Evaluation of the efficacy and safety of nivolumab in the second- or later-line treatment of patients with locally advanced/metastatic non-small cell lung cancer in Türkiye: a retrospective multicenter non-interventional registry study.

OBJECTIVE: To evaluate the efficacy and safety of nivolumab in the second-line (2L) or later-line (LL) treatment of patients with locally advanced/metastatic non-small cell lung cancer (NSCLC) in real-life setting in Türkiye. METHODS: This study was designed as a national, multi-center, retrospective study. The study population was evaluated in two groups for the line of nivolumab therapy: those receiving nivolumab in the 2L (Group 2L) and third-line (3L) or LL (Group 3L/LL). Efficacy was evaluated based on one-year overall survival (OS) and progression-free survival (PFS). Safety was evaluated based on treatment-related adverse events (AEs) and nivolumab discontinuation rate. RESULTS: Of 244 patients, 52.9% were in Group 2L and 47.1% were in Group 3L/LL. Demographic and clinical characteristics did not differ between the groups. In Group 2L and Group 3L/LL, one-year OS and PFS rates were 60.8% and 61.4% (p = 0.592) and 31.2% and 21.3% (p = 0.078), respectively. The objective response rate (ORR) was 34.7% in Group 2L and 27.3% in Group 3L/LL (p = 0.262). The percentage of patients reporting at least one AE in Groups 2L and 3L/LL was 34.9% and 43.5%, respectively (p = 0.169). Fatigue was the most common (16.4%) treatment-related AE in each group. The groups were comparable regarding the AE frequency. Nivolumab was discontinued in 61 patients in Group 2L and 53 patients in Group 3L/LL, with the most common reason being disease progression (57.4% and 66.0%, respectively). CONCLUSION: Nivolumab is safe and effective in the 2L or 3L/LL treatment of locally advanced/metastatic NSCLC and associated with acceptable AEs in real-life setting.

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer (around 85% of all lung cancers). Patients with NSCLC are usually diagnosed at advanced or metastatic stages. When cancer cells spread to other areas from where they first formed, it is called metastatic cancer. Surgery may not be a treatment option for such patients. Currently, immunotherapeutic agents are used in the treatment of NSCLC. Nivolumab is one of the approved immunotherapeutic agents in the treatment of patients with metastatic NSCLC, who have failed after receiving chemotherapy. Our study explored the efficacy and safety of nivolumab in real-life setting in Türkiye. Nivolumab effectiveness was evaluated by overall survival (OS) and progression-free survival (PFS) rates. OS indicates the proportion of patients who are still alive at a given time after diagnosis or treatment initiation. PFS refers to "the length of time during and after cancer treatment that a person lives with the disease but does not get worse". In the present study, one-year OS for 244 patients who received nivolumab was 61.1% and one-year PFS was 26.4%. Nivolumab safety was evaluated based on the frequency of adverse events observed during nivolumab therapy. Of the patients 38.9% had at least one side effect, with fatigue being the most common (16.4%). Our results support the earlier studies and showed that nivolumab was a safe and effective agent and is associated with acceptable side effecrs.

The effects of low HER2 expression on survival in patients with metastatic breast cancer treated with CDK 4/6 inhibitors: a multicenter retrospective study.

PURPOSE: Endocrine therapy (ET) in combination with CDK 4/6 inhibitors (CDK 4/6i) is the standard treatment modality for hormone receptor (HR)-positive and HER2-negative metastatic breast cancer (mBC). There is uncertainty about the prognostic and predictive value of HER2-low status and whether HER2-low BC is an individual biologic subtype. In this study, we aimed to investigate the prognostic effect of HER2 expression status on survival in mBC patients treated with first-line ET plus CDK 4/6i. METHODS: This multicenter retrospective study included patients with HR + /HER2-negative mBC cancer who were treated with first-line CDK 4/6i in combination with ET from January 2016 to March 2023. Patients were divided into two groups (HER2-low and zero), and survival and safety analyses were performed. RESULTS: A total of 201 patients were included in this study; of these, 73 (36.3%) had HER2-low disease and 128 (63.7%) had HER2-zero. There were 135 patients (67.2%) treated with ribociclib and 66 (32.8%) with palbociclib. Most of the patients (75.1%) received aromatase inhibitors as combination-endocrine therapy. Baseline characteristics were similar between the two groups. The median follow-up was 19.1 months (range: 2.5-78.4). The most common side effect was neutropenia (22.4%). The frequency of grade 3-4 toxicity was similar between the HER2-zero and low patients (32% vs 31.5%; p = 0.939). Visceral metastases were present in 44.8% of patients. Between the HER2-low and zero groups, median PFS (25.2 vs 22.6 months, p = 0.972) and OS (not reached vs 37.5 months, p = 0.707) showed no statistically significant differences. CONCLUSION: The prognostic value of HER2-low status remains controversial. Our study showed no significant effect of HER2 low expression on survival in patients receiving CDK 4/6i plus ET.

