Biomarkers of treatment benefit with atezolizumab plus vemurafenib plus cobimetinib in BRAFV600 mutation-positive melanoma.

BACKGROUND: The phase III IMspire150 study (NCT02908672) demonstrated significantly improved progression-free survival (PFS) with atezolizumab, vemurafenib, and cobimetinib (atezolizumab group) versus placebo, vemurafenib, and cobimetinib (control group) in patients with BRAFV600-mutated advanced melanoma. We report exploratory biomarker analyses to optimize targeting of patients who are more likely to benefit from triplet combination therapy. PATIENTS AND METHODS: Five hundred fourteen patients were randomized to atezolizumab (n = 256) or control (n = 258). Outcomes were evaluated in subgroups defined by key biomarkers, including programmed death-ligand 1 (PD-L1) expression, lactate dehydrogenase (LDH) level, tumor mutational burden (TMB), and interferon-γ (IFN-γ) gene signature. Exploratory recursive partitioning analysis was then used to model associations between PFS and baseline covariates, including key biomarkers. RESULTS: PFS benefit for atezolizumab versus control was greater in patients with high TMB [≥10 mutations/Mb; hazard ratio (HR) 0.73; 95% confidence interval (CI) 0.52-1.02; P = 0.067] versus low TMB (<10 mutations/Mb; HR 0.92; 95% CI 0.65-1.30; P = 0.64) and similar between patients with strong IFN-γ (≥median; HR 0.76; 95% CI 0.54-1.06) versus weak IFN-γ (

[Oral vinorelbine therapy for non-small cell lung cancer: clinical and pharmacoeconomic aspects].

AIM: To evaluate clinical and pharmacoeconomic aspects of treatment for non-small cell lung cancer (NSCLC) by oral vinorelbine. MATERIAL AND METHODS: The evaluation was conducted based on randomized trials that compared NSCLC therapy by oral vinorebline with injectable form of vinorelbine and peme- trexed. Treatment costs were calculated on the basis of prices registered in 2016 including VAT and 10% of trade allow- ances. Medical services costs were calculated based on tariffs of obligatory health insurance for St. Petersburg in 2016. RESULTS: Clinical trials showed that with comparable effi- cacy and tolerability 3 of 4 patients preferred oral vinorelbine to its injectable form, although therapy costs of oral form in- creased 1,9 times. Compared with pemetrexed, therapy of pa- tients with NSCLC by oral vinorelbine allowed reducing costs 1,74 times and the savings occurred 310.0 thousand rubles per 1 patient. CONCLUSION: Currently oral vinorelbine therapy can be regarded as a mode that is comparable by efficacy and tol- erability both with intravenous injections of vinorelbine and pemetrexed therapy. As compared with intravenous vinorelbine its oral form requires additional costs but, being compared with pemetrexed, oral vinorelbine can significantly reduce the burden on the health budget.

[The first results of assessment of clinical efficacy of melatonin and metformin in patients with disseminated skin melanoma receiving dacarbazine as first-line systemic therapy].

The aim of the study was to assess efficacy and safety of combined therapy with dacarbazine and melatonin or metformin in comparison with dacarbazine alone in the 1st line of therapy of cutaneous melanoma. Thirty-six patients with disseminated melanoma, therapy naïve, were included between March 2014 and December 2015. Patients received DTIC 1000 mg/m2 in day 1 of 28-day cycle either as monotherapy (group 1) or in combination with melatonin 3 mg PO daily (group 2) or metformin 850 mg 2 times a day PO daily (group 3). Thirty-four patients were randomized (15-in group 1, 8 - in group 2, 13 - in group 3) and received 119 cycles of therapy. Response rate was 11% in groups 1 and 2, and 8,3% - in group 3 (p=0,57). Median time to progression was 52, 79 and 63 days, respectively in the 1st, 2nd and 3rd group (р=0,468). Two patients from the 2nd and 3rd group showed delayed response to therapy. No adverse events of grade 3-4 were seen. Thus, DTIC with melatonin or metformin was well tolerated. No meaningful increase of adverse event incidence was seen. No benefit of either combination was shown in this interim analysis. Delayed responses in melatonin and metformin combination groups were registered. This suggests immunologic effect of both drugs and warrants further study.

