First-line Treatment Option For Patients Research Articles

Aspiration thrombectomy as the first-line treatment of M2 occlusions

The aim of the present study was (i) to evaluate the safety and efficacy of aspiration thrombectomy in patients with M2 occlusions and (ii) to compare outcome of treatment of occlusion of different M2 segments. Between March 2016 and June 2019, 82 patients with acute ischemic stroke and isolated M2 occlusions were treated in cerebrovascular stroke center with aspiration thrombectomy as the first-line treatment. Functional outcomes of patients with different types of M2 occlusions were statistically compared. Multivariable logistic regression analysis was performed to determine the factors associated with good clinical outcome. The mean age was 71.9 ± 13.4 years, 47.6% were men. Aspiration thrombectomy alone was utilized in 72.5% of patients, with 27.5% of patients being treated with a combination of aspiration thrombectomy and stent retriever. At the three-month follow-up, there was no statistically significant difference in functional outcome between different types of M2 occlusions (p = 0.662), however in the underpowered analysis because of the small sample size of patients, with good clinical outcome mRS 0-2 in 50% of all treated patients. Symptomatic intracranial hemorrhage was found in 6.1% of patients. Lower age (OR 0.932, 95% CI 0.878-0.988) and lower NIHSS score upon admission (OR 0.893, 95% CI 0.805-0.991) were independent predictors of good clinical outcome. Aspiration thrombectomy appeared to be a safe and effective first-line treatment option for patients with M2 occlusion, being the first-line option for almost three-quarters of patients.

PCN14 UPDATED NETWORK META-ANALYSIS OF FIRST-LINE EGFR-TARGETED TYROSINE KINASE INHIBITOR TREATMENTS FOR LOCALLY ADVANCED OR METASTATIC NON-SMALL CELL LUNG CANCER WITH EGFR-ACTIVATING MUTATIONS

Lung cancer is one of the most common cancers and a worldwide health burden, with 2.1 million new cases reported globally in 2018. The aim of this study was to conduct a network meta-analysis (NMA) utilizing updated/mature randomized controlled trial (RCT) results for overall survival (OS) to examine the efficacy of first-line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) comparators for the treatment of EGFR mutation positive (EGFR+) non-small cell lung cancer (NSCLC). An NMA of EGFR-TKI comparators was previously conducted and published. This updated NMA includes the latest published OS data for dacomitinib and osimertinib. Eleven electronic databases were systematically searched for RCTs of first-line EGFR-TKI therapies that measured OS. Bayesian NMA was used to compare OS among patients receiving afatinib, dacomitinib, erlotinib, gefitinib, and osimertinib in the overall EGFR+ NSCLC population and in subgroup analyses by ethnicity (Asian and non-Asian) and by EGFR mutational status (exon 19 deletion or exon 21 L858R substitution mutations). Based on the NMA dacomitinib demonstrated statistically significant improvement in OS versus gefitinib (hazard ratio (HR): 0.75, 95% credible interval (CrI): 0.59-0.95). Dacomitinib trended toward improved OS versus afatinib (HR:0.87, CrI: 0.61-1.24) and erlotinib (HR: 0.79, CrI: 0.44-1.42), and had comparable OS to osimertinib (HR: 0.94, CrI: 0.69-1.29). In addition, dacomitinib had the highest probability of being ranked first in the network (50.1%) followed by osimertinib (24.6%). Dacomitinib trended towards improved OS compared to other EGFR-TKIs and had the highest probability of being ranked first in the network. Therefore, dacomitinib should be considered as one of the standard first-line treatment options for patients diagnosed with advanced EGFR+ NSCLC.

A Retrospective Analysis of the Role of Single-Session Gamma Knife Stereotactic Radiosurgery in Sporadic Vestibular Schwannomas with Tumor Volumes Greater Than 10 cm3: Is It Worth Stretching the Boundaries?

Objective: To evaluate the role of single-session Gamma Knife stereotactic radiosurgery (GK-SRS) in the treatment of vestibular schwannomas (VSs) with volumes of greater 10 cm³. Methods: A retrospective analysis was performed of 103 patients treated with single-session GK-SRS between 1993 and 2011 with a mean follow-up of 6.2 years ± 4.4 SD. Treatment, clinical and outcome details were recorded and assessed. Results: Eighty-one (78.6%) patients achieved radiological control with slow progression in a further 5 (4.9%) patients, who did not require further treatment. Linear measurements did not correlate well with volume, which can predict outcome following treatment more precisely. 2.9% of patients developed a new facial paresis, 5.8% trigeminal numbness and 2.9% facial pain. In all, 26 (25.2%) patients who were tested preserved some level of hearing following treatment. Conclusions: The overall radiological control rate in this study was 78.6%, while tumor volumes less than 20 cm³ can be safely treated with single-stage GK-SRS with an expected control rate of 83.2% without unacceptable morbidity rates. GK-SRS can be utilized as a first-line treatment option in patients with large-volume VSs especially in whom surgery is unattractive.

