Overall Response Rate In Patients Research Articles

MEK inhibition overcomes everolimus resistance in gastric cancer.

Although substantial evidence has shown that the mammalian target of rapamycin (mTOR) pathway is an important therapeutic target in gastric cancer, the overall response rates in patients to mTOR inhibitor everolimus have been less than initially expected. We hypothesized that the limited efficacy of everolimus in gastric cancer is due to the activation of extracellular signal-regulated kinase (ERK). ERK activation was investigated using western blot. The effects of dual inhibition of ERK and mTOR via genetic and pharmacological approaches were determined using cellular assays and xenograft mouse model. We observed the decreased phosphorylation of mTOR, rS6, and 4EBP1 and increased phosphorylation of ERK and p90RSK in gastric cancer cells exposed to everolimus at clinically relevant concentration. Using both in vitro cell culture assays and in vivo xenograft mouse model, we found that trametinib overcame everolimus resistance by either effectively targeting resistant cells or further enhancing everolimus' efficacy in sensitive cells. Mechanism studies confirmed that trametinib overcame everolimus resistance via specifically inhibiting ERK and regulating ERK-mediated Bcl-2 family proteins in gastric cancer cells. Inhibition of mTOR pathway can induce "paradoxical" activation of ERK in gastric cancer, and this activation can be reversed by trametinib. Since both drugs are clinically available, our findings might accelerate the initiation of clinical trials on gastric cancer using everolimus and trametinib combination.

Erlotinib plus Gemcitabine in metastatic pancreatic cancer: Resultsfrom a non-interventional trial

Metastatic pancreatic cancer has the worst prognosis of all cancers. With nab-Paclitaxel/gemcitabine, FOLFIRINOX, and gemcitabine/erlotinib, several treatment options are available which improve the patient's overall survival. Especially for patients who develop rash under erlotinib treatment can benefit from gemcitabine/erlotinib combination therapy. This non-interventional study (NIS ML21284) investigated the effectiveness and tolerability of gemcitabine/erlotinib therapy in the treatment routine of metastatic pancreatic cancer, in particular, in the context of the occurrence of a rash.Between 2007 and 2010, the treatment data of 433 patients in 98 centres were documented. All parameters recorded were assessed descriptively.Treatment with gemcitabine/erlotinib resulted in both a significant increased median overall survival of the patient subgroup with rash grade ≥ 1 (9.90; 95 % confidence interval [CI], 8.19 to 11.05 vs. 6.48 months; 95 % CI, 5.66 to 7.40, p = 0.0010) and median progression-free survival (5.43, 95 % CI, 4.90 to 6.12 vs. 3.98 months, 95 % CI, 3.52 to 5.03, p = 0.0131). The overall response rate of patients treated with gemcitabine/erlotinib, who had developed rash grade ≥ 1, was 5.9 % higher compared to patients without rash (31.7 % vs. 25.8 %).In conclusion, these results from the daily treatment routine of metastatic pancreatic cancer underline the importance of combined gemcitabine/erlotinib therapy for a subgroup of patients who develop a rash in the course of erlotinib treatment.

In Vivo Epigenetic CRISPR Screen Identifies Asf1a as an Immunotherapeutic Target in Kras-Mutant Lung Adenocarcinoma.

Despite substantial progress in lung cancer immunotherapy, the overall response rate in patients with KRAS-mutant lung adenocarcinoma (LUAD) remains low. Combining standard immunotherapy with adjuvant approaches that enhance adaptive immune responses-such as epigenetic modulation of antitumor immunity-is therefore an attractive strategy. To identify epigenetic regulators of tumor immunity, we constructed an epigenetic-focused single guide RNA library and performed an in vivo CRISPR screen in a Kras G12D/Trp53 -/- LUAD model. Our data showed that loss of the histone chaperone Asf1a in tumor cells sensitizes tumors to anti-PD-1 treatment. Mechanistic studies revealed that tumor cell-intrinsic Asf1a deficiency induced immunogenic macrophage differentiation in the tumor microenvironment by upregulating GM-CSF expression and potentiated T-cell activation in combination with anti-PD-1. Our results provide a rationale for a novel combination therapy consisting of ASF1A inhibition and anti-PD-1 immunotherapy. SIGNIFICANCE: Using an in vivo epigenetic CRISPR screen, we identified Asf1a as a critical regulator of LUAD sensitivity to anti-PD-1 therapy. Asf1a deficiency synergized with anti-PD-1 immunotherapy by promoting M1-like macrophage polarization and T-cell activation. Thus, we provide a new immunotherapeutic strategy for this subtype of patients with LUAD.See related commentary by Menzel and Black, p. 179.This article is highlighted in the In This Issue feature, p. 161.

