Efficacy of everolimus plus hormonal treatment after cyclin-dependent kinase inhibitor; real-life experience, A TOG study.

PURPOSE: In advanced breast cancer, endocrine therapy is preferred in the absence of visceral crisis. Cyclin-dependent kinase inhibitors (CDKi) are the gold standards. The selection of subsequent treatments after CDKi treatment is still controversial, and the efficacy of everolimus (EVE) combinations is unknown. In this study, we aimed to investigate the efficacy of EVE after CDKi administration in real-life experiences. METHOD: The study received data from 208 patients from 26 cancer centers. Demographic and histologic features, diagnosis, progression, last visit dates, and toxicities were recorded. This study was a retrospective case series. RESULTS: One hundred and seven patients received palbociclib, while 101 patients received ribociclib as a CDKi. The overall response and disease control rates of EVE combinations were 60% and 88%, respectively. In univariate analysis, the absence of liver metastasis, age > 40 years, better type of response, and immediate treatment after CDKi were related to increased progression-free survival. Liver metastasis and response type were significantly associated with overall survival. In the multivariate analysis, response remained significant in terms of progression-free survival, while response type, liver metastatic disease, and hematologic toxicity were prognostic in terms of overall survival. CONCLUSION: This study provides evidence of the benefits of EVE combinations after CDKi treatment. EVE combinations may be more appropriate for patients with non-liver metastasis, and the first treatment response shows the benefit of treatment. In addition, immediate treatment after CDKi treatment is more beneficial than later lines of treatment.

Hyperprogression and hypercalcemia after nivolumab treatment in three cases with renal cell carcinoma.

INTRODUCTION: Hyperprogression is a specific type of response seen with immunotherapy that is observed in all malignancies with a frequency of 9% - 29%, characterized by a rapid increase in tumor burden. Many possible related factors and possible markers have been evaluated but a clinical or laboratory parameter associated with hyperprogression has not yet been established. For renal cell carcinoma, hypercalcemia is known to be a poor prognostic factor but it has not been linked to hyperprogression. CASE REPORT: We retrospectively evaluated 52 patients diagnosed with renal cell carcinoma who had nivolumab treatment in any line. 3 of 9 patients who had hyperprogression were noticed to have hypercalcemia preceding hyperprogression. Here we present those 3 cases who developed hypercalcemia after nivolumab and had hyperprogression at follow-up. MANAGEMENT AND OUTCOME: All cases had less than 4 courses of nivolumab and showed hyperprogression in assessment. Nivolumab was discontinued. However, patients' survival was extremely poor, as expected. DISCUSSION: The development of hypercalcemia may help predict hyperprogression in patients with renal cell carcinoma who receive immunotherapy. In such cases, early evaluation of progression and cessation of nivolumab may be considered.

Immunotherapy experience in sinonasal NUT midline carcinoma, case report.

NUT midline carcinoma (NMC) is an aggressive malignant neoplasm arising from midline structures. Although it is classified as a rare disease, the pathological nonspecific appearance as undifferentiated/poorly differentiated carcinoma and the difficulty in making the definitive diagnosis are probably the reasons for the underdiagnosis; the disease is thought to be more prevalent. There is no standard treatment for the disease. The disease shows a poor response to chemotherapy and radiotherapy, and patients' survival is poor. We present a case of sinonasal NMC treated with chemotherapy and immunotherapy in first-line, which is the first in the literature. The patient presented with metastatic disease and received cisplatin-fluorouracil-docetaxel-pembrolizumab treatment. The tumor's PD-L1 expression was 10%, evaluated by tumor proportion score. The response to the therapy was poor, and the patient died of disease progression 5.4 months after the diagnosis. The efficacy of immunotherapy in NMC is not known. More reports are needed to draw conclusions.

The prognostic factors in patients with advanced hepatocellular carcinoma: impact of treatment sequencing.