Nivolumab plus low-dose ipilimumab as first-line therapy in microsatellite instability-high/DNA mismatch repair deficient metastatic colorectal cancer: Clinical update.

11 Background: In the phase 2 CheckMate 142 trial, nivolumab plus low-dose ipilimumab provided robust and durable clinical benefit and was well tolerated as first-line therapy for microsatellite instability-high/DNA mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) (Lenz et al. Ann Oncol 2018;29:LBA18). Longer follow-up data will be presented. Methods: Patients with MSI-H/dMMR mCRC and no prior treatment for metastatic disease received nivolumab 3 mg/kg every 2 weeks plus low-dose ipilimumab 1 mg/kg every 6 weeks until disease progression or discontinuation. The primary endpoint was investigator-assessed objective response rate (ORR). Results: For all 45 patients (median follow-up was 13.8 months), ORR was 60% (95% CI 44.3–74.3). Responses were consistent with the overall population across subgroups including age, Eastern Cooperative Oncology Group (ECOG) performance status, prior adjuvant/neoadjuvant therapy, and mutation status (Table). Seven patients (16%) had grade 3–4 treatment-related adverse events; 3 (7%) had any grade treatment-related adverse events leading to discontinuation. Updated response, survival, and safety data after a longer follow-up (median 19.9 months) will be presented. Conclusions: Nivolumab plus low-dose ipilimumab demonstrated robust and durable clinical benefit and was well tolerated. Evaluated subgroups had responses consistent with the overall population. Nivolumab plus low-dose ipilimumab may represent a new first-line treatment option for patients with MSI-H/dMMR mCRC. Clinical trial information: NCT02060188. [Table: see text]

Cost-effectiveness of first-line treatment options for patients with advanced-stage Hodgkin lymphoma: a modelling study

Several strategies are available for the initial treatment of advanced-stage Hodgkin lymphoma, but the optimal strategy in terms of cost-effectiveness is unclear. The aim of this study was to compare the quality-adjusted effectiveness and costs of five modern treatment options for transplantation-eligible patients with newly diagnosed advanced-stage Hodgkin lymphoma. A Markov decision-analytic model was developed using a 20-year time horizon. Five of the most common treatment approaches were selected based on clinical experience and expert opinion: (1) six cycles of doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD), including data from the HD2000 trial, Viviani and colleagues, and EORTC trial; (2) six cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP; from the HD15 trial or PET-adapted as in the HD18 trial, two initial cycles of BEACOPP followed by four additional cycles for patients with a positive PET and either two or four additional cycles of BEACOPP for patients with a negative PET); (3) PET-adapted escalation (as in the RATHL trial, two cycles of standard ABVD chemotherapy followed by an additional four cycles of ABVD or AVD in PET-negative patients and four cycles of BEACOPP in PET-positive patients); (4) six cycles of brentuximab vedotin, doxorubicin, vinblastine, dacarbazine (A-AVD) or ABVD as in the Echelon-1 trial; and (5) PET-adapted de-escalation (as in the AHL2011 trial, two cycles of BEACOPP followed by PET2 scan; PET-positive patients received two additional BEACOPP cycles and PET-negative patients received two cycles of ABVD; at PET4, PET-negative patients completed two further cycles of either ABVD or BEACOPP depending on what they received after PET2, and PET-positive patients received salvage therapy). Note that all uses of BEACOPP in these strategies were BEACOPPescalated. The randomised groups of interest from these studies comprised 4255 patients enrolled between April, 2000, and January, 2016. Baseline probability estimates and utilities were derived from the included trials in addition to a systematic review of published studies. A Canadian public health payer's perspective was considered (CAN$1=US$0·74) and adjusted for inflation for 2018. All costs and benefits were discounted by 1·5% per year because life-years now are more valuable than future potential life-years. Probabilistic analyses (10 000 simulations) showed that, for a willingness-to-pay threshold of CAN$50 000, a PET-adapted de-escalation strategy based on AHL2011 was more cost-effective 87% of the time. This strategy had the highest number of life-years (14·6 years [95% CI 13·7-15·1]) and quality-adjusted life years (13·2 years [95% CI 10·2-14·4]), and the lowest direct costs ($53 129 [95% CI 31 914-94 446]) compared with the other treatment regimens. Sensitivity analyses showed that the model was robust to key variables, including probability of treatment-related mortality, relapse, frequency of secondary malignancy, death from secondary malignancy, and probability of infertility after BEACOPP. Our results suggest that, when considering cost, effectiveness, and short and long-term toxicities, the preferred treatment strategy for patients with newly diagnosed advanced-stage Hodgkin lymphoma is the PET-adapted de-escalation regimen starting with BEACOPP and de-escalating to ABVD as appropriate. Although our findings do not provide an absolute best treatment approach for clinicians to follow for all patients, they can contribute to shared decision making between patients and treating physicians. None.