Clinical analyses of 24 patients with primary pulmonary NK/T-cell lymphoma

目的探讨原发性肺NK/T细胞淋巴瘤的临床特点、最佳治疗方案及预后因素，以提高对原发性肺NK/T细胞淋巴瘤的认识。方法回顾性分析2011年4月至2019年5月收治的24例明确诊断为原发性肺NK/T细胞淋巴瘤患者的临床资料，并对其临床特征、治疗及预后进行分析。采用Kaplan-Meier进行生存分析，应用Cox比例风险回归模型确定影响总生存（OS）期和疾病无进展生存（PFS）期的预后因素。结果①入组的24例患者中男16例，女8例，中位年龄为49（4~76）岁。②患者初始症状大多为发热（66.7%）、咳嗽、呼吸困难。主要的胸部影像学表现为单侧（45.8%）或双侧（54.2%）肺部浸润、结节或肿块。③24例患者中20例接受放化疗或造血干细胞移植，4例接受姑息治疗。所有患者的中位OS期为9.5（0.1~26.0）个月，1年OS率为45.8%。以门冬酰胺酶为基础化疗方案的总有效率（ORR）为88.2%。④单因素分析显示，年龄≤60岁患者的OS和PFS显著优于年龄>60岁的患者（P值分别为0.002、0.004），美国东部肿瘤协作组体能状态评分（ECOG评分）≤2分患者的OS和PFS显著优于ECOG评分>2分患者（P值分别为0.042、0.004）。多因素分析显示，年龄>60岁和ECOG评分>2分与不良OS和PFS相关（OS：P值分别为0.024、0.024；PFS：P值分别为0.035、0.024）。结论原发性肺NK/T细胞淋巴瘤罕见且预后差，以门冬酰胺酶为基础的化疗方案疗效显著，年龄>60岁和ECOG评分>2分是患者独立的不良预后因素。

Real-World Effectiveness and Safety of Eltrombopag in Patients with Aplastic Anemia: A Chinese Nationwide Survey

Immunosuppressive therapy (IST) based on antithymoglobin (ATG) and cyclosporin (CsA) is the first-line treatment for severe aplastic anemia (SAA) patients who are unfit for transplantation,and the overall response rate (ORR) is about 70%.The utility of eltrombopag (EPAG),a TPO receptor agonist, achieved robust hematologic response in refractory and treatment-naïve SAA patients in clinical trials and some other studies. However, only a few data came from Asia countries where higher incidence of AA has been reported. A retrospective study on the use of EPAG in AA was conducted in mainland China. Aplastic anemia (transfusion dependent non-severe, severe, and very severe) patients who started eltrombopag before Feb 2019 and continued for at least 3 months either as first-line treatment or as rescue treatment, were enrolled. The maximum daily dosage of EPAG used continuously for at least 2 weeks is defined as the stable dosage. Response criteria were referred to that used in previous reports (Townsley DM, NEJM 2017; BCSH, BJH 2016). Fifty-six patients from eleven centers were enrolled in this study, including 26 males and 30 females at the median age of 39 (7-80) years. All patients were transfusion-dependent by the time of EPAG administration, and there were 14 VSAA, 24 SAA and 18 transfusion dependent non-severe aplastic anemia (TD-NSAA). Nineteen treatment-naïve patients received EPAG and IST (ATG+CsA, n=10; CsA/CsA+androgen, n=9) as first-line treatment. Thirty-seven patients were refractory to IST. Eltrombopag was administered at a median dose of 75 (25-150) mg per day for 7 (3-31) month. The median follow-up time was 9 (3-40) months. The overall response rate in patients receiving EPAG as first-line therapy was 78.9% (15/19), and most patients achieved complete response (CR) (10/15). Among the 10 patients receiving ATG+CsA, 6 patients achieved hematologic response (HR) at 3 months post-treatment, including 3 CR. Six patients were diagnosed as VSAA and three achieved HR. For the 9 patients treated with CsA/CsA+androgen, 8 achieved HR (88.9%) and 4 were CR (44.4%) at 3 months. By last follow-up, the cumulative HR rate was 70% in ATG+CsA group and 89% in CsA/CsA+ androgen group. Among the 14 responders, 11 patients receiving EPAG at a stable dosage ≤75mg/d and achieved HR at 3 months. The overall response rate in IST-refractory patients was 46% (17/37), with trilineage response in 27% patients at 3 months. For the 18 ATG+CsA refractory SAA patients,trilineage HR occurred in 4 patients (22.2%, 4/18), bi-lineage HR in one patient and single lineage HR in one patient. Thus, the total HR was 33.3% (6/18) at 3 months and increased to 44% (8/18) by last follow-up. Among the 19 CsA/CsA+ androgen refractory patients, 6 (31.5%, 6/19) achieved trilineage HR, one achieved bi-lineage HR and 4 achieved single lineage response. Total HR rate was 57.9% (11/19) at 3 months after EPAG initiation and 68% (13/19) by last follow-up, including 9 patients with trilineage HR. Among 17 responders, 13 received a stable EPAG dose of≤75mg/d. Most patients tolerated EPAG well. Adverse events occurred in 29 patients (52%) and most were mild to moderate, including gastrointestinal symptom (n=15, e.g. abdominal pain, nausea), impaired liver function (n=5), skin changes (n=7, e.g. skin pruritus and rash) and musculoskeletal pain (n=6), and venous thrombus (n=2). Eltrombopag dosage was reduced in 2 patients due to severe digestive symptoms at 100 mg/d and discontinued in one patient who suffered from upper limb venous thrombus. In conclusion, EPAG is effective and safe in treating Chinese AA patients at a daily dose of 75mg and less. The real-world result of EPAG in Chinese patients is similar to those reported in Western countries. Disclosures No relevant conflicts of interest to declare.

