bluuebunny/crossref_metadata_2025 huggingface dataset:
Immune-related adverse events and outcomes during treatment with immune checkpoint inhibitors in non-small cell lung cancer (NSCLC) patients.
Authors: López Gallego Javier , Ayala de Miguel Pablo , Gorospe García Itziar , Rivera Vargas Pablo René , Posada Restrepo Andrea , Aires Machado Jonathan , Alonso Calderón Rubén , Rodríguez García José Manuel , Ceballos Barbancho Eduardo , Acero Caballero Alfonso , Illán Varella Andrea , Quintana Cortés Laura , Borrega Garcia Pablo
Published: May 2020

e21662

Background: Immunotherapy of cancer has changed the paradigm of treatment of many tumours, specially non-small cell lung cancer (NSCLC). The use of immune-checkpoint inhibitors (ICI) is associated in some patients with the development of new immune-related adverse events (irAEs). Our aim was to study if there is any correlation between the appearence of irAEs and the efficacy of ICI. Methods: We collected data of 104 patients diagnosed of advanced NSCLC and treated with ICI in monotherapy at our institution between December 2015 and December 2019. Several variables as clinical, tumour-related and therapeutical were included and univariate and multivariate Cox regression analysis were performed. Results: Cohort of 84 men and 20 women, median age of 67 years and 86% with Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1. 89% were active or ex-smokers and 11% had never smoked. 60% of patients had adenocarcinoma histology, 39% scamous and 1% had not otherwise specified (NOS) carcinoma histology. 3% of patients had III-B stage at the moment of start of immunotherapy, 37% M1a, 30% M1b and 30% M1c. 2 patients had driver mutations in EGFR gene. 41% of patients had unknown PDL1 status; 14% had no PDL1 expression, 14% low expression and 31% high expression. 78% of patients had progressed to prior line of treatment, while 22% were treatment-naive. irAEs occured in 65% of patients; 12% developed grade 3 to 4 toxicities. More frequent irAEs were fatigue (54%) and rash (27%). Significant statistical variables in univariate analysis were included in multivariate analysis by Cox regression. The appearence of any grade of iRAE was associated with improved progression-free survival (PFS) (median 17.9 months vs 5.1 months; HR 7.12; p = 0.008). Those patients who experimented any grade of irAE were more likely to achieve stabilization or response than those who suffered progression of disease (HR 13.00; p < 0.001; 95% CI [3.47-48.78]. The use of corticosteroids during treatment with ICI was not related to the benefit of treatment. Conclusions: Appearence of immune-related adverse effects during treatment with ICI was associated with better outcomes in our population. The use of corticosteroids during immunotherapy didn´t have any deleterious effect on the efficacy of treatment.
Radiogenomics for the prognosis in advanced non-small cell lung cancer patients receiving bevacizumab.
Authors: Li Butuo , Jiang Chao , Pang Linlin , Fan Bingjie , Ding Mingjun , Sun Xindong , Yu Jinming , Wang Linlin
Published: May 2020

e21669

Background: In the new era of immunotherapy, the regimen based on bevacizumab is still one of the standard options for treatment of advanced non-small cell lung cancer (NSCLC) patients without driver mutations. However, the prognostic factors for bevacizumab are still missing. We aimed to determine the integrative value of computed tomography (CT), epigenetic modifications, clinicopathological and systemic inflammatory factors for predicting the survival of advanced NSCLC patients with bevacizumab. Methods: Clinicopathological parameters, dynamic systemic inflammatory factors, radiomics features, and DNA methylation profiling in advanced non-squamous NSCLC patients receiving first- or second- line bevacizumab plus chemotherapy were included in this study. The prognostic radiomics signature were constructed by least absolute shrinkage and selection operator (LASSO) Cox analysis. A multi-omics prediction nomogram for progression-free survival (PFS) based on radiomics, clinicopathological and systemic inflammatory features was established and independently validated. Furthermore, radiomics signature-related DNA methylation were submitted to functional enrichment analysis. Results: Total of 272 patients were included in analysis, 224 in training cohort and 48 in validation cohort. Five radiomics features, including Information Measure Corr1, Inverse Variance, Local Std Max, Gauss Area, Spherical Disproportion, were finally selected to construct radiomics signature with the AUC of 0.71. Smoking history, anatomical feature, liver metastasis, LDH4, NLR2 and radiomics signature were found to be independent prognostic factors for PFS. A multi-omics nomogram was developed based on these features in training cohort with the C-index of 0.76, and external validated with the C-index of 0.75. The tissue slices of 20 patients receiving bevacizumab were used for DNA methylation profiling. Functional enrichment analysis indicated widespread and statistically significant associations between radiomics features and DNA methylation changes which involved in several pathways related to angiogenesis and immune system, such as Notch signaling pathway, small GTPase Rho signal transduction, TGFβ signal transduction. Conclusions: This multi-omics nomogram integrating radiomics, clinicopathological, systemics inflammatory features improved the prediction of PFS in advanced NSCLC patients receiving bevacizumab. And the radiomics signature were found to be related to angiogenesis and immune status.
The potential of a CLIA-certified prognostic/predictive molecular test to address the rising costs of non-small cell lung cancer.
Authors: Mann Michael J , Jablons David , O'Day Ken , Su Wayne , Sundar Padma
Published: May 2020