Retrospective Analysis of S-1 plus Bevacizumab as Maintenance Therapy after Induction of S-1 and Oxaliplatin (SOX) plus Bevacizumab as First-Line Chemotherapy in Patients with Metastatic Colorectal Cancer

Background: The SOFT study was a phase III trial designed to validate the non-inferiority of S-1 and oxaliplatin (SOX) plus bevacizumab to mFOLFOX6 plus bevacizumab in terms of PFS in patients with metastatic colorectal cancer (mCRC) who had not previously received chemotherapy. In this study, we retrospectively reviewed cases in which S-1 plus bevacizumab as maintenance therapy after induction of S-1 and Oxaliplatin (SOX) plus bevacizumab as first-line chemotherapy in patients with metastatic colorectal cancer was applied in order to evaluate its efficacy and safety in clinical practice. Material and method: Among the 40 patients with mCRC at the Fuchu Hospital who received SOX plus bevacizumab as a first line treatment between August 2013 and December 2018. The eligible patients had histologically confirmed mCRC. On day 1 of each 3-week period during the study, patients in the SOX plus bevacizumab received a 7.5 mg/kg intravenous infusion of bevacizumab, followed by an intravenous infusion of 130 mg/m2 oxaliplatin. S-1 (40 - 60 mg) was administered orally two times per day from after dinner on day 1 to after breakfast on day 15, followed by a 7-day rest. Results: The median PFS was 15.0 months and median OS was 36.0 months. The response rate (RR: complete pus partial response) was 85.0%, and the disease control rate (DCR: RR plus stable disease) was 92.5%. The most common adverse events with SOX plus bevacizumab were hypertension (50%), neurosensory toxicity (50%), anorexia (32.5%), fatigue (45%), pigmentation (39%), Neutrophil count decreased (30%), and platelet count decreased (40%). The most common grade 3/4 adverse events were neurosensory toxicity (5%) and fatigue (9%). Conclusion: This study revealed that the survival benefit of S-1 and oxaliplatin (SOX) plus bevacizumab in Japanese patients with mCRC was like that observed in previous clinical trials. Therefore, S-1 and oxaliplatin (SOX) plus bevacizumab can be considered as routine first-line treatment option for patients with mCRC.

Cost effectiveness of therapeutic drug monitoring for imatinib administration in chronic myeloid leukemia.

BackgroundImatinib mesylate (IM) is a first-line treatment option for patients with chronic myeloid leukemia (CML). Patients who fail or are intolerant to IM therapy are treated with more expensive second and third-generation tyrosine kinase inhibitors. Patients show wide variation in trough concentrations in response to standard dosing. Thus, many patients receive subtherapeutic or supratherapeutic doses. Therapeutic drug monitoring (TDM) may improve dose management that, in turn, may reduce costs and improve outcomes. However, TDM also adds to the cost of patient care. The objective of this study was to determine the cost-effectiveness of TDM for generic IM therapy.MethodsWe developed a microsimulation model for the trough plasma concentration of IM which is related to a cytogenetic or molecular response. We compared two cohorts: one with TDM and one without TDM (NTDM). The lifetime incremental cost-effectiveness ratio (ICER) was calculated using quality-adjusted life years (QALYs) as the effectiveness measure. One-way and probabilistic sensitivity analyses were performed.ResultsThe lifetime cost and QALY of treatment with TDM were $2,137K [95% Ci: 2,079K; 2,174K] and 12.37 [95% CI: 12.07; 12.55], respectively. The cost and QALY of NTDM were $2,132K [95% CI: 2,091K; 2,197K] and 12.23 [95% CI: 11.96; 12.50], respectively. The incremental cost and QALY for TDM relative to NTDM was $4,417 [95% CI: -52,582; 32,097]) and 0.15 [95% CI: -0.13; 0.28]. The ICER for TDM relative to NTDM was $30,450/QALY. Probabilistic sensitivity analysis showed that TDM was cost-effective relative to NTDM in 90% of the tested scenarios at a willingness-to-pay threshold of $100,000/QALY.ConclusionsAlthough the impact of TDM is modest, the cost-effectiveness over a lifetime horizon (societal perspective, ($30,450/QALY) falls within the acceptable range (< $100k/QALY).