Plasmablastic Lymphoma - Experience with Infusional EPOCH Chemotherapy from India

Background: Plasmablastic lymphoma (PBL) is a rare type of aggressive large B - cell Non Hodgkin Lymphoma (NHL) which was initially described in HIV positive individuals and later was also described in immune competent individuals. It constitutes about 2-3% of HIV associated malignancies. It was included as a distinct entity in WHO lymphoma classification in 2008. Methods: The clinical features, HIV status, treatment details and outcomes of patients diagnosed with plasmablastic lymphoma during the period of January 2012 to December 2018 were retrospectively collected from the patient records and analyzed. The survival analysis was done by Kaplan Meier analysis and the comparison was done by Log Rank test. Results: Median age of 25 patients, included in the study was 41 years (Range 13 - 71 years). Males constituted 76% (n=19). HIV positivity was 72% (n=18). Stage 4 disease was present in 76% (n=19). Extra nodal involvement was seen in 96% (n=24), of which the common sites were gastrointestinal tract and bone. Out of 25 patients, 7 did not receive any treatment and 3 received metronomic oral chemotherapy due to poor performance status at presentation. Fifteen patients received chemotherapy on a curative intent. Infusional EPOCH chemotherapy was given in 13 patients. CHOP and CHOPE chemotherapy was given in one patient each. The median number of cycles was 6 (Range: 3 - 8). The overall response rate of patients treated on a curative intent was 80% (Complete response and partial response in 8 and 4 respectively). Three patients underwent high dose chemotherapy with autologous stem cell rescue at first remission (2 HIV patients and 1 Non HIV patient). The median overall survival (OS) of the whole study population was 12.4 months with a median follow of 15.9 months. The Medial OS was not reached in the curative intent group and the 2 year OS of the curative group was 55% with a median follow up of 22.8 months. The factors adversely influencing the OS were Age > 40 years and High IPI (International prognostic index). Conclusion: Plasmablastic lymphoma commonly presents as stage 4 disease with extra nodal involvement. It is more common in immunodeficient individuals especially HIV positive patients. Infusional EPOCH chemotherapy is a promising option which induces long term remission in fit patients. Figure Disclosures No relevant conflicts of interest to declare.

Analysis of the Efficacy of Thalidomide Plus Dexamethasone-Based Regimens in Patients With Relapsed/Refractory Multiple Myeloma Who Received Prior Chemotherapy, Including Bortezomib and Lenalidomide: KMM-166 Study

BackgroundFor patients with multiple myeloma (MM) that relapsed after treatment with bortezomib- and lenalidomide-based regimens, there were no other treatment options in Korea until 2016. We aimed to determine the efficacy of thalidomide plus dexamethasone-based regimens in patients with relapsed/refractory MM (RRMM). Patients and MethodsWe conducted a multicenter retrospective analysis in Korea for patients with RRMM treated with thalidomide-based regimens who previously received bortezomib and immunomodulatory agents (IMiDs), including thalidomide and lenalidomide. ResultsIn 47 patients with RRMM, the median age was 64 years and the median number of previous treatment lines, including bortezomib and IMiDs, was 3. Primary resistance to bortezomib and lenalidomide was observed in 12 (26%) and 8 (17%) patients, respectively. The most common regimen was a combination of thalidomide, cyclophosphamide, and dexamethasone. The overall response rate was 38%; 2 patients (4%) experienced a complete response, and 2 patients (4%) experienced a very good partial response. The overall response rate of patients previously exposed to thalidomide was 53%. The median progression-free survival was 5.9 months, and overall survival was 9.2 months. Patients with disease that responded to the thalidomide-based regimen had better progression-free survival compared to those who did not (median, 8.8 vs. 2.5 months; P = .008). The most common adverse events were anemia (51%) for hematologic toxicities and peripheral neuropathy (30%) for nonhematologic toxicities. ConclusionThalidomide-based regimens are potential salvage treatment options for patients with RRMM, even those with disease with prior resistance to IMiDs.

