Pawel Teterycz

Immunotherapy of melanoma

The immunotherapy is currently changing the landscape of oncology. Nowadays the standard of care in metastatic or unresectable melanoma patients include immunomodulating modalities such as anti-PD-1 drugs (nivolumab, pembrolizumab) and anti-CTLA-4 antibody ipilimumab. The improvements of progression free survival and overall survival connected with those treatments were unprecedented and have been confirmed in stage III trials. The efficacy of immunotherapy in metastatic setting can be further upgraded in some groups of patients by combining both types of antibodies. Latest clinical data suggest that treatment with immunotherapy can be also favorable for patients in adjuvant setting. Other treatment approaches based on immunological response (e.g. oncolytic viruses or adoptive cell therapy) have been proven useful in specific clinical situations. The future of melanoma treatment is still evolving, new molecular targets are being invented and hopefully current endeavors will led to further improvement of patients’ survival. This review aims to summarize current state of immunotherapy in melanoma and identifying possible directions of development.

Blood neutrophil-to-lymphocyte ratio is associated with prognosis in advanced gastrointestinal stromal tumors treated with imatinib

Introduction: Neutrophil-to-lymphocyte ratio (NLR) was shown to be prognostic in several solid malignancies. There are limited data about predictive/prognostic value of NLR during targeted therapy of patients with advanced gastrointestinal stromal tumors (GIST). The aim of this study was to asses a clinical value of this ratio in patients with advanced GIST. Methods: Between 2001 and 2016, 385 patients with metastatic/unresectable GIST treated initially with imatinib were included in the analysis. In all patients, the NLR was assessed at the baseline, after 3 months of treatment, and upon disease progression (or last observation). The cutoff values for NLR were set at 2.7 and 5.4. Kaplan-Meier survival probability estimation with log-rank test and Cox proportional hazards model were used for analysis. Results: Median progression-free survival (PFS) on imatinib treatment was 44.8 months, 5-year rate 43%; median overall survival (OS) 87.2 months, 10-year rate 36.3%. NLR >2.7 at baseline was significantly associated with poorer OS and PFS: median OS was 89.3 months (95% confidence interval [CI] 80.2-115) for NLR ratio ≤2.7 vs 59.4 months (95% CI 48.6-82) for NLR >2.7 (p < .001); median PFS was 59.4 vs 32.7 (p < .001), respectively. In multivariate model adjusted for mitotic index and driver mutation in the tumor (KIT exon 11 mutation versus other), NLR ratio was proven to be statistically significant (hazard ratio 1.09; 95% CI 1.01-1.19; p = .030). Among patients with disease progression, NLR >2.7 assessed at the third month of treatment was linked with significantly shorter median time to progression (7.5 vs 19 months). Conclusions: Our results demonstrate the usefulness of NLR as a prognostic and predictive marker as well as a marker for treatment monitoring in patients with advanced GIST treated with imatinib.

Treatment outcomes in older patients with advanced gastrointestinal stromal tumor (GIST)

BACKGROUNDnThe aim of the study was to analyze the treatment results of advanced GIST in the largest, homogenous series of older patients.nnnMETHODSnBetween 2001 and 2016, 686 patients with metastatic/unresectable GIST were treated initially with imatinib and 656 were included in the analysis. Subsequently 232 patients were treated with sunitinib after imatinib failure. We have analyzed the outcomes of patients who have been treated with the tyrosine kinase inhibitor at the ageu202f≥u202f70u202fyears and compared to control group of patients younger than 70u202fyears old.nnnRESULTSnIn the group of patients treated with imatinib, 139 (21%) started therapy at the age of at least 70u202fyears (median age of the entire cohort: 60). Median progression-free survival (PFS) on 1st line imatinib did not differ between patients ≥70u202fyo (years old) andu202f<u202f70yo (38.5 vs 44.9u202fmonths), but median overall survival (OS) was significantly better for younger patients (81u202fmonths vs. 50; pu202f=u202f0.0001; although disease-specific survival - DSS was similar). Distribution of primary tumor mutational status was generally similar in older and younger patients. Permanent dose reduction (300-100u202fmg/day) was required for 23 patients (16.9%) in the older group and was significantly more frequent as compared to younger patients (5%). Drug-related adverse events were mainly of grades 1/2, but grade 3/4 toxicity occurred more frequently in older (14.7%) than in younger patients (3.8%). Similarly in group of patients treated with second-line sunitinib median PFS and DSS were comparable in groups of patients ≥70u202fyo (nu202f=u202f55) andu202f<u202f70yo (9.7u202fmonths vs 10.3u202fmonths; pu202f=u202f0.7, and 21.5 vs 22.9u202fmonths). >40% of patients in both groups required dose adjustments to 37.5-25u202fmg daily.nnnCONCLUSIONSnOur study confirms that current therapy of advanced GIST with tyrosine kinase inhibitors (both in 1st and 2nd line) in older patients enable to achieve the similar disease control rate and final outcomes as in younger patients, but it demands close cooperation of experienced oncologist with patients for dose modifications and side effects management. Limitation of our study is that the patients did not undergo a comprehensive geriatric assessment, what might be helpful for personalized management of patients. Nevertheless, we confirm that older patients with GIST should not receive less treatment irrespective of comorbidities.