1934 Atrioesophegeal Fistula, a Rare but Devastating Cause of Upper Gastrointentinal Bleeding

INTRODUCTION: Atrial fibrillation is the most common cardiac arrhythmia globally, with an estimated prevalence of 33.5 million persons. Over the past 20 years, catheter ablation for atrial fibrillation has grown in acceptance and is now a first-line treatment option for patients with symptomatic paroxysmal atrial fibrillation. Atrioesophegeal fistula (AEF) is a rare but often fatal complication associated with atrial fibrillation ablation. CASE DESCRIPTION/METHODS: A 73-year-old woman who underwent radiofrequency ablation for atrial fibrillation 7 weeks prior to presentation to the hospital presented with right-hand weakness, numbness, and ataxia. Initial laboratory evaluation was remarkable for hemoglobin 9.2 g/dL(13.0–17.0 g/dL). Initially, a head computerized tomography (CT) was unremarkable but a subsequent magnetic resonance imaging study demonstrated a right cerebellar stroke. Tissue plasminogen was not prescribed. Transthoracic echocardiogram showed normal left ventricular systolic function, with dilated atria. Later on the day of admission, she developed hematemesis. On day 2 of her admission, she underwent esophagogastroduodenoscopy (EGD) and was found to have a large esophageal defect with thrombus and active bleeding (See Figures 1 and 2). Her clinical status declined quickly and she was taken emergently to the operating room. Unfortunately, despite maximal supportive care, she died prior to surgery. Autopsy revealed an atrioesophageal fistula involving the middle 1/3 of the esophagus and the posterior wall of the left atrium adjacent to the left pulmonary veins. The defects measured 1.5 × 1.0 cm on the esophageal portion and 1 cm × 1 cm on the atrial aspect (See Figure 3). The stomach contained 910 cc of both liquid and clotted blood. DISCUSSION: AEF typically occur 20 ± 12 days post-ablation, ranging from 2 to 60 days. AEF has been reported in surgical RFA, percutaneous RFA, and cryoballoon ablation for atrial fibrillation. CT of the chest with intravenous contrast can show pneumomediastinum, pericardial effusion, and communication between the atrium and esophagus. EGD and transesophageal echocardiogram are not recommended if AEF is suspected, as air insufflation during either procedure may lead to massive air embolization and worsening bleeding. Following the diagnosis of AEF, early surgical intervention is critical as the mortality rate without intervention is 100%. AEF is a rare but often fatal complication of catheter ablation for atrial fibrillation. Untreated, the mortality rate of AEF is 100%.

Urokinase Plasminogen Activator: A Potential Thrombolytic Agent for Ischaemic Stroke.

Stroke continues to be one of the leading causes of mortality and morbidity worldwide. Restoration of cerebral blood flow by recombinant plasminogen activator (rtPA) with or without mechanical thrombectomy is considered the most effective therapy for rescuing brain tissue from ischaemic damage, but this requires advanced facilities and highly skilled professionals, entailing high costs, thus in resource-limited contexts urokinase plasminogen activator (uPA) is commonly used as an alternative. This literature review summarises the existing studies relating to the potential clinical application of uPA in ischaemic stroke patients. In translational studies of ischaemic stroke, uPA has been shown to promote nerve regeneration and reduce infarct volume and neurological deficits. Clinical trials employing uPA as a thrombolytic agent have replicated these favourable outcomes and reported consistent increases in recanalisation, functional improvement and cerebral haemorrhage rates, similar to those observed with rtPA. Single-chain zymogen pro-urokinase (pro-uPA) and rtPA appear to be complementary and synergistic in their action, suggesting that their co-administration may improve the efficacy of thrombolysis without affecting the overall risk of haemorrhage. Large clinical trials examining the efficacy of uPA or the combination of pro-uPA and rtPA are desperately required to unravel whether either therapeutic approach may be a safe first-line treatment option for patients with ischaemic stroke. In light of the existing limited data, thrombolysis with uPA appears to be a potential alternative to rtPA-mediated reperfusive treatment due to its beneficial effects on the promotion of revascularisation and nerve regeneration.