Factors Affecting Patient Satisfaction With Their Anesthesiologist: An Analysis of 51,676 Surveys From a Large Multihospital Practice.

An increasing focus of health care quality is the assessment of patient-reported outcomes, including satisfaction. Because anesthesia care occurs in the context of perioperative surgical care, direct associations between anesthetic management and patient experience may be difficult to identify. We analyzed anesthesia-specific patient satisfaction survey data from a large private practice group to identify patient, procedure, and anesthetic-specific predictors of patient satisfaction with their anesthesiologist, measured via responses to a validated patient satisfaction survey instrument. We hypothesized that some factors governing satisfaction with an anesthesia provider are beyond their ability to control. We retrospectively reviewed responses to the Anesthesia Patient Satisfaction Questionnaire (APSQ), administered online to patients cared for by US Anesthesia Partners, a multistate anesthesia group practice. The APSQ focuses on patient satisfaction with their anesthesiologist and patient-reported outcomes and is administered after discharge. Responses from May to November 2016 were aggregated, and relationships between responses and patient, procedural, and clinician-related factors were assessed using multivariable logistic regression. Out of 629,220 adult patients cared for during the study period, 51,676 responded to the survey request for a 9.3% overall response rate for patients. Nonresponders were slightly older and more likely to be male than responders. After multivariable regression, no patient or procedural factor was associated with patient rating of their anesthesiologist. However, ≥55 years of age, inpatient (versus outpatient) setting, and nighttime surgery (between 6 PM and 6 AM) were associated with lower scores on other satisfaction questions. Our data suggest that some factors governing satisfaction with an anesthesia provider are beyond their ability to control. Further work is needed to identify elements of patient satisfaction with their anesthesiologist and to optimize these aspects of perioperative care.

2532 Lynch Syndrome With Lung Adenocarcinoma and Their Response to Nivolumab

INTRODUCTION: Lynch syndrome is caused by mutations in mismatch repair genes which cause microsatellite instability (MSI). Patients with Lynch syndrome are at high risk for developing synchronously and metasynchronously developing colorectal, uterine, ovarian, stomach, small bowel, pancreatic, kidney and brain cancers; however, the risk of lung cancer is same as that of general population. Programmed death-1 (PD-1) inhibitors such has nivolumab have shown good overall response rate in patients with mismatch repair-deficient non-colorectal cancers. CASE DESCRIPTION/METHODS: A 72-year-old female with 57-pack-year history of smoking was diagnosed with stage IV adenocarcinoma of the transverse colon in 2007. She underwent resection of the transverse colon followed by chemotherapy. In 2016, she was diagnosed with stage IV duodenal carcinoma with metastasis to the liver. A 14.4 mm right lower lobe nodule was also seen on computed tomography (CT) scan (Figure 1). This nodule was suspected to be metastatic from the duodenal carcinoma, however, biopsy of this nodule showed it to be poorly differentiated adenocarcinoma of the lung. Staining was positive for TTF-1 and CK7 confirming it to be a primary lung cancer. Since this was a stage 1 adenocarcinoma, testing for PD-L1 expression was not done. EGFR, ROS, ALK-1 and BRAF mutations were negative. The patient's mother had breast cancer, father had lung, stomach and liver cancer while her sister had lung cancer with metastases to the brain. Given this history, familial cancer syndrome was suspected and microsatellite instability was tested. Loss of MSH2 and MSH6 was detected via immunohistochemistry (IHC) in duodenal cancer, making it a high-frequency MSI (MSI-H) tumor. Immunotherapy with Nivolumab was started in April 2017 and CT scans 8 months later showed markedly decreased size of the duodenal mass and the hepatic metastases while the lung nodule was reduced to 9.7 mm (Figure 2). DISCUSSION: As per the results of CHECKMATE-142 trial, immunotherapy with Nivolumab has shown durable response and disease control in pre-treated patients with DNA mis-match repair deficient/MSI-H metastatic colorectal cancer. PD-L1 tends to be expressed at higher levels in MSI-H cancers than in microsatellite-stable cancers. Even though lung adenocarcinoma was not tested for PD-L1 expression, it was likely to be high given its response to Nivolumab. The findings of this case suggest that lung adenocarcinoma in patients with Lynch syndrome may be susceptible to immune check-point blockade.

Patient-doctor concordance of perceived mental health service needs in Chinese hospitalized patients: a cross-sectional study.