[Modern methods of immunotherapy for metastatic melanoma].

Over the past five years drug therapy of disseminated melanoma took a giant step forward. In clinical practice there are several fundamentally new classes of drugs: inhibitors of the individual components of MAPK-signaling pathway and modulators of a work of immunological synapse (inhibitor of CTLA4 ipilimumab, inhibitors of PD1 nivolyumab and pem- brolizumab).Here are presented features of the mechanism of action of new immunotherapeutic agents, the review of results of their clinical use, the description of the main treatment- related adverse events. The interaction of new approaches with other methods of systemic treatment and an algorithm for per- sonalized use of these methods is regarded. Modern means of therapy allow achieving expressed and long effects giving pos- sibility in some cases to cure a patient. Rational sequential and combined use of different variants of systemic treatment for disseminated melanoma, appropriate diagnosis and treatment of treatment-related adverse events can significantly increase the length and quality of life of patients.

[Gefitinib therapy in advanced non-small cell lung cancer in patients with EGFR mutations: cost-effectiveness analysis].

Therapy for advanced non-small cell lung cancer (NSCLC) is very complex clinical problem. The optimal choice of therapy demands not only the analysis of data on clinical effectiveness, but also an assessment of cost-effectiveness of the applied drugs. The current options for first- or second/third-line of lung cancer treatment are tirosine kinase inhibitors (TKI)--gefitinib, erlotinib and afatinib. According to the received results TKI first-line therapy for NSCLC in patients with EGFR mutations is not only clinically effective but also is economically acceptable from a position of the Russian budgetary health care. TKI second-line therapy for NSCLC patients who fail first-line therapy also provides improvement of the quality of life and prolonged time to progression. Comparable clinical effectiveness and safety of erlotinib and gefitinib in patients with EGFR mutations allows making drug choice on the basis of regional price characteristics. Afatinib is highly effective both in the first- and in the second/third-line of therapy in patients with the most frequent mutations (a deletion in exon 19 or a point mutation L858R in exon 21) but first-line therapy demands an increase of financial expenses caused by substantial increase of time to progression and duration of therapy. Thus TKI therapy of both the first-, and second/third-line of patients with NSCLC with EGFR mutations is characterized by acceptable cost-effectiveness.

[Systemic therapy of soft tissue sarcomas].

Soft tissue sarcomas (STS) comprise a heterogeneous group of rare malignancies from mesenchymal tissues. The biology of STS causes high aggressiveness, poor prognosis due to early development of distant metastases and limited chemotherapeutic options due to tumor resistance. The paper considers the current principles of chemotherapy for early and metastatic disease. Results of own experience of advanced STS patients' treatment are presented and discussed.

[Efferent therapy in the treatment of solid tumors].

Endogenous intoxication and immune insufficiency accompany neoplastic process. Complex therapy for cancer worsens these pathologic conditions by its adverse effects (AE) and thus complicates treatment. Efferent therapy can provide continuity of antineoplastic therapy with normalization of hemostasis and decreasing the rate of AE and their intensity. Efferent therapy meaningfully increases patient's quality of life and decreases the needed drug support when used as a part of complex therapy. Proper use of efferent therapy can markedly increase efficacy of surgical treatment, radiation therapy and drug therapy.

[Treatment of patients with disseminated testicular germ cell tumors].

Testicular germ cell tumors are rare diseases of young age with high sensitive to cytostatic therapy. Their complex treatment should be based on prognostic factors and individual properties of disease. It includes chemotherapy followed by cytoreductive surgery of residual lesions according to international standards and guidelines. This approach is highly effective and allows curing the majority of patients with advanced disease.

Pancreatic fat necrosis and hemorrhagic necrosis as separate morphological and functional entities.