The prognosis of patients with advanced HCC can vary widely depending on factors such as the stage of the cancer, the patient's overall health, and treatment regimens. This study aimed to investigate survival outcomes and associated factors in patients with hepatocellular carcinoma (HCC). In this retrospective study, data from 23 medical oncology clinics were analyzed. Progression-free survival (PFS) and overall survival (OS) values were estimated using the Kaplan-Meier method. Prognostic factors associated with survival which were identified in univariate analysis were subsequently evaluated in a multivariate Cox-regression survival analysis was conducted using the backward stepwise (Conditional LR) method to determine the independent predictors of PFS and OS. Of 280 patients, 131 received chemotherapy and 142 received sorafenib, 6 received atezolizumab plus bevacizumab and 1 received nivolumab for first-line setting. The median follow-up time was 30.4 (95%CI 27.1-33.6) months. For-first line, median PFS was 3.1 (95%CI2.7-3.5) months, and it was significantly longer in patients who received sorafenib or atezolizumab-bevacizumab or nivolumab (PFS 5.8 (95%CI 4.2-7.5) than in those received chemotherapy (PFS 2.1 (95%CI 1.9-2.3) in the first-line setting (p < 0.001). Multivariate analysis revealed that male gender (HR: 2.75, 95% CI: 1.53-4.94, p = 0.01), poor ECOG performance score (HR: 1.88, 95% CI: 1.10-3.21, p = 0.02), higher baseline AFP level (HR: 2.38, 95% CI: 1.54-3.67, p < 0.001) and upfront sorafenib treatment (HR,0.38; 95% CI: 0.23-0.62, p < 0.001) were significantly associated with shorter PFS. The median OS was 13.2 (95%CI 11.1-15.2) months. It was significantly longer in patients who received sorafenib or atezolizumab-bevacizumab or nivolumab in the first-line setting followed by TKIs (sorafenib or regorafenib, OS 18.6 (95%CI 13.8-23.5)) compared to those who received chemotherapy (OS 10.3 (95%CI 6.6-14.1)) in the first-line setting. The multivariate analysis revealed that upfront chemotherapy treatment approach, male gender (HR: 1.77, 95% CI: 1.07-2.94, p = 0.02), poor ECOG performance score (HR: 1.96, 95% CI: 1.24-3.09, p = 0.004) and Child-Pugh score, presence of extrahepatic disease (HR: 1.54, 95% CI: 1.09-2.18, p = 0.01), and higher baseline AFP value (HR: 1.50, 95% CI: 1.03-2.19, p = 0.03) were significantly associated with poor prognosis. Additionally, regarding of treatment sequence, upfront sorafenib followed by regorafenib showed a significantly lower risk of mortality (HR: 0.40, 95% CI: 0.25-0.66, p < 0.001). Sorafenib followed by regorafenib treatment was associated with a significantly lower risk of mortality rather than upfront sorafenib followed by BSC group or upfront chemotherapy followed by TKIs. These findings underscore the importance of the optimal treatment sequences to improve survival in patients with advanced HCC.

Early thrombocytopenia predicts longer time­to­treatment discontinuation in trastuzumab emtansine treatment.

Thrombocytopenia is a characteristic adverse event of trastuzumab emtansine (T-DM1), one of the essential treatment options for human epithelial growth factor receptor 2 (HER2)-positive breast cancer. The present study investigated the predictive value of thrombocytopenia for time-to-treatment discontinuation (TTD) in patients receiving T-DM1 for advanced-stage HER2-positive breast cancer. The present observational study enrolled 138 patients who received T-DM1 at six oncology centers from January 2016 to December 2021. Univariate and multivariate Cox regression analyses were performed to determine the factors affecting TTD. The median age of patients was 50 years (range, 26-83). The median number of T-DM1 cycles was 9 (range, 2-58), the overall response rate was 50.0% and the disease control rate was 69.6%. At a median follow-up time of 19.3 months, the median TTD was 9.5 months [95% confidence interval (CI), 7.3-11.7], and the median overall survival was 28.2 months (95% CI, 19.2-37.2). Thrombocytopenia during treatment was observed in 39% of all patients, and 66.7% of these patients experienced early thrombocytopenia (in the first four treatment cycles). Multivariate analysis revealed that the independent factors for TTD were hormone receptor status [hazard ratio (HR), 1.837; 95% CI, 1.249-2.701; P=0.002], Eastern Cooperative Oncology Group performance status score (HR, 3.269; 95% CI, 1.788-5.976; P<0.001) and thrombocytopenia during treatment (HR, 0.297; 95% CI, 0.198-0.446; P<0.001). Patients with early thrombocytopenia had a significantly longer TTD of 17.3 months (95% CI, 11.8-22.8) compared with 7.6 months (95% CI, 5.8-9.4) for patients without early thrombocytopenia (P<0.001). The results of the present study indicated that patients with early thrombocytopenia had improved survival outcomes compared with those without. Thus, maximum benefit from T-DM1 treatment may be achieved by confirming the predictive role of thrombocytopenia in T-DM1 treatment in prospective studies and large-scale cohorts.