3-4 Cycles versus 6 Cycles Neoadjuvant Chemotherapy in Advanced-Stage Epithelial Ovarian Cancer: Survival Is Not Determined by the Number of Neoadjuvant Chemotherapy Cycles.

INTRODUCTION: The aim of this study was to compare the disease-free survival (DFS) and overall survival (OS) of patients who underwent interval cytoreductive surgery after 3-4 cycles or 6 cycles of neoadjuvant chemotherapy (NACT) in advanced epithelial ovarian cancer patients. METHODS: Out of 219 patients with advanced epithelial ovarian cancer, 123 patients received 3-4 cycles and 96 patients received 6 cycles of platinum-based NACT. Afterward, laparotomy was performed for interval cytoreductive surgery. RESULTS: No statistically significant difference was found for DFS and OS of the patients who received 3-4 cycles and those who received 6 cycles of NACT (HR: 1.047, 95.0% CI [0.779-1.407]; p: 0.746 for DFS, and HR: 1.181, 95.0% CI [0.818-1.707]; p: 0.368 for OS). Evaluating 123 patients who received 3-4 cycles of NACT, 87 patients (70.7%) without macroscopic residual tumor after interval cytoreductive surgery had significantly longer DFS and OS compared to 36 patients (29.3%) with any residual tumor (HR: 1.830, 95.0% CI [1.194-2.806]; p: 0.003 for DFS, and HR: 1.946, 95.0% CI [1.166-3.250]; p: 0.009 for OS). 96 patients who received 6 courses of NACT were evaluated; 63 patients (65.6%) without macroscopic residual tumor after interval cytoreductive surgery had significantly longer DFS and OS than 33 patients (34.4%) with any residual tumor (HR: 1.716, 9 5.0% CI [1.092-2.697]; p: 0.010 for DFS, and HR: 1.921, 95.0% CI [1.125-3.282]; p: 0.013 for OS). CONCLUSION: In patients with advanced ovarian cancer, there is no significant difference in DFS and OS between 3 and 4 cycles or 6 cycles of NACT. The most important factor determining survival is whether macroscopic residual tumor tissue remains after interval cytoreductive surgery following NACT.

Effect of antibiotic treatment on immune checkpoint inhibitors efficacy in patients with advanced non-small cell lung cancer.

BACKGROUND: Gut microbiotaplays a crucial role in immune response. Recent data have shown that antibiotic (ATB) usage influences efficacy of immune check point inhibitors (ICIs) via altering microbiota of the gut. METHODS: We retrospectively analyzed patients with advanced non-small cell lung cancer (NSCLC) treated with ICIs as monotherapy or combination with chemotherapy (ChT) at the one academic center. Those receiving ATB for the first 12 weeks of the initiation of ICIs were compared with those who did not. The primary objective of this study was to assess the impact of ATB use on overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) during ICIs therapy. RESULTS: 90 patients were included in our analysis. Of these 90 patients, 27 (30%) received ATB in the first 12 weeks of the treatment. In patients who received ATB in the first 12 weeks of ICIs administration, PFS was significantly shorter (4.9 vs. 24.8 months, HR 2.52, 95% CI (1.52-4.18), p < 0.001). OS was also significantly shorter (5.4 vs. 37.8 months, HR 2.55, 95% CI (1.48-4.40), p = 0.001). We also examined the impact of ATB on ORR. Exposure to ATB for the first weeks consistently worsened the response rate; the ORR was 25.9% in the ATB group and 55.6% in the no ATB group (p = 0.01). CONCLUSION: Our findings demonstrated that the use of antibiotics around ICIs initiation was associated with decreased OS, PFS, and ORR in patients with NSCLC. This suggests that microbiota diversity may be one of the factors predicting the efficacy of ICIs.

Radiation recall myositis with pazopanib in a patient with soft tissue sarcoma.

INTRODUCTION: Radiation recall reaction is an acute inflammatory reaction confined to previously irradiated areas that are most commonly triggered by the administration of anti-cancer agents after radiotherapy. Radiation recall myositis is a relatively rare form of radiation recall reaction. CASE REPORT: Here we report a 29-year-old female patient who suffered from metastatic monophasic synovial sarcoma. 8.5 months after post-operative radiotherapy of the right thigh region, the patient suffered pain, edema, redness, and increased temperature locally on the right thigh. Physical exam showed red fixed skin, rigidity and severe tenderness of region, and thigh magnetic resonance imaging revealed dense edema areas at the addiction, semimembranous-semitendinous muscle, and superior part of the biceps femoris and vastus lateralis isointense on T1AG, hyperintense T2AG images. Based on these findings, the patient was diagnosed with pazopanib-induced radiation recall myositis. MANAGEMENT & OUTCOME: Pazopanib was stopped and pentoxifylline (2 × 400 mg), Vitamin E (3 × 400 mg), and methylprednisolone (2 × 8 mg) were prescribed. After 1 month, complete relief of thigh pain and marked recovery of rigidity, as well as erythema, were achieved and no recurrence of radiation recall reaction-related symptoms was observed after the pazopanib rechallenge. DISCUSSION: Myositis is a relatively rare presentation of radiation recall reaction and physicians must be aware of the symptoms of the patients who are treated by radiotherapy and pazopanib.

