Introduction. The presence of a germinal BRCA mutation occurs in 3–4% of all breast cancer (BC) patients with various biological subtypes, but significantly with a high frequency in patients with a triple negative biological subtype (in 10–20% of cases). For the treatment of patients with HER2-negative metastatic breast cancer associated with gBRCA mutation, the effectiveness of biologically targeted drugs from the group of PARP inhibitors (olaparib and talazoparib) has been proven.Purpose. Comparison of the results of our experience with the use of talazoparib in patients with HER2-gBRCA+ + mBC with the data of the EMBRACA registration study.Materials and methods. As part of the multicenter compassionate use program (CUP) with the support of Pfizer, 24 patients with HER2-negative metastatic gBRCA-associated mutation metastatic breast cancer (HER2-gBRCA+ breast cancer) received biologically targeted therapy with the PARP inhibitor talazoparib at a standard oral dose of 1 mg per day for vital indications . The average age of patients with HER2-gBRCAm+ breast cancer was 50 years (29–90 years).Results. Objective response (OR) was registered in 29% of cases, disease control (OR+stabilization) – in 71% of cases. The median progression-free survival (PFS) was 6.5 months (95% CI [3–10]). Objective response, disease control, and median PFS were evaluated depending on the biological subtype, the number of lines of previous therapy, and the presence of platinum-containing agents in the anamnesis.Objective response and disease control were evaluated depending on the biological subtype: in patients with ER+HER2-mBC versus patients with triple negative subtype, OR was 33% vs 22%, and disease control was 83% vs 61%, respectively. In the presence of < 3 vs ≥ 3 lines of therapy for metastatic disease in the anamnesis, OR was 31% vs 12.5%, disease control – 75% vs 50% of cases, respectively. In the presence or absence of platinum-containing agents in the anamnesis, OR was observed in 22% vs 33% of cases, and disease control – 67% vs 67%, respectively.In patients with the luminal subtype versus patients with the triple negative subtype, the PFS was 9 months vs 5 months, respectively (HR = 0.705; 95% CI [0.231–2.147]; p = 0.5208). Median PFS in the presence of <3 vs ≥3 lines of therapy for metastatic disease in the anamnesis was 9 months vs 4 months, respectively (HR = 4,216; 95% CI [1,334–13,327]; p = 0.0056). In the presence or absence of platinum-containing agents in previous lines of therapy 5 months vs 9.5 months, respectively (HR =1.484; 95% CI [0.48–4.582]; p = 0.4750).During the treatment with talazoparib adverse events of the 3rd-4th grades were observed in 5 patients (20,8%). These include moderate and severe anemia in 3 patients (12.5%), thrombocytopenia in 1 patient (4%), and neutropenia in 1 patient (4%). The majority of patients (79,5%), which received talazoparib, did not require dose adjustment. The need to reduce the dose to 0.75 mg was noted in 3 patients (12.5%), to 0.5 mg – in 2 patients (8%). Hemotransfusion was performed in 3 patients. For effective therapy safety management regular monitoring of blood parameters is necessary.Conclusion. Thus, targeted therapy with talazoparib is an effective treatment option for HER2-gBRCA+ mBC.
Objective. To assess the overall and disease-free survival rates in patients with EGFR-mutated lung adenocarcinoma, who underwent surgery after achieving the objective response to tyrosine kinase inhibitor (TKI) therapy.Material and Methods. The overall and disease-free survival rates were analyzed in 18 patients with EGFR-positive lung adenocarcinoma, which was inoperable at presentation due to locally advanced disease or the evidence of distant metastasis. In accordance with the clinical standards, patients were recommended for TKI therapy. Surgical resection was performed after achieving the objective tumor response to TKI therapy. The control group included 23 patients with EGFR mutation-positive lung adenocarcinoma, who did not undergo surgery after receiving TKI therapy.Results. The study revealed a statistically significant effect of surgical resection on the overall survival (OS) in patients with EGFR mutation-positive stage III–IV lung adenocarcinoma after response to TKI therapy (p=0.004). However, there was no statistically significant effect on the disease-free survival (DFS) (p=0.40). There was a tendency to increase in the median OS in patients of the study group (46 months) compared to that in patients of the control group (26 months). Surgery in the study group was characterized with some technical difficulties associated with severe fibrosis. However, this did not affect the duration of surgery and the volume of blood loss.Conclusion. Tumor resection in patients with EGFR mutation-positive stage III–IV lung adenocarcinoma is feasible and safe, but requires highly qualified team surgeons in well-equipped medical centers. Our study revealed that the combination of EGFR-TKI and tumor resection provided better PFS and OS than EGFR-TKI alone. However, further studies are required.