Platin­based chemotherapy does not improve survival in patients with non­metastatic resected typical carcinoid tumors.

Chemotherapy is controversial in non-metastatic typical carcinoid (TC) tumors. Therefore, it was aimed to evaluate the impact of platin-based chemotherapy on the survival of patients with lung TC. The medical records of patients who underwent surgical resection for non-metastatic TC from 2002 to 2020 at our institution were retrospectively reviewed. Multivariate regression analysis was performed for chemotherapy and prognostic factors in disease-free survival (DFS) in 72 patients. The pathological stages of patients were as follows: 73.6% of the patients were in stage I, 15.3% in stage II and 11.1% in stage III. A total of 5 patients (6.9%) received platin-based chemotherapy and 6 patients (8.3%) had recurrences. The DFS rates at 12, 36 and 60 months were 98.5, 95.1 and 92.5%, respectively. Log-rank testing showed that patients who received chemotherapy and had stage III disease had shorter DFS (P=0.021 for chemotherapy and P<0.001 for stage). However, multivariate analysis revealed that the pathological stage was the only statistically significant factor affecting DFS (P=0.016). Platin-based chemotherapy did not improve DFS, and the eighth edition of TNM (tumor, nodes, metastases) staging did have prognostic value for patients with non-metastatic TC. Although resection has satisfying long-term outcomes, studies on new agents are needed to decrease the recurrence rate, particularly in patients with stage III disease.

The real-life efficacy and safety of osimertinib in pretreated advanced non-small cell lung cancer patients with T790M mutation: a Turkish Oncology Group Study.

INTRODUCTION: Osimertinib, an irreversible third-generation EGFR-TKI, is the standard of care for second-line treatment of T790M-mutant advanced NSCLC patients whose disease progressed after first-line EGFR-TKI therapy. In this multicenter study, we aimed to determine the real-life efficacy and safety of Osimertinib in pretreated advanced NSCLC patients with T790M mutation. MATERIALS AND METHODS: This retrospective trial included advanced T790M-mutant pretreated NSCLC patients who received Osimertinib from 24 different centers in Turkey. Primary endpoint was time-to-treatment discontinuation (TTD). Secondary endpoints were objective response rate (ORR), overall survival (OS), and safety. RESULTS: Of 163 patients, 68.7% had EGFR exon 19 deletion and 22.7% had exon 21 L858R mutation. Osimertinib was given as second-line treatment in 96 patients (58.9%) and third-line in 48 patients (29.4%). After median of 13-month follow-up, median TTD was 21.6 months with an 82.2% ORR. Estimated median OS was 32.1 months. Grade 3-4 adverse events were seen in 11.7% of the patients. CONCLUSION: Osimertinib is a highly effective option in second- or third-line treatment of NSCLC patients with T790M mutation, with a favorable safety profile.

Contemporary treatment approaches for metastatic colorectal cancer driven by BRAF V600 mutations.