The Predictive Importance of Body Mass Index on Response to Neoadjuvant Chemotherapy in Patients with Breast Cancer.

Purpose: The aim of the study was to investigate the effects of body mass index (BMI) on the response to neoadjuvant chemotherapy (NACT) in Turkish patients with local and locally advanced breast cancer. Methods: The pathological responses for the breast and axilla were assessed according to the Miller-Payne grading (MPG) system. Tumors were grouped into molecular phenotypes and classified as response rates according to the MPG system after the completion of NACT. A 90% or greater reduction in tumor cellularity was considered a good response to treatment. Additionally, patients were grouped according to BMI into <25 (group A) and ≥25 (group B). Results: In total, 647 Turkish women with breast cancer were included in the study. In the univariate analysis, age, menopause status, tumor diameter, stage, histological grade, Ki-67, estrogen receptor (ER) status, progesterone receptor (PR) status, human epidermal growth factor receptor 2 (HER2) status, and BMI were assessed to determine which of these factors were associated with a ≥90% response rate. Stage, HER2 positivity, triple-negative breast cancer (TNBC; ER-negative, PR-negative, and HER2-negative breast cancer), grade, Ki-67 levels, and BMI were found to be the statistically significant factors for a ≥90% response rate. In the multivariate analysis, grade III disease, HER2 positivity, and TNBC were found to be the factors associated with a high pathological response. Meanwhile, hormone receptor (HR) positivity and a higher BMI were associated with a decreased pathological response in patients receiving NACT for breast cancer. Conclusion: Our results show that a high BMI and HR positivity are associated with a poor response to NACT in Turkish patients with breast cancer. The findings presented in this study may guide novel studies to examine the NACT response in obese patients with and without insulin resistance.

Relationship between pathological response and molecular subtypes in locally advanced breast cancer patients receiving neoadjuvant chemotherapy.

Majority of patients with breast cancer were diagnosed with locally advanced stages of the disease (54%). This study aimed to explain the pathological response received to neoadjuvant chemotherapy (NACT) according to the molecular classification of breast cancer in patients with locally advanced tumors. One hundred and one patients with locally advanced breast cancer treated with neoadjuvant chemotherapy were analyzed. Patients were classified into five molecular subtypes based on the profile of the estrogen receptor, progesterone receptor, HER2, and Ki-67. We determined associations between complete pathological response (no invasive tumor after neoadjuvant chemotherapy) and molecular subgroups. Most patients had luminal A tumors (n: 28, 27.7%). The overall rate of complete pathological response (pCR) was 34.7% (n:35). Tumors that presented with the highest rate of pCR were pure HER2-positive, at 60% (n:6; OR, 3.2; 95% CI, 0.8-12.2). According to logistic regression analysis, the factors affecting pCR were HER2 positivity and clinically positive axilla before NACT. Luminal A tumors had a significantly lower pCR rate. (7.1%,p: 0.001). Despite the low pCR rate, Luminal A tumor had the best survival rate in the subgroups (p < 0.001). However, there was no difference between EFS and OS according to pCR in any molecular subgroups. Pathological complete response is directly related to the subtypes of breast cancer. A high complete pathological response rate is observed in the pure HER2-positive group. However, EFS and OS were not statistically significant in patients with and without pCR.