To assess the subjective concordance on mental health service needs in hospitalized patients between patients and doctors in China. A cross-sectional study was performed in one day. All hospitalized inpatients from selected departments of West China Hospital were recruited as potential participants. A questionnaire set including demographic variables and the Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder 7-item scale (GAD-7) questionnaires were completed by the included patients. They and their doctors in-charge were asked if they perceived that the patients needed mental health services. The overall response rate in patients was 84.25% and the final sample consisted of 1,273 patients. Among those, 605 patients (47.53%) themselves believed that they needed mental health services, whereas only 345 patients (27.10%) were deemed to be in need of mental health services only by their doctors. Kappa statistics showed that the concordance rate between patients and doctors was low in the total patient group (kappa =0.055) and in the group of patients with significant depression or anxiety (kappa =0.080). A logistic regression analysis showed that the ward where the patients were treated was related to a consistent recognition of mental health needs (OR =1.667). The concordance between Chinese inpatient perception and doctor evaluation of mental health service needs for these patients was low. Therefore, it seems necessary to develop effective strategies to improve the detection rate, such as the use of screening-instruments and the training of health professionals in the detection of psycho-social distress.

Neratinib-Based Therapy in Patients with Metastatic HER2-Positive Breast Cancer from Asia

Aim: To evaluate the safety and efficacy of neratinib-based therapy in Asian patients with HER2-positive metastatic breast cancer (MBC). Patients & methods: We performed a pooled analysis of seven early-phase studies of neratinib given either as monotherapy or in combination with chemotherapeutic agents or trastuzumab in patients with advanced solid tumors. Results: A total of 793 patients with HER2-positive MBC were included in the efficacy analysis (Asia: 271 patients; other regions: 522 patients). The overall response rate in patients from Asia was 66.4% (180/271) and the median progression-free survival was 55.6weeks. The most common adverse event in patients from Asia was diarrhea (all-grade: 96.3%; grade 3: 27.4%). Conclusion: Neratinib-based therapy is safe and effective in patients with HER2-positive MBC from Asia.

Abstract CT052: A Phase Ib and II clinical trial investigating the efficacy of nitric oxide deprivation and docetaxel in triple negative breast cancer

Abstract Triple negative breast cancer (TNBC) is an aggressive disease that currently lacks an efficacious form of therapy. Cancer relapse is thought to be initiated by chemotherapy-resistant breast cancer stem cells (BCSCs). Our previous studies revealed that BCSCs utilize inducible nitric oxide synthase (iNOS)-derived nitric oxide to promote their proliferation, migration, and self-renewal capacity. In an effort to target BCSCs, we found that iNOS inhibition with NG-monomethyl-L-arginine (L-NMMA) sensitized BCSCs to docetaxel in TNBC xenograft models, leading to decreased tumor burden. These findings suggest that BCSC resist conventional therapy in a nitric oxide-dependent manner and that combination of L-NMMA with docetaxel will effectively target BCSCs to prevent further relapse. A phase Ib/II clinical trial was conducted to determine the maximum tolerated dose, recommended phase 2 dose (R2PD), dose-limiting toxicities (DLTs), and efficacy of the L-NMMA and docetaxel combination in chemo-refractory Stage III and IV TNBC patients. For the phase Ib portion of the study, a standard Bayesian continual reassessment method is being used to investigate 7 dose levels of L-NMMA (5, 7.5, 10, 12.5, 15, 17.5, and 20 mg/kg) and two dose levels of docetaxel (75 and 100 mg/m2). Twenty patients have been recruited to date, and based on current pharmacokinetics, pharmacodynamics, and safety data, the RP2D is expected to be docetaxel 100 mg/m2 (Day 1) and L-NMMA 20 mg/kg (Days 1-5) every 3 weeks. At the RP2D, 87.5% of the patients experienced a decrease in total serum nitrates and nitrates at Day 2 (p = 0.0156, Wilcoxon Signed-Rank) as compared to baseline, and 75% experienced a decrease at Day 5 (p = 0.1484). Two and three patients received 15 mg/kg L-NMMA + 75 mg/m2 docetaxel and 17.5 mg/kg L-NMMA + 100 mg/m2 docetaxel, respectively. Of these 5 patients, one partial responder completed 8 cycles before discontinuing treatment due to taxane-associated neuropathy. Among the nine patients treated at the RP2D, only one taxane-associated DLT occurred. The overall response rate for patients treated at the higher doses was 33.3% as determined by RECIST 1.1. Early results of the phase Ib/II trial indicate the safety, tolerability, and promising activity of the first-in-class pan-NOS inhibitor L-NMMA in combination with chemotherapy in the treatment of chemo-refractory TNBC. Citation Format: Andrew W. Chung, Joe E. Ensor, Jorge Darcourt, Anna Belcheva, Tejal Patel, Jenny C. Chang, Polly A. Niravath. A Phase Ib and II clinical trial investigating the efficacy of nitric oxide deprivation and docetaxel in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT052.