Effect of angiotensin receptor blockers on blood pressure and renal function in patients with concomitant hypertension and chronic kidney disease: a systematic review and meta-analysis

Objective: Angiotensin receptor blockers (ARB) are among the recommended first-line treatment options in patients with hypertension and chronic kidney disease (CKD). This meta-analysis evaluated the effect of ARB on blood pressure (BP) and renal function in patients with concomitant hypertension and CKD with or without diabetes.Methods: Literature search was performed in PubMed/MEDLINE, EMBASE and BIOSIS to identify parallel-group, randomized controlled trials (≥8 weeks) reporting the effects of ARB on office systolic/diastolic BP (SBP/DBP), estimated glomerular filtration rate (eGFR), serum creatinine (SCr), creatinine clearance (CrCl) or proteinuria in adults with hypertension and CKD. Mean difference (MD, generic inverse variance) with 95% confidence intervals (CIs) was used to report an outcome.Results: Among the 24 studies identified, 19 evaluated ARB as monotherapy, 4 evaluated ARB as combination therapy and one evaluated ARB both as monotherapy and combination therapy. Median (range) duration of the studies was 12 (1.84–54.0) months. ARB monotherapy significantly (p < 0.01) reduced BP (treatment ≥1 year: SBP [MD: −14.84 mmHg; 95% CI: −17.82 to −11.85]/DBP [−10.27 mmHg; −12.26 to −8.27]) and proteinuria (≥1 year [−0.90 g/L; −1.22 to −0.59]). Results were consistent for combination therapy. In these studies, non-significant changes were observed for eGFR, CrCl and SCr. The impact of SBP changes on eGFR was not significant; however, studies were of a relatively short duration.Conclusion: ARB had a favorable impact on BP and renal parameters such as proteinuria with monotherapy as well as with combination therapy, highlighting their potential benefits in patients with hypertension and CKD. During the short follow-up of these studies, no significant change in eGFR was observed.

An effective drug sensitizing agent increases gefitinib treatment by down regulating PI3K/Akt/mTOR pathway and up regulating autophagy in non-small cell lung cancer

Gefitinib is one of commonly used first-line treatment options for patients with positive EGFR mutation in non-small cell lung cancer (NSCLC). However, most patients with gefitinib treatment relapse over time due to the loss of drug sensitivity. Compound Kushen injection (CKI) has been used to treat lung cancer, including EGFR-mutated NSCLC. In this report, we examined the anti-cancer and drug sensitivity increased activities of CKI in gefitinib less sensitive NSCLC cell lines H1650 and H1975. Bioinformatics analysis was applied to uncover gene regulation and molecular mechanisms of CKI. Our results indicated that when associating with gefitinib in a dose-dependent fashion, CKI demonstrated the ability to inhibit the proliferation and to increase the sensitivity to gefitinib treatment in gefitinib less sensitive cell lines. This could be the results of down regulation of the PI3K/Akt/mTOR pathway and up regulation of autophagy, which were identified as the potential primary targets of CKI to increase gefitinib treatment effect.

Systematic review and network meta-analysis of first-line therapy for advanced EGFR-positive non-small-cell lung cancer.

Here, we compare the relative clinical efficacy of EGFR-targeted tyrosine kinase inhibitors (EGFR TKIs) for EGFR-positive advanced non-small-cell lung cancer (NSCLC). The authors systematically searched 11 electronic databases from January 2004 to August 2018 for randomized controlled trials measuring clinical efficacy of first-line TKI therapies. Clinical efficacy outcomes included overall survival and progression-free survival. Bayesian network meta-analysis was used to assess the relative efficacy of first-line EGFR TKIs for overall survival and progression-free survival. This network meta-analysis showed that dacomitinib and osimertinib resulted in improved efficacy outcomes compared with afatinib, erlotinib and gefitinib. Both osimertinib and dacomitinib should be considered as standard first-line treatment options for patients diagnosed with advanced EGFR-positive non-small-cell lung cancer.

Caveolin-1 knockdown increases the therapeutic sensitivity of lung cancer to cisplatin-induced apoptosis by repressing Parkin-related mitophagy and activating the ROCK1 pathway.