Five-Year Outcomes With Pembrolizumab Versus Chemotherapy as First-Line Therapy in Patients With Non-Small-Cell Lung Cancer and Programmed Death Ligand-1 Tumor Proportion Score ≥ 1% in the KEYNOTE-042 Study.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We report 5-year results from the phase III KEYNOTE-042 study (ClinicalTrials.gov identifier: NCT02220894). Eligible patients with locally advanced/metastatic non-small-cell lung cancer (NSCLC) without EGFR/ALK alterations and with programmed death ligand-1 (PD-L1) tumor proportion score (TPS) ≥ 1% received pembrolizumab 200 mg once every 3 weeks for 35 cycles or chemotherapy (carboplatin + paclitaxel or pemetrexed) for 4-6 cycles with optional maintenance pemetrexed. Primary end points were overall survival (OS) in PD-L1 TPS ≥ 50%, ≥ 20%, and ≥ 1% groups. Patients who completed 35 cycles of pembrolizumab with ≥ stable disease could begin second-course pembrolizumab upon progression. One thousand two hundred seventy-four patients were randomly assigned (pembrolizumab, n = 637; chemotherapy, n = 637). Median follow-up time was 61.1 (range, 50.0-76.3) months. OS outcomes favored pembrolizumab (v chemotherapy) regardless of PD-L1 TPS (hazard ratio [95% CI] for TPS ≥ 50%, 0.68 [0.57 to 0.81]; TPS ≥ 20%, 0.75 [0.64 to 0.87]; TPS ≥ 1%, 0.79 [0.70 to 0.89]), with estimated 5-year OS rates with pembrolizumab of 21.9%, 19.4%, and 16.6%, respectively. No new toxicities were identified. Objective response rate was 84.3% among 102 patients who completed 35 cycles of pembrolizumab and 15.2% among 33 patients who received second-course pembrolizumab. First-line pembrolizumab monotherapy continued to show durable clinical benefit versus chemotherapy after 5 years of follow-up in PD-L1-positive, locally advanced/metastatic NSCLC without EGFR/ALK alterations and remains a standard of care.

Merkel cell carcinoma in Turkey: A multicentric study.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare but highly aggressive neuroendocrine carcinoma of the skin. In this study, we aimed to evaluate the clinicopathologic characteristics, treatment outcomes, and survival of MCC cases in Turkey. MATERIALS AND METHODS: The patients diagnosed with MCC between 1999 and 2018 at twenty different centers in Turkey were included in the study. Patient and tumor characteristics and adjuvant and metastatis treatment outcomes were analyzed retrospectively. RESULTS: The median age of totally 89 patients was 70 (26-93). The most common primary location was lower limbs (n = 29, 32.5%). Immunohistochemically, CK20 positivity was present in 59 patients (66.3%). Only two patients had secondary malignancy. The majority of the patients (n = 76, 85.4%) were diagnosed at the localized stage. Surgery was performed for all patients in the early stage, and adjuvant radiotherapy or/and chemotherapy was applied to 52.6% (n = 40) of nonmetastatic patients. The median follow-up was 29 months. Recurrence developed in 21 (27.6%) of the 76 patients who presented with local or regional disease. Two-year disease-free survival (DFS) was 68.1% and 5-year DFS was 62.0% for localized stage. The 5-year DFS was similar for patients receiving adjuvant treatment (chemotherapy, radiotherapy, or sequential chemoradiotherapy) and without adjuvant therapy (P > 0.05). Two-year overall survival in patients who presented with localized disease was 71.3% and 18.5% in metastatic patients (P < 0.001). In the metastatic stage, platinum/etoposide combination was the most preferred combination regimen. Median progression-free survival (PFS) in first-line chemotherapy was 7 months (95% confidence interval: 3.5-10.5 months; standart error: 1.78). CONCLUSIONS: Although MCC is rare in Turkey, the incidence is increasing. Gender, CK20 status, tumor size, lymph node involvement, and adjuvant treatment were not associated with recurrence.

Local aromatase activity alterations in breast cancer tissues: A potential way of decision support for clinicians.

BACKGROUND AND AIMS: It is becoming evident that local estrogen exposure is important in postmenopausal breast cancer patients. The microenvironment is established by breast stromal cells based on communication with tumor cells that is essential to cancer development, invasion, and metastasis. Here we investigated aromatase activity levels in both tumor and matched stromal tissues by showing their impact on the manufacturing of local estrogen and tumor progression in cases of invasive ductal carcinoma (IDC). METHODS: Tumor (T) and tumor-associated stroma (TAS) neighboring tissues were acquired from each postmenopausal patient, diagnosed with IDC, and categorized as luminal A (n = 20). The control group was formed from tumor-free breast tissue samples (N, n = 12). A microsomal-based technique was created to compare breast tissue aromatase activities using liquid chromatography - mass spectrometry. FINDINGS: We observed that the TAS tissues have the highest aromatase activities (p < 0.05). High progesterone receptor (PR) intensity levels were found to be decreasing the activity level in these tissues significantly (p < 0.05). Tumor tissue specific aromatase activity levels of postmenopausal patients' were tend to be lower compared to healthy premenopausal subjects' (3 fold, p < 0.001). In addition low activity in tumor tissues were associated with low grade and late stage cancers. CONCLUSIONS: Early detection and personalized therapy is essential for postmenopausal breast cancer patients. Together, our in-house tandem mass spectrometry technique has the potential for further development and standardization for the measurement of aromatase activity and may assist clinicians decide on therapy policies for postmenopausal IDC patients which could be an invaluable asset for precise and specific evaluation.