Peculiarities of pathomorphogenesis of two destructive forms of acute pancreatitis were compared using three experimental models. We have shown that the direction of the pathological process is determined by specific combinations of pathogenic factors. Pathological processes caused by common bile duct ligation (ductal hypertension) alone and in combination with injection of phospholipase A2 are characterized by mixed pattern with strong predominance of fat necrosis symptoms (coagulative acinar necrosis, inflammatory demarcation, and sites of lipolysis) and hemorrhagic necrosis, respectively. Trypsin injection into the pancreatic tissue induces rapidly progressing hemorrhagic pancreatic necrosis with massive hemorrhages, extensive acinar necrosis, and weak cell reaction. Considerable differences in pathomorphogenesis and outcome of the pathological process allow us to consider pancreatic fat necrosis and hemorrhagic necrosis as separate morphological and functional entities, which is essential for the prognosis and treatment strategy.

Pathomorphological analysis of the pancreaticoduodenal organs in experimental pancreonecrosis induced by trypsin injection.

Acute experimental pancreatitis induced by injection of trypsin into the pancreatic tissue exhibited characteristics of fulminant hemorrhagic pancreonecrosis (intense exudation of interlobular stroma, massive plasmo- and hemorrhages, foci of acinar cell autolysis involving by the end of day 1 an appreciable portion of the organ with formation of fields of necrosis and hemorrhagic imbibition of the glandular parenchyma, virtually completely without demarcation cellular reaction). Marked microcirculatory disorders and degenerative and necrobiotic changes in the duodenal mucosa and liver reflected the polyorgan nature of the pathological process. This model of hemorrhagic pancreonecrosis corresponded to the most severe forms of this conditions observed clinically.

[Pharmacoeconomic analysis of gefitinib therapy in patients with non-cell cell lung cancer].

We performed a treatment efficacy analysis for non-small cell lung cancer (NSCLC) patients' population with EGFR mutation aimed at optimization of pharmacoeconomic factors. The employment of gefitinib leads to an increase in patients' life expectancy for a median of 1.05 years. The average cost-effectiveness of this therapy is 934.8 thousand rubles per additional year (903.9-1100.5 thousand rubles for each year). If gefitinib therapy is given only to patients with proved EGFR mutation it can decrease the average expenses by 211.6-251.8 thousand rubles per patient in comparison to undiagnosed patients's population receiving gefitinib without a decrease in clinical effect. Comparison of selective gefitinib administration with isolated chemotherapy (CT) yields an incremental cost-effectiveness ratio of 960.7 to 1010.0 thousand rubles per additional year. Therefore, the strategy of EGFR gene mutations testing in patients with inoperable NSCLC with consequent gefitinib therapy administration in patients positive for mutation lead to an increase in life expectancy and is characterized by acceptable cost-effectiveness.

[Phase II clinical trial of autologous dendritic cell vaccine with immunologic adjuvant in cutaneous melanoma patients].

This paper describes the clinical results and immunologic changes in cutaneous melanoma patients receiving active specific immunotherapy with autologous dendritic cell vaccine (DCV) in combination with cyclophosphamide used as immunologic adjuvant. Twenty eight patients with morphologically verified stage III-IV cutaneous melanoma receiving therapy in N. N. Petrov Research Institute of Oncology between 2008 and 2011 were included in the study. All patients signed an informed consent form. Nineteen patients (67,9%) received DCV in therapeutic setting, 9 (32,1%) received it in adjuvant setting. DCV therapy was well tolerated. No serious adverse events were registered. Frequent adverse events included Grade 1-2 unspecific symptoms (fever, fatigue, flu-like symptoms) observed in 22% patients after 3,5% of vaccinations. In therapeutic settings the use DCV lead to clinical effect (PR+SD) in 36,6% of patients. PR was observed in 5% of (95% CI 0-15%) patients, SD in 31,6% (95% CI 13-56%). Duration of the objective responses was 168-965+days. Addition of immunologic adjuvant (cyclophosphamide 300 mg/m2 IV 2 hours) 3 days before vaccination increased its efficacy. In this patients group (n=12) the therapy lead to clinical benefit in 42% (95% CI 17-69%) of cases, median time to progression was 91 (95% CI 55-126) days. This regimen was selected for adjuvant therapy. In the adjuvant therapy group (n=9) the median time to progression was 112 (95% CI 58-166) days. Immunologic monitoring showed correlation ofT- and B-cell immune response with DCV clinical efficacy (p<0,05), no correlation with delayed hypersensivity reaction was observed (p>0,1). DCV is well tolerated and shows immunological and clinical response in stage III-IV skin melanoma patients.