Chemotherapy is the first-line treatment option for patients with lung cancer. However, therapeutic resistance occurs through an incompletely understood mechanism. Our research wants to investigate the influence of Caveolin-1 (Cav-1) on the therapeutic sensitivity of lung cancer in vitro. Results in this study demonstrated that Cav-1 levels were markedly inhibited in A549 lung cancer cells after exposure to cisplatin. Knockdown of caveolin further enhanced cisplatin-triggered cancer death in A549 cells. The functional investigation demonstrated that Cav-1 inhibition amplified the mitochondrial stress signaling induced by cisplatin, as evidenced by the mitochondrial reactive oxygen species burst, cellular metabolic disruption, mitochondrial membrane potential reduction, and mitochondrial caspase-9-related apoptosis activation. At the molecular level, cav-1 augmented cisplatin-mediated mitochondrial damage by inhibiting Parkin-related mitochondrial autophagy. Mitophagy activation effectively attenuated the promotive impact of Cav-1 knockdown on mitochondrial damage and cell death. Furthermore, our data indicated that Cav-1 affected Parkin-related mitophagy by activating the Rho-associated coiled-coil kinase 1 (ROCK1) pathway; inhibition of the ROCK1 axis prevented cav-1 knockdown-mediated cell death and mitochondrial damage. Taken together, our results provide ample data illuminate the necessary action exerted by Cav-1 on affecting cisplatin-related therapeutic resistance. Silencing of Cav-1 inhibited Parkin-related mitophagy, thus amplifying cisplatin-mediated mitochondrial apoptotic signaling. This finding identifies the Cav-1/ROCK1/Parkin/mitophagy axis as a potential target to overcome cisplatin-related resistance in lung cancer cells.

Abstract 2195: Real-world experience with afatinib as first-line treatment in advanced non-small cell lung cancer in a university hospital

Abstract Purpose: In patients with non-small cell lung cancer (NSCLC), mutations in the epidermal growth factor receptor (EGFR) have been associated with sensitivity to EFGR-Tyrosin Kinase Inhibitors (TKIs). The aim of this study was to analyze clinical efficacies of first line afatinib treatment. Experimental Design: We collected patients with EGFR mutation positive NSCLC who started first-line afatinib treatment between Jan 2015 and Sep 2017. We reviewed clinical characteristics of the patients, laboratory finding, tumor response rate, side effects, progression free survival (PFS), 2nd biopsy result, and overall survival (OS), retrospectively. Results: Forty six patients were available for analysis among all 62 patients (1st to 8th line chemotherapy). At the time of data analysis in October 2018, nine patients were still on afatinib. Median age was 67.4 years-old. 20 (44%) patient had EGFR 19 deletion, 25 (54%) EGFR L858R mutation, 1 (2%) S768I. 10 patients (21.7%) had brain metastasis at baseline study. Tumor response was 58.7% with partial response, no change 19.6%, progressive disease 2%, and non-evaluable 19.6%. Mean follow-up time was 21.6 months (13.5 to 42.5 month) from start of afatinib treatment. Twenty-eight progression or death events were observed. Median PFS was 13.5 months (95% CI: 10.5 to 16.5 months). There were no differences in smoking, gender, EGFR types. 37 patients (80.4%) had dose reduction from initial dose. 6 patients (13.1%) discontinued due to afatinib toxicity. 6 patients (13%) had G3 toxicity, but usually manageable by dose reduction or supportive care. 1 case of doxycycline induced pneumonitis occurred. The PFS of dose reduction group due to adverse events was longer than standard group (14.9 months vs 10.1 months, p=0.023). In dose reduction group, body weight was low (53.1 kg vs 68.4 kg, p=0.002), the ratio of never smoker (87.9% vs 37.5%, p=0.001) and female (87.4% vs 47.4%, p=0.048) were higher than standard group. After progression, 2nd biopsy was done in 17 patients. T790M mutation was detected in 8 patients, so detection rate was 47.1%. 6 patients received oximertinib treatment. Median OS was 38.6 months. Conclusions: Afatinib is one of appropriate first-line treatment option for patients with advanced EGFR positive NSCLC. The dose reduction due to adverse events was common in low-body weight female never smoking patients, but the PFS was increased. With use of new 3rd-gen EGFR TKIs in the first-line setting, optimal sequencing of EGFR TKIs needs to be validated in maximizes treatment outcomes. Citation Format: Taewon Jang, Jaehoon Kim. Real-world experience with afatinib as first-line treatment in advanced non-small cell lung cancer in a university hospital [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 2195.

Gemcitabine and cisplatin (GP) induction chemotherapy (IC) plus concurrent chemoradiotherapy (CCRT) versus CCRT alone in locoregionally advanced nasopharyngeal carcinoma (NPC): A phase 3, multicenter, randomized controlled trial.