GLASS: Global Lorlatinib for ALK(+) and ROS1(+) retrospective Study: real world data of 123 NSCLC patients.

Lorlatinib is a third-generation tyrosine-kinases inhibitor (TKI) targeting ALK/ROS1 fusions. The FDA has approved lorlatinib for TKI-pretreated ALK(+) NSCLC, while its approval for ROS1(+) is still pending. Here we present the largest real-world data of NSCLC patients harboring ALK/ROS1 rearrangements treated with lorlatinib. METHODS: 123 patients were enrolled retrospectively (data cut-off 1/1/2019). Lorlatinib was administered through an early access program for patients with no other available therapy. Outcome and response were defined by each investigator upon RECIST 1.1 criteria. RESULTS: 106 ALK(+) and 17 ROS1(+) patients recruited from 8 different countries. The ALK(+) cohort included 50 % males, 73 % never-smokers and 68 % with brain metastases. Extracranial (EC) and intracranial (IC) response rates (RR) were 60 % and 62 %, with disease control rates (DCR) of 91 % and 88 % respectively. Mean duration of therapy (DoT) was 23.9 ±â€¯1.6 months and median overall survival (mOS) was 89.1 ±â€¯19.6 months. ROS1 cohort enrolled 53 % males, 65 % never-smokers and 65 % had brain metastases. EC and IC RR were 62 % and 67 % with DCR of 92 % and 78 % respectively. Median DoT was 18.1 ±â€¯2.5 months and mOS of 90.3 ±â€¯24.4 months. OS and DoT in both cohorts were not significantly correlated with line of therapy nor other parameters. The most common adverse events of any grade were peripheral edema (48 %), hyperlipidemia (47 %), weight gain (25 %) and fatigue (30 %). CNS adverse events such as cognitive effect of grade 1-2 were reported in 18 % of patients. CONCLUSION: Lorlatinib shows outstanding EC/IC efficacy in ALK/ROS1(+) NSCLC. The observed mOS of 89 ±â€¯19 months in ALK(+) NSCLC supports previous reports, while mOS from of 90 ±â€¯24 months is unprecedented for ROS1(+) NSCLC.

Quality of life study of patients with unresectable locally advanced or metastatic pancreatic adenocarcinoma treated with gemcitabine+nab-paclitaxel versus gemcitabine alone: AX-PANC-SY001, a randomized phase-2 study.

BACKGROUND: Combination of gemcitabine and nab-paclitaxel has superior clinical efficacy than gemcitabine alone. Nevertheless, health-related quality of life. (QoL) associated with this combination therapy when administered at first-line in advanced pancreatic adenocarcinoma is unknown. METHODS: A total of 125 patients were randomized to combination therapy (1000 mg/m2 gemcitabine + 125 mg/m2 nab-paclitaxel) and single-agent gemcitabine (1000 mg/m2) arms to take treatment weekly for 7 of 8 weeks, and following 3 of 4 weeks, until progression or severe toxicity. Primary endpoints were three-months of definitive deterioration free percent of patients, and QoL. RESULTS: Overall QoL analyses showed that 34 and 58.3% of cases in gemcitabine and gemcitabine+nab-P arms had no deterioration in 3rd month QoL scores (p = 0.018). These proportions were 27.3 and 36.6% in 6th month assessments, respectively (p = 0.357). Median overall survivals in combination and single-agent arms were 9.92 months and 5.95 months, respectively (HR: 0.64, 95% CI: 0.42-0.86, p = 0.038). Median progression free survivals in these treatment arms were 6.28 and 3.22 months, respectively (HR: 0.58, 95% CI: 0.39-0.87, p = 0.008). Median time-to-deterioration were 5.36 vs 3.68 months, and objective response rates were 37.1% vs 23.7% (p = 0.009), respectively in combination and single-agent arms. CONCLUSIONS: Combination therapy with gemcitabine + nab-paclitaxel had better overall and progression-free survival than gemcitabine alone. Also, combination therapy showed increased response rate without toxicity or deteriorated QoL. Combination treatment with gemcitabine and nab-paclitaxel may provide significant benefit for advanced pancreatic cancer. TRIAL REGISTRATION: This study has been registered in ClinicalTrials.gov as NCT03807999 on January 8, 2019 (retrospectively registered).

Prognostic factors for survival in patients with mucosal and ocular melanoma treated with ipilimumab: Turkish Oncology Group study.