Pathomorphological study of the pancreas during phospholipase A2-induced experimental pancreatic necrosis.

The pathomorphogenesis of experimental acute pancreatic necrosis induced by administration of phospholipase A2 into the pancreatic tissue is characterized by pathomorphological signs of hemorrhagic pancreatic necrosis (total necrosis and purulent fusion of some acini and massive hemorrhages in the interlobular and intralobular interstitial tissue) and fatty pancreatic necrosis (necrobiotic and necrotic changes in acinar cells that spread from the peripheral area and form the demarcation line).

Ultrastructure of acinar cell injuries in experimental acute pancreatitis created by common bile duct ligation.

Morphogenesis of acute pancreatitis induced by ligation of the common bile duct and the ultrastructure of autolytic transformations of acinar cells were studied. Autolytic changes in acinar cells started from the basal zones and then involved the apical zones. Violation of the zymogen granules integrity, interactions of their contents with the adjacent ultrastructures, destruction (melting) of ultrastructures, and formation of huge autophagosomes play an important role in the development of autolysis. Disordered secretion of zymogen granules (foci of their accumulation in the apical zone), hyperplasia and hypertrophy of centroacinar cells and ductal epitheliocytes aimed at restoration of the pancreatic secretion discharge pathways were seen in the retained acini.

[Pathomorphological changes in the pancreatic ductal system in fatty and hemorrhagic pancreonecrosis in experiment].

The pancreatic ductal system was morphologically studied in fatty and hemorrhagic pancreonecrosis in experiments. The latter were carried out on 105 male Wistar rats. The use of the study models of fatty (administration of phospholipase A2, common bile duct ligation, and their combination) and hemorrhagic pancreonecrosis (administration of trypsin and snake venom) has shown that in fatty pancreonecrosis there are changes initially revealed in the pancreatic ductal system with subsequent necrosis of its parenchyma. In hemorrhagic pancreonecrosis, the ductal system retains its structure. Based on the findings, the authors soundly identify two forms of acute pancreatitis: primary acinar (parenchymatous) and hypertensive ductal.

[Pathogenetic aspects of proteolysis and hemorrhagic pancreatonecrosis and methods of their correction].

In the work you can find the results of the research on modeling of acute experimental pancreatitis caused by injecting solution of tripsin and vipera berus venom. All the visceral organs are involved, that corresponds to common to the human and animal pathological processes (induction of proteolysis and DIC-syndrome). The results of the research show and prove the effectiveness of sandostatin and anti-ophidic serum influence on the proteolytic processes, blood coagulation. Thus, this research gives the opportunity to possibly expand the usage of sandostatin and anti-ophidic serum on treatment diseases with the participation of cascade proteolytic processes.

[Frequency of expression of markers predictive of sensitivity to cytostatics in skin melanoma].

At present, choice of treatment for skin melanoma depends on empirical data on efficacy of medication. Individual treatment may be promoted if certain markers of sensitivity to chemotherapy are evaluated. We studied frequencies of expression of marker sensitivity to fluoropyrimidin [(FPd) (-1)], TS(-)0 and TS(-). TS(-/+) was reported in 36.1%. Sensitivity to platinum drugs [EPCC1(-) - 64.4%], taxotere drugs- [beta = tubulin(-) -72.7%], cyclooxygenase inhibitors [COX2(+)] - 8.9%, mutant tyrosokinase inhibitors [c = kit(+)] - 21.4%, PDGFR = beta(+) -35.5%. Marker expression in tumor tissue was heterogenous. Data on molecular-genetic characteristics of tumor may be used to individualize choice of drugs, dosage and to lower risk of toxicity. Use of cytostatics should be evaluated in clinic for their efficacy in skin melanoma with due consideration of prognostic markers.