6003 Background: GP regimen has been established as the standard first-line treatment option for patients with recurrent/metastatic NPC. However, its efficacy in locoregionally advanced disease remains unclear. Methods: Patients with previously untreated, non-metastatic stage III-IVB (except T3-4N0M0, AJCC 7th) NPC, aged 18–64 years without severe comorbidities were eligible. They were randomly assigned (1:1) to receive GP IC (gemcitabine 1 g/m2on days 1 &amp; 8, cisplatin 80 mg/m2 on day 1, q3w for 3 cycles) plus CCRT (cisplatin 100 mg/m2, q3w for 3 cycles, concurrently with intensity-modulated radiotherapy) or CCRT alone. The primary endpoint was failure-free survival (FFS). The calculated sample size was 238 per group, with an 80% power (two-sided α 0.05) to detect a treatment failure hazard ratio (HR) of 0.52. Results: From Dec 2013 to Sep 2016, 480 patients from 12 centers were randomly assigned to IC+CCRT (n = 242) or CCRT alone (n = 238) group. Baseline characteristics were well balanced. After a median follow-up of 39 months, 3-year FFS was 85.8% in the IC+CCRT group and 77.2% in the CCRT alone group (intention-to-treat population; HR 0.53, 95% confidence interval 0.34–0.81; P = 0.003). In GP+CCRT group, 239 patients started GP IC and 231 (96.7%) completed all three cycles. The most common ≥grade 3 adverse events (AE) in IC+CCRT and CCRT group were mucositis (28.9% vs. 32.1%), neutropenia (28.0% vs. 10.5%) and leukopenia (26.4% vs. 20.3%). Conclusions: Adding GP IC to CCRT significantly improved FFS in locoregionally advanced NPC and is well tolerated with favorable toxicity profile. Clinical trial information: NCT01872962. [Table: see text]

Checkpoint blockade immunotherapy enhances the frequency and effector function of murine tumor-infiltrating T cells but does not alter TCRβ diversity.

Checkpoint blockade immunotherapy is now a first-line treatment option for patients with melanoma. Despite achieving objective responses in about half of patients, the exact immune mechanisms elicited and those required for therapeutic success have not been clearly identified. Insight into these mechanisms is key for improving outcomes in a broader range of cancer patients. We used a murine melanoma model to track responses by different subsets of tumor-infiltrating lymphocytes (TIL) during checkpoint blockade immunotherapy. Tumors from treated mice had increased frequencies of both CD4+ and CD8+ T cells, which also showed evidence of functional reinvigoration and elevated effector cytokine production after immunotherapy. We predicted that increased T cell numbers and function within tumors reflected either infiltration by new T cells or clonal expansion by a few high-affinity tumor-reactive T cells. To address this, we compared TIL diversity before and after immunotherapy by sequencing the complementarity determining region 3 (CDR3) of all T cell receptor beta (TCRβ) genes. While checkpoint blockade effectively slowed tumor progression and increased T cell frequencies, the diversity of intratumoral T cells remained stable. This was true when analyzing total T cells and when focusing on smaller subsets of effector CD4+ and CD8+ TIL as well as regulatory T cells. Our study suggests that checkpoint blockade immunotherapy does not broaden the T cell repertoire within murine melanoma tumors, but rather expands existing T cell populations and enhances effector capabilities.

First-Line Treatment of Patients With Indolent Non-Hodgkin Lymphoma or Mantle-Cell Lymphoma With Bendamustine Plus Rituximab Versus R-CHOP or R-CVP: Results of the BRIGHT 5-Year Follow-Up Study.

The BRIGHT study ( ClinicalTrials.gov identifier: NCT00877006) was initiated to compare the efficacy and safety of bendamustine plus rituximab (BR) with either rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or rituximab plus cyclophosphamide, vincristine, and prednisone (R-CVP) for treatment-naive patients with indolent non-Hodgkin lymphoma or mantle-cell lymphoma. This publication provides long-term follow-up data. Patients were monitored for a minimum of 5 years after completion of study treatment for the time-to-event end points of progression-free survival (PFS), event-free survival, duration of response, and overall survival per investigator assessment. Data on the number of patients who received second-line anticancer treatment and the occurrence of other malignancies were also collected. The medians were not reached for any of the time-to event end points for either the BR or R-CHOP/R-CVP study treatment groups by study completion. PFS rates at 5 years were 65.5% in the BR treatment group and 55.8% in the R-CHOP/R-CVP group. The difference in PFS was considered significant with a hazard ratio of 0.61 (95% CI, 0.45 to 0.85; P = .0025). The hazard ratio for event-free survival and duration of response (P = .0020 and .0134, respectively) also favored the BR regimen over R-CHOP/R-CVP. However, no significant difference in overall survival was observed. The overall safety profiles of BR, R-CHOP, and R-CVP were as expected; no new safety data were collected during long-term follow-up. A higher number of secondary malignancies was noted in the BR treatment group. Overall, BR demonstrated better long-term disease control than R-CHOP/R-CVP and should be considered as a first-line treatment option for patients with indolent and mantle-cell lymphoma.