OBJECTIVE: To evaluate prognostic factors associated with the use of ipilimumab in patients with mucosal and uveal melanoma. METHODS: In this multicenter, retrospective study, 31 patients with uveal and mucosal melanoma diagnosed between 2010 and 2017 were enrolled. Patients' characteristics, metastatic disease sites, treatment before ipilimumab therapy, performance status, hemoglobin, lactate dehydrogenase levels, B-RAF and c-kit mutation status, toxicity, and survival data were assessed for patients with mucosal and uveal melanoma. SPSS version 17 was used for statistical analysis. Kaplan-Meier method was used for survival analysis. The log-rank test was used for univariate analyses. The Cox regression analysis was used to test the association between multivariate variables and survival. The p-value of less than 0.05 was considered statistically significant. RESULTS: Twenty patients had uveal and eleven patients had mucosal melanoma. The median overall survival was seven months (95% confidence interval: 1.1-12.7). In univariate analysis, while bone metastasis, anemia, high lactate dehydrogenase level, and more metastatic sites were associated with lower overall survival, better treatment response and administration of ipilimumab in first or second lines were associated with favorable overall survival. In multivariate analysis, only treatment response status and administration of ipilimumab in first or second lines were found to be significant as independent prognostic factors for survival. CONCLUSION: Ipilimumab therapy may be associated with increased survival, but this retrospective small N study makes that hard to definitely conclude.

Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial.

BACKGROUND: First-line pembrolizumab monotherapy improves overall and progression-free survival in patients with untreated metastatic non-small-cell lung cancer with a programmed death ligand 1 (PD-L1) tumour proportion score (TPS) of 50% or greater. We investigated overall survival after treatment with pembrolizumab monotherapy in patients with a PD-L1 TPS of 1% or greater. METHODS: This randomised, open-label, phase 3 study was done in 213 medical centres in 32 countries. Eligible patients were adults (≥18 years) with previously untreated locally advanced or metastatic non-small-cell lung cancer without a sensitising EGFR mutation or ALK translocation and with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1, life expectancy 3 months or longer, and a PD-L1 TPS of 1% or greater. Randomisation was computer generated, accessed via an interactive voice-response and integrated web-response system, and stratified by region of enrolment (east Asia vs rest of world), ECOG performance status score (0 vs 1), histology (squamous vs non-squamous), and PD-L1 TPS (≥50% vs 1-49%). Enrolled patients were randomly assigned 1:1 in blocks of four per stratum to receive pembrolizumab 200 mg every 3 weeks for up to 35 cycles or the investigator's choice of platinum-based chemotherapy for four to six cycles. Primary endpoints were overall survival in patients with a TPS of 50% or greater, 20% or greater, and 1% or greater (one-sided significance thresholds, p=0·0122, p=0·0120, and p=0·0124, respectively) in the intention-to-treat population, assessed sequentially if the previous findings were significant. This study is registered at ClinicalTrials.gov, number NCT02220894. FINDINGS: From Dec 19, 2014, to March 6, 2017, 1274 patients (902 men, 372 women, median age 63 years [IQR 57-69]) with a PD-L1 TPS of 1% or greater were allocated to pembrolizumab (n=637) or chemotherapy (n=637) and included in the intention-to-treat population. 599 (47%) had a TPS of 50% or greater and 818 patients (64%) had a TPS of 20% or greater. As of Feb 26, 2018, median follow-up was 12·8 months. Overall survival was significantly longer in the pembrolizumab group than in the chemotherapy group in all three TPS populations (≥50% hazard ratio 0·69, 95% CI 0·56-0·85, p=0·0003; ≥20% 0·77, 0·64-0·92, p=0·0020, and ≥1% 0·81, 0·71-0·93, p=0·0018). The median surival values by TPS population were 20·0 months (95% CI 15·4-24·9) for pembrolizumab versus 12·2 months (10·4-14·2) for chemotherapy, 17·7 months (15·3-22·1) versus 13·0 months (11·6-15·3), and 16·7 months (13·9-19·7) versus 12·1 months (11·3-13·3), respectively. Treatment-related adverse events of grade 3 or worse occurred in 113 (18%) of 636 treated patients in the pembrolizumab group and in 252 (41%) of 615 in the chemotherapy group and led to death in 13 (2%) and 14 (2%) patients, respectively. INTERPRETATION: The benefit-to-risk profile suggests that pembrolizumab monotherapy can be extended as first-line therapy to patients with locally advanced or metastatic non-small-cell lung cancer without sensitising EGFR or ALK alterations and with low PD-L1 TPS. FUNDING: Merck Sharp & Dohme.

Prognostic factors for survival in patients with metastatic malign melanoma treated with ipilimumab: Turkish Oncology Group study.