The treatment of metastatic colorectal cancer (mCRC) harboring BRAF V600 mutations is challenging. These tumors are often refractory to standard treatment. Therefore, the patients may exhibit rapid clinical deterioration, depriving them of the chance to receive salvage therapy. In newly diagnosed patients with good performance status, the administration of an intensive chemotherapy regimen like FOLFOXIRI (5-fluorouracil, leucovorin, oxaliplatin, and irinotecan) along with the antiangiogenic agent bevacizumab can modify this aggressive behavior of the disease and improve patient clinical outcomes. The recently published results of the BEACON (Binimetinib, Encorafenib, and Cetuximab Combined to Treat BRAF-Mutant Colorectal Cancer) study demonstrated that a combination therapy consisting of BRAF, epidermal growth factor receptor, and mitogen-activated protein kinase kinase inhibitors could be a useful second-or third-line alternative. This review summarizes the current treatment strategies for BRAF-mutant mCRC.

Efficacy of regorafenib in the second-and third-line setting for patients with advanced hepatocellular carcinoma: A real life data of multicenter study from Turkey.

PURPOSE: After failure of the first-line sorafenib treatment in advanced or metastatic stage hepatocellular carcinoma (HCC), regorafenib is one of the newly-approved targeted agents. We aimed to evaluate the efficacy of regorafenib in patients with advanced HCC treated in the second- or third-line setting. METHODS: In this retrospective and multicenter study, advanced HCC patients not eligible for local therapies, who received a second- or third-line regorafenib therapy after progression on the first-line sorafenib or sequential therapy with chemotherapy (CT) followed by sorafenib, were included. RESULTS: In the first-line setting, 28 (28.9%) patients received CT and 69 (71.1%) patients received sorafenib. There were 24 (24.7%) patients who were intolerant to sorafenib. Disease control rate (DCR) was 53.6% for all patients treated with regorafenib, 62.3% in patients who received regorafenib in the second-line, and 32.1% for those receiving regorafenib in the third-line (p=0.007). Median progression-free survival (PFS) and overall survival (OS) were 5.6 (range; 4.3-6.9) and 8.8 (range, 6.3-11.3) months for all patients treated with regorafenib vs. 7.1 months and 10.3 months for patients who received regorafenib in the second-line vs. 5.1 and 8.7 months for patients who received regorafenib in the third-line, respectively; however, there was no statistically significant difference (pPFS=0.22 and pOS=0.85). CONCLUSION: Although receiving CT as a first-line therapy in advanced HCC patients did not affect the survival rates of subsequent regorafenib therapy, it might diminish the DCR of regorafenib.

Dual HER2 inhibition strategies in the management of treatment-refractory metastatic colorectal cancer: History and status.

Human epidermal growth factor receptor 2 (HER2) signaling pathway activation has been identified as a contributor to de novo or acquired resistance to epidermal growth factor receptor (EGFR) inhibitors in a small subset of patients with metastatic colorectal cancer (mCRC). Dual anti-HER2-targeted treatment exhibits strong antitumor activity in preclinical models of HER2-positive mCRC, supporting its testing in clinical trials. The HERACLES trial at four Italian academic cancer centers has confirmed the effectiveness of dual blockage of HER2 with trastuzumab plus lapatinib in patients with heavily pretreated HER2-positive mCRC, refractory to the anti-EGFR antibodies cetuximab or panitumumab. Here, we reviewed the preclinical studies exploring the role of HER2 signaling in the development of anti-EGFR therapy resistance and discussed the status of clinical trials assessing the activity of HER2 inhibitors in this setting.

Platinum-induced neurotoxicity: A review of possible mechanisms.

Patients treated with platinum-based chemotherapy frequently experience neurotoxic symptoms, which may lead to premature discontinuation of therapy. Despite discontinuation of platinum drugs, these symptoms can persist over a long period of time. Cisplatin and oxaliplatin, among all platinum drugs, have significant neurotoxic potential. A distal dose-dependent symmetrical sensory neuropathy is the most common presentation of platinum neurotoxicity. DNA damage-induced apoptosis of dorsal root ganglion (DRG) neurons seems to be the principal cause of neurological symptoms. However, DRG injury alone cannot explain some unique symptoms such as cold-aggravated burning pain affecting distal extremities that is observed with oxaliplatin administration. In this article, we briefly reviewed potential mechanisms for the development of platinum drugs-associated neurological manifestations.