Immune checkpoint inhibitors are promising agents for anticancer therapy. But despite their high efficacy in the treatment of solid tumors, there is still a problem with immune-related adverse events, especially cardiovascular complications with a very high mortality rate. Myocarditis or ischemic heart disease progression is not the only possible cause of cardiovascular death in patients treated with checkpoint inhibitors. We report a case of a patient with mucinous carcinoma of the lung, with a previous history of hypertension and moderate left ventricular dysfunction. The patient was prescribed atezolizumab, but the first atezolizumab infusion resulted in the patient cardiovascular death. Postmortem histopathological evaluation of myocardium revealed several possible reasons for hemodynamic instability: tumor embolism of the coronary arteries, micrometastases of mucinous carcinoma in the myocardium, and myocarditis diagnosed by both Dallas and immunohistochemistry criteria. In addition, testing for expression of PD-L1 detected the high levels of membranous and cytoplasmic PD-L1 protein even in the myocardium area free from tumor cells. The present clinical case demonstrates a problem of cardiovascular death in patients treated with checkpoint inhibitors and actualizes the need for future research of potential risk factors for cardiovascular complications.
e21120 Background: Various EGFR TKIs and several combinations are the standard of initial treatment for NSCLC with EGFR mutations. For this moment one size fits all approach is used. Due to the limited nature of this subgroup direct prospective survival comparison of various options is time and resource consuming. The main objective of this study was to compare available prospective trials in a network meta-analysis in order to determine the overall survival (OS) advantage. Methods: Using frequentist approach (netmeta R package) we performed a network meta-analysis of prospective randomized trials comparing having platinum doublet or 1G TKI as a control arm and 1G TKI, 2G TKI, 3G TKI, combination of chemotherapy (CT)+1G TKI, combination anti-VEGF/R+1G TKI as investigation arm in pts with EGFRmut NSCLC. Between trials we compared OS and progression free survival (PFS ) for overall population and subgroups by mutation, sex, age, smoking status. Results: 17 trials involved 4671 pts were considered eligible for meta-analysis. Trials investigated various combinations of TKIs in untreated EGFR mutated NSCLC: 8 had chemotherapy (CT) as control arm (ENSURE, EURTAC, IPASS, NEJ002, OPTIMAL CTONG-0802, WJTOG3405, LUX-Lung-3/6) and 9 with 1G TKIs as control arm (JO25567, NEJ026, 14034 H3E-CR-JIMIT, NEJ009, Noronha et. al, LUX-LUNG7, ARCHER1050, SWOGS1403, FLAURA). Compared to 1G TKIs improved OS was observed for combination of 1G TKI and CT (HR 0.64 (0.53– 0.78)), 3G TKIs (HR 0.80 (0.64-1.00)), 2G TKIs (HR 0.83 (0.72-0.96)) (The OS benefit was ranked No.1 for TKI+chemo (P-score – 0.96), No.2 – 3G TKI (P-score – 0.68), No.3 – 2G TKI (P-score – 0.64)) Addition of anti-VEGF/R therapy did not improve OS (HR 0.91 (0.68-1.21) over 1G TKIs alone. Importantly OS advantage remained significant in a subgroup of ex19del only for 2G TKIs (HR 0.71 (0.53-0.96)). No advantage for particular regimen was seen for L858R subgroup. 3G TKIs (HR 0.46 (0.27-0.78)), combinations with CT (HR 0.55 (0.40-0.75)) and anti-angiogenic agents (HR 0.57 (0.37-0.89), improved PFS over 1GTKIs, while 2G TKIs had a tendency for improving (HR 0.78 (0.58-1.06)). Conclusions: Our network meta-analysis showed that compared to initial treatment with 1G TKI monotherapy - 1G combination with CT, monotherapy with 3G and 2G may provide OS advantage. Still for ex19del subgroup OS benefit was significant only for 2G TKI. The availability of multiple first line options force the importance of stratification of patients for particular treatment type.
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