PURPOSE: Studies in the last decade show survival improvement with checkpoint blocker therapy in patients with metastatic malign melanoma. Our purpose was to define the efficacy of ipilimumab according to the patient's baseline characteristics including absolute lymphocytes count. METHODS: We collected the data of 97 patients with advanced malign melanoma treated with ipilimumab (3 mg/kg, q3w) retrospectively. Log-rank test was used to analyze the univariate effects of patient's characteristics (age, gender, metastatic sites, ECOG PS, type of melanoma, lactic dehydrogenase levels, anemia, lymphocytes (L), neutrophils (N), N/L ratio), c-kit and BRAF status. Survival analyses were estimated with Kaplan-Meier method. Cox regression analysis was used to assess the possible factors identified with log-rank test. RESULTS: The median age was 58, and 58% were male and 90% of patients had at least one prior systemic therapy. The median survival was 9.7 months for all patients; and the 12- and 24-month survival rates were 43% and 19%, respectively. Absolute lymphocytes count, lactic dehydrogenase level, bone metastasis, the number of metastatic sites, and RECIST response were significantly related to survival. After Cox regression analysis, RECIST response (complete or partial response), absolute lymphocytes count (more than 1500/mm3) and the number of metastatic sites (less than three sites) remained as significant independent prognostic factors for longer survival. CONCLUSION: Ipilimumab improved survival of patients with metastatic malign melanoma. However, patients with fewer metastatic sites and higher absolute lymphocytes count have a significantly better benefit. To determine if these markers could be used to direct patient therapy, further validation analysis is needed.

Prognostic value of aldehyde dehydrogenase 1 (ALDH1) in invasive breast carcinomas.

Aldehyde dehydrogenase 1 (ALDH1) has been identified as a marker of cancer stem cells in breast cancer (BC). Recent studies showed that ALDH1 expression is correlated with poor prognostic parameters and worse clinical outcome in BC. We evaluated ALDH1 expression by immunohistochemistry in a series of 217 invasive BCs and investigated the correlation between ALDH1 expression and clinicopathological parameters, molecular subtypes (luminal A, luminal B, human epidermal growth factor receptor 2 [HER2] type, and triple-negative BC [TNBC]), and patient survival. There was a significant association between ALDH1 expression and tumor grade (p < 0.001), i.e., the expression of ALDH1 was higher in high-grade tumors. ALDH1 expression was significantly associated with estrogen and progesterone receptor (ER and PR) negativity (p < 0.001) and HER2 positivity (p = 0.001). ALDH1 expression ratios were higher in HER2 type and TNBC. There was a statistically significant correlation between ALDH1 negativity and luminal A subtype (p < 0.001). The overall and disease free survival were shorter in ALDH1+ tumors, although without statistical significance. We confirm that ALDH1 is a potentially important, poor prognostic factor in BC, associated with high histological grade, ER/PR negativity and HER2 positivity. For more accurate results, ALDH1 expression should be evaluated in larger case series including various types/subtypes of BC.

A national, multicenter, non-interventional, observational study on treatment patterns in patients with metastatic renal cell carcinoma in Turkey - NOTES study.

INTRODUCTION: The introduction of targeted therapies in renal cell carcinoma has significantly improved its prognosis and treatment outcomes in recent years. Such treatment options are targeted therapies of the vascular endothelial growth factor (VEGF) pathway and the mammalian target of the rapamycin pathway. With the use of tyrosine kinase inhibitors (TKIs) and mammalian target of the rapamycin inhibitors, overall survival has increased up to 2 years. In Turkey, due to applicable reimbursement conditions for patients with metastatic renal cell carcinoma (mRCC), interferon use is mandated as a first-line treatment, thus providing information on the use of everolimus only after initial interferon and second-line VEGF-targeted treatments such as VEGF-TKI. PATIENTS AND METHODS: To provide a first real-life data set in Turkey, we conducted a prospective, non-interventional, observational study and assessed the efficacy and safety of everolimus after two lines of treatment including interferon. A total of 100 patients with histologically confirmed mRCC were enrolled in the study from 11 centers between June 2012 and March 2014 (70 males and 30 females). Efficacy was assessed on the basis of progression-free survival and overall survival; safety of everolimus was assessed on the basis of adverse event occurrence. RESULTS: The study results showed that the median progression-free survival with everolimus treatment was 8.1 months (95% CI: 5.1-11.1) and the median overall survival was 17.6 months (95% CI: 10.1-25.1), thus indicating a better overall response based on survival durations than those from the randomized Phase III REnal Cell cancer treatment with Oral RAD001 given Daily study results (4.9 and 14.8 months, respectively). CONCLUSION: The study showed that everolimus treatment is a safe and effective treatment option in the treatment of mRCC after VEGF-TKI, with an acceptable safety and tolerability profile in real-life settings.

Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial.