Meta-analytical methods for estimating outcomes from overall response rate in patients with relapsed/refractory diffuse large B-cell lymphoma.

Relapsed/refractory diffuse large B-cell lymphoma (DLBCL) is highly heterogeneous and current trials are investigating new approaches to improve outcomes. Limited data on response endpoints can confound estimation of a treatment effect when designing studies of novel agents in this setting, which can hinder study sample size calculations, especially if a net estimate is required for a ‘physician’s choice’ comparator arm. Here we estimate complete response rate (CRR), overall response rate (ORR), and extrapolate durable response rates (DRR; CR/partial response lasting ≥16 weeks) for such a comparator arm from published ORRs in DLBCL.CRR, ORR, and DRR (if reported) were obtained from published clinical trials for approved single-agent therapies in patients with relapsed/refractory aggressive non-Hodgkin lymphoma after ≥2 prior therapies. Meta-analyses were performed to estimate CRR, ORR, and DRR based on ORR data reported from these studies.Published data from studies of eight monotherapies were included. Meta-analyses using fixed and random effects models showed a pooled estimate for a CRR of 12% (95% confidence interval [CI]: 9−15) and 11% (95% CI: 8−15), respectively, an ORR of 30% (95% CI: 25−35) and 30% (95% CI: 24−36), respectively, and a DRR of 14% (95% CI: 11−18; same for fixed and random effects models). Bayesian meta-analysis estimated a pooled DRR of 14% (95% credible interval: 11−19).CRR estimates for a physician’s choice comparator arm in patients with relapsed/refractory DLBCL were 11−12%; DRR estimates were 14% regardless of methodology. Lack of consistency in reported data and choice of endpoints can be addressed using meta-analytic approaches.

Abstract OT3-08-01: A phase Ib/II clinical trial investigating the efficacy of nitric oxide deprivation and docetaxel in triple negative breast cancer

Abstract Triple negative breast cancer (TNBC) is an aggressive disease that currently lacks an efficacious form of therapy. Although chemotherapy is the current standard of care for metastatic TNBC, the 5-year prognosis remains grim with a high rate of disease recurrence. Cancer relapse is thought to be initiated by chemotherapy-resistant breast cancer stem cells (BCSCs). These BCSCs give rise to a diverse clonal population that results in a heterogeneous cancer, which complicates targeted therapeutic strategies. Our previous studies revealed that BCSCs utilize inducible nitric oxide synthase (iNOS)-derived nitric oxide to promote their proliferation, migration, and self-renewal capacity. In an effort to target the BCSC population, we found that iNOS inhibition with NG-monomethyl-L-arginine (L-NMMA) sensitized BCSCs to docetaxel in vivo in TNBC xenograft models, leading to decreased BCSC viability and tumor burden. These findings suggest that BCSC resist conventional therapy in a nitric oxide-dependent manner and that combination of L-NMMA with docetaxel will effectively target BCSCs to prevent further relapse. A phase Ib/II clinical trial was conducted to determine the maximum tolerated dose, recommended phase 2 dose (R2PD), dose-limiting toxicities (DLTs), and efficacy of the L-NMMA and docetaxel combination in TNBC patients with chemotherapy-refractory locally advanced or metastatic disease. For the phase Ib portion of the study, a standard Bayesian continual reassessment method is being used to investigate 7 dose levels of L-NMMA (5, 7.5, 10, 12.5, 15, 17.5, and 20 mg/kg) and two dose levels of docetaxel (75 and 100 mg/m2). Sixteen patients have been recruited to date, and based on current pharmacokinetics, pharmacodynamics, and safety data, the RP2D is expected to be docetaxel 100 mg/m2 (Day 1) and L-NMMA 20 mg/kg (Days 1-5) every 3 weeks. Two and three patients received 15 mg/kg L-NMMA + 75 mg/m2 docetaxel and 17.5 mg/kg L-NMMA + 100 mg/m2 docetaxel, respectively. Of these 5 patients, one partial responder completed 8 cycles before discontinuing treatment due to taxane-associated neuropathy. Among the five patients treated at the RP2D, only one taxane-associated DLT occurred. The overall response rate for patients treated at the higher doses was 22.2%. Early results of the phase Ib/II trial indicate the safety, tolerability, and promising activity of the first-in-class pan-NOS inhibitor L-NMMA in combination with chemotherapy in the treatment of chemotherapy-refractory TNBC. Citation Format: Chung AW, Ensor JE, Darcourt J, Belcheva A, Patel T, Chang JC, Niravath PA. A phase Ib/II clinical trial investigating the efficacy of nitric oxide deprivation and docetaxel in triple negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT3-08-01.

