderly and < 70 years group, respectively (p = 0.03). Three-year survival rate was 26% and 37.6% in elderly vs. < 70 years group (p = 0.03). Overall rates of bevacizumab-related adverse events were similar in both groups: proteinuria 21/22 %, hypertension 25/19 %, haemorrhage 2/4 % and thromboembolic events 10/6 %, for elderly and < 70 years group, respectively. CONCLUSIONS: In routine clinical practice, the combination of bevacizumab and chemotherapy is effective and well-tolerated regimen in elderly patients with metastatic colorectal cancer.

Bevacizumab and irinotecan in recurrent malignant glioma, a single institution experience.

BACKGROUND: Treatment options of recurrent malignant gliomas are very limited and with a poor survival benefit. The results from phase II trials suggest that the combination of bevacizumab and irinotecan is beneficial. PATIENTS AND METHODS: The medical documentation of 19 adult patients with recurrent malignant gliomas was retrospectively reviewed. All patients received bevacizumab (10 mg/kg) and irinotecan (340 mg/m(2) or 125 mg/m(2)) every two weeks. Patient clinical characteristics, drug toxicities, response rate, progression free survival (PFS) and overall survival (OS) were evaluated. RESULTS: Between August 2008 and November 2011, 19 patients with recurrent malignant gliomas (median age 44.7, male 73.7%, WHO performance status 0-2) were treated with bevacizumab/irinotecan regimen. Thirteen patients had glioblastoma, 5 anaplastic astrocytoma and 1 anaplastic oligoastrocytoma. With exception of one patient, all patients had initially a standard therapy with primary resection followed by postoperative chemoradiotherapy. Radiological response was confirmed after 3 months in 9 patients (1 complete response, 8 partial responses), seven patients had stable disease and three patients have progressed. The median PFS was 6.8 months (95% confidence interval [CI]: 5.3-8.3) with six-month PFS rate 52.6%. The median OS was 7.7 months (95% CI: 6.6-8.7), while six-month and twelve-month survival rates were 68.4% and 31.6%, respectively. There were 16 cases of hematopoietic toxicity grade (G) 1-2. Non-hematopoietic toxicity was present in 14 cases, all G1-2, except for one patient with proteinuria G3. No grade 4 toxicities, no thromboembolic event and no intracranial hemorrhage were observed. CONCLUSIONS: In recurrent malignant gliomas combination of bevacizumab and irinotecan might be an active regimen with acceptable toxicity.

Randomized prospective phase II study to compare the combination chemotherapy regimen epirubicin, cisplatin, and 5-fluorouracil with epirubicin, cisplatin, and capecitabine in patients with advanced or metastatic gastric cancer.

OBJECTIVES: The aim of this study was to compare the efficacy and safety of the epirubicin, cisplatin, and continuous infusion of 5-fluorouracil (ECF) regimen with that of the epirubicin, cisplatin, and capecitabine (ECX) regimen in patients with advanced or metastatic gastric cancer. METHODS: Patients were randomized to receive either the ECF or ECX regimen. The primary end point was the response rate. The secondary end points were time to progression (TTP), overall survival (OS), and safety. RESULTS: Eighty-five patients were enrolled in the study from January 2003 to March 2007. Forty-five patients received the ECF regimen and 40 patients received the ECX regimen. The objective response rate was 31% [9% complete response (CR) and 22% partial response (PR)] for ECF and 30% (10% CR and 20% PR) for ECX. The disease control rate was 51% and 73%, respectively (P<0.05). Median OS and TTP were 6.8 and 5.5 months, respectively, in the ECF group and 8.3 and 6.0 months, respectively, in the ECX group. The majority of adverse events were grade 1/2. The most frequent grade 3/4 adverse events in both groups were fatigue (ECF 15%, ECX 21%), neutropenia (ECF 16%, ECX 16%), vomiting (ECF 11%, ECX 8%), nausea (ECF 9%, ECX 3%), and anemia (ECF 7%, ECX 5%). CONCLUSIONS: The ECX regimen was at least as effective as the ECF regimen with a similar tolerability profile, and could therefore replace the ECF regimen for the first-line treatment of patients with advanced gastric cancer.

Bevacizumab in first-line therapy of metastatic colorectal cancer: a retrospective comparison of FOLFIRI and XELIRI.

BACKGROUND: The antivascular endothelial growth factor monoclonal antibody bevacizumab with infusional 5-fluorouracil, leucovorin and irinotecan (FOLFIRI) is a standard first-line treatment option for metastatic colorectal cancer. However, clinical data for capecitabine and irinotecan (XELIRI) with bevacizumab are limited. PATIENTS AND METHODS: A retrospective study was conducted on 139 patients with metastatic colorectal cancer to assess the efficacy and safety of first-line bevacizumab in combination with XELIRI or FOLFIRI. Primary endpoints were overall response rate (ORR), disease control rate and radical resection rate. Secondary endpoints included overall survival (OS), progression-free survival (PFS) and safety. RESULTS: No significant differences in efficacy were observed between patients administered XELIRI or FOLFIRI with bevacizumab. The ORR, median OS and PFS and recorded adverse events (AEs) were comparable to those previously reported, with no new or unexpected AEs observed. CONCLUSION: Bevacizumab is similarly efficacious and well tolerated when administered with XELIRI or FOLFIRI.

Efficacy of first-line systemic treatment in correlation with BRAF V600E and different KRAS mutations in metastatic colorectal cancer - a single institution retrospective analysis.

BACKGROUND: KRAS mutation status in codons 12 and 13 is recognized as a predictive factor for resistance to anti-EGFR monoclonal antibodies. Despite having a wild type KRAS (wt-KRAS), not all patients with wt-KRAS respond to anti-EGFR antibody treatment. Additional mechanisms of resistance may activate mutations of the other main EGFR effectors pathway. Consequently, other molecular markers in colorectal cancer are needed to be evaluated to predict the response to therapy. PATIENTS AND METHODS: In this retrospective study, objective responses (OR), time to progression (TTP), overall survival (OS) were analyzed in 176 metastatic colorectal cancer (mCRC) patients treated with first-line chemotherapy in combination with monoclonal antibodies in respect of KRAS status in codons 12 and 13 and BRAF mutational status. RESULTS: The KRAS mutations were found in 63 patients (35.8 %), the KRAS mutation in codon 12 in 53 patients (30.1%) and the KRAS mutation in codon 13 in 10 patients (5.7%). The BRAF V600E mutation was detected in 13 of 176 patients (7.4%). In the subgroup of mCRC patients having wt-KRAS and wild type BRAF (wt-BRAF), the objective response rates were higher (OR 54.0% ,CR 14.7%, PR 39.3%) than in the patients with wt-KRAS and mt-BRAF (OR 38.5%,CR 15.4%, PR 23.1%), the difference was not statistically significant (p= 0.378). Median OS in patients with wt-KRAS wt-BRAF, and in patients with wt-KRAS mt-BRAF, was 107.4 months and 45 months, respectively. The difference was statistically significant (p= 0.042). TTP in patients with wt-KRAS wt-BRAF, and in patients with wt-KRAS mt-BRAF, was 16 months and 12 months, respectively. The difference was not statistically significant (p= 0.558). CONCLUSIONS: Patients with BRAF V600E mutation have statistically significantly worse prognosis than the patients with wt-BRAF and progress earlier during treatment. The definitive role of the BRAF V600E mutation as a prognostic and predictive factor for the response to anti-EGFR monoclonal antibodies needs to be analyzed in large prospective clinical studies.