BACKGROUND: Atezolizumab is a humanised antiprogrammed death-ligand 1 (PD-L1) monoclonal antibody that inhibits PD-L1 and programmed death-1 (PD-1) and PD-L1 and B7-1 interactions, reinvigorating anticancer immunity. We assessed its efficacy and safety versus docetaxel in previously treated patients with non-small-cell lung cancer. METHODS: We did a randomised, open-label, phase 3 trial (OAK) in 194 academic or community oncology centres in 31 countries. We enrolled patients who had squamous or non-squamous non-small-cell lung cancer, were 18 years or older, had measurable disease per Response Evaluation Criteria in Solid Tumors, and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients had received one to two previous cytotoxic chemotherapy regimens (one or more platinum based combination therapies) for stage IIIB or IV non-small-cell lung cancer. Patients with a history of autoimmune disease and those who had received previous treatments with docetaxel, CD137 agonists, anti-CTLA4, or therapies targeting the PD-L1 and PD-1 pathway were excluded. Patients were randomly assigned (1:1) to intravenously receive either atezolizumab 1200 mg or docetaxel 75 mg/m2 every 3 weeks by permuted block randomisation (block size of eight) via an interactive voice or web response system. Coprimary endpoints were overall survival in the intention-to-treat (ITT) and PD-L1-expression population TC1/2/3 or IC1/2/3 (≥1% PD-L1 on tumour cells or tumour-infiltrating immune cells). The primary efficacy analysis was done in the first 850 of 1225 enrolled patients. This study is registered with ClinicalTrials.gov, number NCT02008227. FINDINGS: Between March 11, 2014, and April 29, 2015, 1225 patients were recruited. In the primary population, 425 patients were randomly assigned to receive atezolizumab and 425 patients were assigned to receive docetaxel. Overall survival was significantly longer with atezolizumab in the ITT and PD-L1-expression populations. In the ITT population, overall survival was improved with atezolizumab compared with docetaxel (median overall survival was 13·8 months [95% CI 11·8-15·7] vs 9·6 months [8·6-11·2]; hazard ratio [HR] 0·73 [95% CI 0·62-0·87], p=0·0003). Overall survival in the TC1/2/3 or IC1/2/3 population was improved with atezolizumab (n=241) compared with docetaxel (n=222; median overall survival was 15·7 months [95% CI 12·6-18·0] with atezolizumab vs 10·3 months [8·8-12·0] with docetaxel; HR 0·74 [95% CI 0·58-0·93]; p=0·0102). Patients in the PD-L1 low or undetectable subgroup (TC0 and IC0) also had improved survival with atezolizumab (median overall survival 12·6 months vs 8·9 months; HR 0·75 [95% CI 0·59-0·96]). Overall survival improvement was similar in patients with squamous (HR 0·73 [95% CI 0·54-0·98]; n=112 in the atezolizumab group and n=110 in the docetaxel group) or non-squamous (0·73 [0·60-0·89]; n=313 and n=315) histology. Fewer patients had treatment-related grade 3 or 4 adverse events with atezolizumab (90 [15%] of 609 patients) versus docetaxel (247 [43%] of 578 patients). One treatment-related death from a respiratory tract infection was reported in the docetaxel group. INTERPRETATION: To our knowledge, OAK is the first randomised phase 3 study to report results of a PD-L1-targeted therapy, with atezolizumab treatment resulting in a clinically relevant improvement of overall survival versus docetaxel in previously treated non-small-cell lung cancer, regardless of PD-L1 expression or histology, with a favourable safety profile. FUNDING: F. Hoffmann-La Roche Ltd, Genentech, Inc.

Evaluation of Local CYP17A1 and CYP19A1 Expression Levels as Prognostic Factors in Postmenopausal Invasive Ductal Breast Cancer Cases.

There is growing attention focused on local estrogen production in the breast tissue and its possible role in breast cancer initiation and progression. Understanding the underlying mechanisms for estrogen synthesis and the microenvironment consisting of tumor and its surrounding adipose tissue might open new avenues in breast cancer prevention, prognosis and treatment. In order to obtain insight, we compared peritumoral and tumor tissue expressions of CYP17A1 and CYP19A1 genes, which play an important role in estrogen biosynthesis. The paired tissue samples of 20 postmenopausal ER+/PR+ patients diagnosed with invasive ductal breast cancer were studied. In addition, 12 breast tissue samples obtained from premenopausal women without a history of breast cancer were also investigated as representative of normal conditions. Peritumoral adipose tissues expressed CYP19A1 approximately threefold higher than tumor itself (p = 0.001). A nonsignificant trend toward low expression of CYP17A1 was observed in peritumoral compared to tumor tissue (p = 0.687). Clinicopathological parameters and patient characteristics which are accepted as risk factors for breast cancer were also associated with individual and combined expressions of CYP17A1 and CYP19A1. This study offers that evaluation of CYP17A1 and CYP19A1 local expression levels might be useful for deciding on personalized treatment approaches and more accurate diagnosis, when evaluated together with several clinicopathological and disease risk factors. Considering the key role of these CYPs in estrogen synthesis, determining their expression levels may be useful as a postdiagnostic marker and for choosing the right treatment method in addition to the conventional approach.