Phase 1 Study of MDR1 Inhibitor Plus Brentuximab Vedotin in Relapsed/Refractory Hodgkin Lymphoma

Phase 1 Study of MDR1 Inhibitor Plus Brentuximab Vedotin in Relapsed/Refractory Hodgkin Lymphoma

Efficacy and safety of PD-1 inhibitors for treating advanced melanoma: a systematic review and meta-analysis.

We conducted a meta-analysis to systematically review the efficacy and safety of programmed cell death 1 (PD-1) inhibitors for advanced melanoma. The relevant studies of the randomized controlled trials in melanoma patients treated with PD-1 inhibitors were retrieved and the systematic evaluation was conducted. Databases were searched till June 2018. PD-1 inhibitors significantly improved the progression-free survival, overall survival and overall response rate in patients with advanced melanoma. Progression-free survival, overall survival and overall response rate did not vary significantly according to PD-L1 status, V-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations and type of drug, but varied significantly by control therapy. PD-1 inhibitors were associated with a decreased risk of adverse events compared with ipilimumab, but an increased risk of immune-related events compared with chemotherapy. The PD-1 inhibitors-containing therapy was efficacious in treating advanced melanoma.

Irinotecan-platinum combination therapy for previously untreated extensive-stage small cell lung cancer patients: a meta-analysis

BackgroundThere is still a debate regarding whether regimens combining irinotecan with platinum could replace regimens combining etoposide with platinum, as first-line chemotherapy for extensive-stage small cell lung cancer (ES-SCLC). We performed a meta-analysis to compare these regimens as first-line chemotherapy for ES-SCLC.MethodsA literature search for randomized controlled trials was performed using the Cochrane Library, PubMed, and Embase. The inverse variance method was used to estimate summary hazard ratios and their 95% confidence intervals for overall survival and progression free survival. Relative risk was used to estimate the overall response rate, disease control rate, 1-year survival, 2-year survival, and adverse event data.ResultNine randomized controlled trials (2451 patients) were included. Regimens combining irinotecan and platinum improved overall survival, progression-free survival and overall response rate compared to combination etoposide and platinum regimens. Meanwhile, superior progression-free survival and overall response rate outcomes were observed in the Asian subgroup of patients. These patients receiving a combination irinotecan and platinum regimen experienced grade 3–4 diarrhea more frequently and experienced less hematologic toxic events than the non-Asian groups.ConclusionsOur data suggest that a combination irinotecan and platinum regimen can prolong overall survival, progression-free survival and overall response rate for patients with ES-SCLC as compared to a combination etoposide and platinum regimen. And the Asian patients could benefit from irinotecan combined with platinum easier.

Abstract 2603: Exploratory analysis of Janus kinase 1 (JAK1) loss-of-function (LoF) mutations in patients with DNA mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) metastatic colorectal cancer (mCRC) treated with nivolumab + ipilimumab in CheckMate-142

Abstract Background JAK1 LoF mutations were reported as a mechanism of resistance to anti-PD-1 therapy in patients with metastatic melanoma (n = 2) or mCRC (n = 1).1,2 Here, we report an exploratory analysis of CheckMate-142 (NCT02060188) investigating whether JAK1 LoF mutations were present in patients with dMMR/MSI-H mCRC who achieved clinical benefit with nivolumab + ipilimumab treatment. Methods Patients received nivolumab 3 mg/kg + ipilimumab 1 mg/kg Q3W × 4 doses and then nivolumab 3 mg/kg Q2W. Whole-exome sequencing was performed on pretreatment biopsies preserved in RNAlater and germline DNA from peripheral blood mononuclear cells. Single nucleotide variants and insertions/deletions were called by 2 variant callers in paired normal and tumor samples, and the union of mutations was included in the downstream analysis as previously described.3 Best overall response was assessed by investigators (RECIST v1.1). Results JAK1 LoF mutations were identified in 4 of 40 patients evaluated in this analysis. Of these 4 patients, 1 had an ongoing partial response of 9.7 months at data cutoff, and 3 had stable disease (Table); 2 patients with stable disease were still on treatment (12 and 17 months) at data cutoff, and 1 discontinued treatment after 2.9 months due to an unrelated adverse event and had not progressed after 10 months off treatment. Conclusions Clinical benefit was achieved with nivolumab + ipilimumab in patients with dMMR/MSI-H mCRC who harbored a JAK1 LoF mutation. Additional analyses are needed to assess the effect of concurrent JAK1 loss of heterozygosity and other genetic alterations in patients with dMMR/MSI-H mCRC. 1. Zaretsky JM et al. N Engl J Med. 2016;375:819-829. 2. Shin D et al. Cancer Discov. 2017;7:188-201. 3. Carbone DP et al. N Engl J Med. 2017;376:2415-2426. Table. Best overall response in patients with dMMR/MSI-H mCRC identified as having wild-type JAK1 or a JAK1 LoF mutationJAK1 LoF mutant n = 4JAK1 wild type n = 36Best overall response, nComplete response01Partial response1a18Stable disease3b11Progressive disease04Not evaluable02fs, frameshift. a JAK1 mutation: I975*. b JAK1 mutations: D899Gfs*10, K860Nfs*16, and K142Rfs*26. Citation Format: Scott Kopetz, Theirry Andre, Michael J. Overman, Vittorina Zagonel, Sara Lonardi, Massimo Aglietta, Fabio Gelsomino, Ray McDermott, Ka Yeung Mark Wong, Alain Hendlisz, Pilar Garcia Alfonso, Heinz-Josef Lenz, Alice Walsh, Rebecca A. Moss, Danielle Greenawalt, Z. Alexander Cao. Exploratory analysis of Janus kinase 1 (JAK1) loss-of-function (LoF) mutations in patients with DNA mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) metastatic colorectal cancer (mCRC) treated with nivolumab + ipilimumab in CheckMate-142 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2603.