[Effectiveness of gefitinib (Iressa) as first-line therapy for inoperable non-small-cell lung cancer with mutated EGFR gene (phase II study)].

Tumor regression was reported in 20-30% of patients with inoperable non-small-cell lung cancer (NSLC) following standard first-line chemotherapy. Clinical trials with second-line gefitinib (Iressa) showed a strikingly high response in patients with mutated EGFR. However, clinical experience with gefitinib as first-line therapy had been limited to small-scale trials mostly among subjects of Asian origin. Our study was not associated with the drug manufacturer and included 25 chemotherapy-naive patients with mutated EGFR inoperable lung adenocarcinoma. Standard dose was 250 mg/day. Complete response was observed in 1 patient (4%), partial--11 (44%), sustained stabilization--13 (52%); median time until tumor progression--186 days. Median overall survival failed to be registered within the duration of the study. Among most frequent side-effects were skin rash (19; 76%) and diarrhea (14; 56%): marked side-effect -toxicity grade III (4; 16%). Gefitinib appeared highly efficient and tolerable and may be recommended as first-line treatment of mutated EGFR inoperable NSLC.

[High-dose Roncoleukin in patients with disseminated cutaneous melanoma: a phase 1 study].

High doses of recombinant interleukin-2 (rlL-2) have been shown to provide clinical effect and long-term survival in patients with malignant melanoma. We have performed a phase 1 study of rIL-2 "Roncoleukin", produced in Saccharomyces cerevisiae. Twenty six patients with disseminated malignant melanoma received from 12 up to 108 millions international units (MIU) of IL-2 as 3-hour i.v. infusions days 1-5 of the 21-day cycle. From 2 to 6 patients were included on each dose level. Response was assessed according to RECIST criteria. Twenty two patients were available for response and 26 for toxicity; 68 cycles of therapy performed. No grade 4 toxicity or toxic death occurred. Main dose limiting toxicity was cardiologic, skin and constitutional (fever) symptoms. One hundred and eight MIU of "Roncoleukin" was considered the highest tolerable dose because of grade 3 toxicity in 2/2 patients, receiving this dose. One complete response (CR) and 2 partial responses (PR) were observed at dose levels of 72 MIU (1 CR and 1 PR) and 84 MIU (1 PR). 3/4 objective responses were in patients with metastases in soft tissues and lymph nodes. Overall response rate was 13.7%. "Roncoleukin" provide certain efficiency in patients with malignant melanoma. This drug has acceptable toxicity; the maximum tolerable dose is 108 MIU. Recommended dose for phase 2 clinical trails is 72 MIU.

[Assessment of influence of dose variation on the effectiveness and toxicity of cytostatic therapy of disseminated breast cancer].

Main indices of efficacy such as objective response and stabilization frequency, objective response median and survival rate were evaluated in 84 patients with disseminated breast cancer receiving different doses of cytostatics: high-dose chemotherapy (HDC) plus transplantation of peripheral blood stem cells, standard-dose (SDC), dose reduced by 20% (RDC20) or by 50% (RDC50). There was an inverse correlation between complete+partial response frequency, on the one hand, and dosage, on the other: highest dose--70% and lowest dose--11.1%. Objective response median in both groups was pretty close--8.5 +/- 5.5 and 5 +/- 0.4% months, respectively. The lowering of dose involved a higher risk of tumor progression from 15% after HDC, 46.6%--SDC and 44.4%--RDC20 to 61.1% after RDC50, with likelihood of objective response decreasing. Nether median nor mean survival rates depended on dosage, nor the difference was significant (p = 0.72). Hence, adequate dose proved to be an important factor, as far as treatment efficacy is concerned. Escalation to high dose was followed by an increase in objective response rates to 70%, SDC - 35.7%, RDC20--33.4% and RDC50--11.1%. Yet, nether dose escalation nor dose reduction involved significant variation in survival (p = 0.72).