Medical Treatment Options for Patients with Epidermal Growth Factor Receptor Mutation-Positive Non-Small Cell Lung Cancer Suffering from Brain Metastases and/or Leptomeningeal Disease.

Brain metastases and/or leptomeningeal disease (LMD) with associated central nervous system (CNS) metastases are known complications of advanced epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC). It is important, therefore, to assess the activity of EGFR tyrosine kinase inhibitors (TKIs) versus such CNS complications. This review explores the literature reporting the intracranial activity of EGFR TKIs, and finds that there is evidence for varying efficacy of the approved agents, erlotinib, gefitinib, afatinib, and osimertinib in patients with CNS metastases. Other EGFR TKIs in development, such as AZD3759, may have a future role as therapeutic options in this setting. Emerging evidence indicates that the second- and third-generation EGFR TKIs, afatinib and osimertinib, effectively penetrate the blood-brain barrier, and therefore represent viable treatment options for CNS lesions, and can reduce the risk of CNS progression. These agents should therefore be considered as first-line treatment options in patients with EGFR mutation-positive NSCLC who have brain metastases and/or LMD. While there are currently no prospective data comparing the intracranial efficacy of second- and third-generation EGFR TKIs in this setting, CNS activity and protection offered by different EGFR TKIs should be an additional consideration when making decisions about the optimal sequence of treatment with EGFR TKIs in order to maximize survival benefit in individual patients.

Efficacy of pemetrexed-based regimens in advanced non&amp;ndash;small cell lung cancer patients with activating epidermal growth factor receptor mutations after tyrosine kinase inhibitor failure: a systematic review

Pemetrexed-based chemotherapy regimens (pem regimens) are the standard first-line treatment option in patients with non-squamous non–small cell lung cancer (NSCLC). The objective of this systematic review was to assess the efficacy of pemetrexed in the context of epidermal growth factor receptor (EGFR) mutation-positive NSCLC following the failure of EGFR–tyrosine kinase inhibitor (TKI) treatment. We searched biomedical literature databases (PubMed, EMBASE, and the Cochrane library) and conference proceedings for studies evaluating the efficacy of pemetrexed monotherapy or pemetrexed combined with platinum or any other chemotherapeutic agent in EGFR–mutation-positive NSCLC after EGFR-TKI failure. We extracted data of primary outcomes of interest (progression-free survival [PFS], overall survival [OS], and overall response rate [ORR]). The weighted median PFS, OS, and ORR were then calculated. Of 83 potentially relevant studies, eight (three randomized studies and five retrospective studies) were identified (involving 1,193 patients) and included in this systematic review, with 640 patients receiving pem regimens. The weighted median PFS, median OS, and ORR for patients treated with pem regimens were 5.09 months, 15.91 months, and 30.19%, respectively. Our systematic review results showed a favorable efficacy profile of pem regimens in NSCLC patients with EGFR mutation after EGFR–TKI failure.

Outcomes of endoscopic biliary drainage in pancreatic cancer patients with an indwelling gastroduodenal stent: a multicenter cohort study in West Japan

Gastroduodenal and biliary obstruction may occur synchronously or asynchronously in advanced pancreatic cancer, and endoscopic double stent placement may be required. EUS-guided biliary drainage (EUS-BD) often is performed after unsuccessful placement of an endoscopic transpapillary stent (ETS), and EUS-BD may be beneficial in double stent placement. This retrospective multicenter cohort study compared the outcomes of ETS placement and EUS-BD in patients with an indwelling gastroduodenal stent (GDS). We recorded the clinical outcomes of patients at 5 tertiary-care medical centers who required biliary drainage after GDS placement between March 2009 and March2014. Thirty-nine patients were included in this study. Patients' mean age was 68.5 years; 23 (59.0%) were men. The GDS overlay the papilla in 23 patients (59.0%). The overall technical success rate was significantly higher with EUS-BD (95.2%) than with ETS placement (56.0%; P< .01). Furthermore, the technical success rate was significantly higher with EUS-BD (93.3%) than with ETS placement (22.2%; P< .01) when the GDS overlies the papilla. The overall clinical success rate of EUS-BD also was significantly higher than for ETS placement (90.5% vs 52.0%, respectively; P= .01), and there was no significant difference in the incidence of adverse events (ETS, 32.0% vs EUS-BD, 42.9%; P= .65). Endoscopic double stent placement with EUS-BD is technically and clinically superior to ETS placement in patients with an indwelling GDS. EUS-BD should be considered the first-line treatment option for patients with an indwelling GDS that overlies the papilla. ETS placement remains a reasonable alternative when the papilla is not covered by the GDS.