Meta-analysis of whole-brain radiotherapy plus temozolomide compared with whole-brain radiotherapy for the treatment of brain metastases from non-small-cell lung cancer.

The aim of this meta‐analysis was to compare the efficiency of whole‐brain radiotherapy (WBRT) plus temozolomide (TMZ) with WBRT for the treatment of brain metastases from non‐small‐cell lung cancer (NSCLC). For dichotomous variables, outcomes were reported as relative risk ratio (RR) and 95% confidence interval (CI) was used to investigate the following outcome measures: overall response rate, headache, gastrointestinal adverse reactions, and hematological adverse reactions. Twelve randomized controlled trials involving 925 participants (480 received WBRT plus TMZ; 445 received WBRT) were included in the meta‐analysis. There was a significant difference between the overall response rate (RR = 1.40, 95% CI 1.24–1.57; Z = 5.51; P < 0.00001), gastrointestinal adverse reactions (RR = 1.46, 95% CI 1.05–2.04; Z = 2.27; P = 0.02), and hematological adverse reactions (RR = 1.45, 95% CI 1.04–2.02; Z = 2.21; P = 0.03) of patients treated with WBRT plus TMZ compared with patients treated with WBRT alone. There was no significant difference between headaches (RR = 1.11, 95% CI 0.93–1.02; Z = 1.13; P = 0.26) in patients treated with WBRT plus TMZ compared with patients treated with WBRT alone. In conclusion, the currently available evidence shows that WBRT plus TMZ increases the overall response rate in patients with brain metastases of NSCLC compared with WBRT alone.

Activity of the PI3K-δ,γ inhibitor duvelisib in a phase 1 trial and preclinical models of T-cell lymphoma

AbstractDuvelisib (IPI-145) is an oral inhibitor of phosphatidylinositol 3-kinase (PI3K)–δ/γ isoforms currently in clinical development. PI3K-δ/γ inhibition may directly inhibit malignant T-cell growth, making duvelisib a promising candidate for patients with peripheral (PTCL) or cutaneous (CTCL) T-cell lymphoma. Inhibition of either isoform may also contribute to clinical responses by modulating nonmalignant immune cells. We investigated these dual effects in a TCL cohort from a phase 1, open-label study of duvelisib in patients with relapsed or refractory PTCL (n = 16) and CTCL (n = 19), along with in vitro and in vivo models of TCL. The overall response rates in patients with PTCL and CTCL were 50.0% and 31.6%, respectively (P = .32). There were 3 complete responses, all among patients with PTCL. Activity was seen across a wide spectrum of subtypes. The most frequently observed grade 3 and 4 adverse events were transaminase increases (40% alanine aminotransferase, 17% aspartate aminotransferase), maculopapular rash (17%), and neutropenia (17%). Responders and nonresponders had markedly different changes in serum cytokine profiles induced by duvelisib. In vitro, duvelisib potently killed 3 of 4 TCL lines with constitutive phospho-AKT (pAKT) vs 0 of 7 lines lacking pAKT (P = .024) and exceeded cell killing by the PI3K-δ–specific inhibitor idelalisib. Administration of duvelisib to mice engrafted with a PTCL patient-derived xenograft resulted in a shift among tumor-associated macrophages from the immunosuppressive M2-like phenotype to the inflammatory M1-like phenotype. In summary, duvelisib demonstrated promising clinical activity and an acceptable safety profile in relapsed/refractory TCL, as well as preclinical evidence of both tumor cell–autonomous and immune-mediated effects. This trial was registered at www.clinicaltrials.gov as #NCT01476657.