IDH1/2 Mutations Predict Shorter Survival in Chondrosarcoma

Background. Recent studies have shown that isocitrate dehydrogenase 1/2 (IDH1/2)- activating mutations occur in a variety of cancers, including acute myeloid leukaemia, gliomas, and chondrosarcomas (CHS)s. The effect of IDH1/2 mutation on overall survival (OS) has not been reported in CHS. The aim of our study was to assess the prevalence of known cancer-related gene mutations in CHS, as well as their prognostic role in patient survival. Methods. DNA from FFPE samples of 80 patients (F:M- 1:1.3; mean age: 58 years; range 27-86) with histologically confirmed CHS (G1:29; G2:34; G3:17) was subjected to library preparation with the Ion AmpliSeq Cancer Hotspot Panel v2 and sequenced on the PGM Ion Torrent. Results. Among the clinical features only histological grade influenced OS. Deep sequencing identified 1784 single nucleotide variants. Of them, 426 were considered to be pathogenic or probably pathogenic. Activating IDH1/2 mutations were found in 27 patients (34%) including 17 R132 IDH1 (21%), 10 R172 IDH2 (13%) and 3 R140 IDH2 variants (4%). Three patients had concurrent IDH1 and IDH2 mutations. The R140 IDH2 mutant has not been reported to date in CHS patients. OS for CHS patients with IDH1/2 mutations was significantly lower than in patients without mutations (93% vs 64%; p<0.001). No other genetic feature of the Cancer Hotspot Panel had an impact on OS. Conclusions. In CHS, IDH1/2-mutation status and the histological aggressiveness of the CHS are important predictors for OS. The R140 IDH2 may also be a novel target for the treatment of CHS patients.

Anthracycline, Gemcitabine, and Pazopanib in Epithelioid Sarcoma: A Multi-institutional Case Series

Importance Epithelioid sarcoma (ES) is an exceedingly rare malignant neoplasm with distinctive pathologic, molecular, and clinical features as well as the potential to respond to new targeted drugs. Little is known on the activity of anthracycline-based regimens, gemcitabine-based regimens, and pazopanib in this disease. Objective To report on the activity of anthracycline-based regimens, gemcitabine-based regimens, and pazopanib in patients with advanced ES. Design, Setting, and Participants Seventeen sarcoma reference centers in Europe, the United States, and Japan contributed data to this retrospective analysis of patients with locally advanced/metastatic ES diagnosed between 1990 and 2016. Local pathological review was performed in all cases to confirm diagnosis according to most recent criteria. Exposures All patients included in the study received anthracycline-based regimens, gemcitabine-based regimens, or pazopanib. Main Outcome and Measures Response was assessed by RECIST. Progression-free survival (PFS) and overall survival (OS) were computed by Kaplan-Meier method. Classic and proximal subtypes were defined based on morphology (according to 2013 World Health Organization guidelines). Results Overall, 115 patients were included, 80 (70%) were men and 35 (30%) were women, with a median age of 32 years (range, 15-77 years). Of the 115 patients with ES, 85 were treated with anthracycline-based regimens, 41 with gemcitabine-based regimens, and 18 with pazopanib. Twenty-four received more than 1 treatment. Median follow-up was 34 months. Response rate for anthracycline-based regimens was 22%, with a median PFS of 6 months. One complete response (CR) was reported. A trend toward a higher response rate was noticed in morphological proximal type (26%) vs classic type (19%) and in proximal vs distal primary site (26% vs 18%). The response rate for gemcitabine-based regimens was 27%, with 2 CR and a median PFS of 4 months. In this group, a trend toward a higher response rate was reported in classic vs proximal morphological type (30% vs 22%) and in distal vs proximal primary site (40% vs 14%). In the pazopanib group, no objective responses were seen, and median PFS was 3 months. Conclusions and Relevance This is the largest retrospective series of systemic therapy in ES. We confirm a moderate activity of anthracycline-based and gemcitabine-based regimens in ES, with a similar response rate and PFS in both groups. The value of pazopanib was low. These data may serve as a benchmark for trials of novel agents in ES.

IDH mutations to predict shorter survival in chondrosarcoma.

11024Background: Recent studies have shown that isocitrate dehydrogenase 1/2 (IDH1/2) activating mutations occur in a variety of cancers, including acute myeloid leukemia, gliomas, and chondrosarco...