e21671

Background: Treating recurrences of non-small cell lung cancer (NSCLC) is increasingly expensive but still rarely curative. Disease free survival (DFS) among resected stage I-IIA patients remains only 50-70%. Guidelines advocate adjuvant therapy in “high-risk” patients in this population to reduce these costly and deadly recurrences, but recognize that conventional criteria have not been validated to stratify risk or predict benefit. A CLIA-certified, commercially available 14-gene expression risk profile (DetermaRx) has been extensively validated among stage I-IIA non-squamous NSCLC patients; prospective data now suggest that the test predicts improved DFS with adjuvant therapy. We therefore studied the potential economic impact of this molecular test on early stage NSCLC. Methods: Model variables included: relative increase in DFS with adjuvant treatment of molecular intermediate- and high-risk patients (25.5%; range 12.3-41.3%); cost of adjuvant ($8,760; $8,144-$9,376) or late-stage ($284,500; $224,900-345,200) treatment; and compliance with recommendations for adjuvant therapy (75%; 60-90%). Ranges were based on: historical trials and recent prospective data, published cost literature, and published survey data, respectively. Parameters were varied in a multifactorial, one-way sensitivity analysis to assess the impact of parameter uncertainty. Results: Reduction of recurrences with implementation of the 14-gene assay resulted in an average cost savings of $11,608/patient (potential systems savings of ~$450 million), even when including the cost of molecular risk stratification ($4000/patient) and of cisplatin-based adjuvant chemotherapy for molecular high- and intermediate-risk patients. Lower bound assumptions for relative improvement, cost of care, and compliance yielded persistent savings of $3,699, $8,091 and $8,486, respectively. Conclusions: Utilization of this predictive molecular risk stratification assay in the management of stage I-IIA non-squamous NSCLC has the potential to significantly reduce lung cancer costs in an era of targeted therapy and immunotherapy, while at the same time improving DFS and saving lives.
A pilot study of nintedanib in molecularly selected patients with advanced non-small cell lung cancer (NSCLC) (NCT02299141).
Authors: Waqar Saiama Naheed , Rawat Usha , Morgensztern Daniel , Shah Sanjana , Ward Jeffrey P. , Devarakonda Siddhartha Hk , Rearden Timothy Patrick , Gao Feng , Govindan Ramaswamy
Published: May 2020

e21694

Background: Nintedanib is a small molecule tyrosine kinase inhibitor targeting VEGFR1-3, PDGFR and FGFR. The purpose of the study was to evaluate the response rate for patients with advanced non-small cell lung cancer (NSCLC) with mutations in TP53, VEGFR1-3, PDGFR-A, PDGFR-B, and FGFR1-3 treated with nintedanib as part of an open label, single arm pilot study. Methods: Patients with advanced NSCLC previously treated with platinum-doublet chemotherapy with ECOG PS≤1 and adequate organ function were enrolled. Exclusion criteria included cavitary or necrotic tumors with invasion of major blood vessels, history of recent thromboembolic events, predisposition to bleeding or thrombosis, myocardial infarction and weight loss > 10% within past 6 months. Nintedanib was administered at a dose of 200 mg orally twice daily during each 28-day cycle until disease progression or unacceptable toxicity. Response assessments were performed every 8 weeks. The primary endpoint was overall response (ORR) by RECIST 1.1. Secondary endpoints included progression-free survival (PFS) and correlating outcomes with specific mutations. Results: Between 5/7/2015 and 11/15/2019, 20 patients were enrolled to study. The median age was 66 years, 15/20 (75% were females), 17/20 (85%) had received prior immunotherapy and 11/20 (55%) had received at least three prior lines of systemic therapy. The ORR was 15% with 3/20 partial responses (PR), while 12 patients had stable disease (SD), with disease control (PR+SD≥16 weeks) rate of 60% (12/20). The median progression-free survival and median overall survival were 18 weeks (95% CI: 8-31) and 48 weeks (95% CI:15-56) respectively. All three responders had a TP53 mutation and had received prior immunotherapy. There were nine grade 3 events including transaminitis in 20%, while one patient each (5%) experienced hyperbilirubinemia, anorexia, fatigue, hypertension, and nausea. Grade 4 events included transaminitis (10%) and cerebral edema (5%). There was one grade 5 cardiac event, which was unrelated to nintedanib. Conclusions: In this pilot study in heavily pretreated and molecularly selected patients with metastatic NSCLC, nintedanib showed modest activity. Clinical trial information: NCT02299141.
Clinical outcome of local treatment in synchronous oligometastatic non-small cell lung cancer (NSCLC): A preliminary analysis of prospective data.
Authors: Li Shangbiao , Zhu Xiaoxia , Zheng Zhihao
Published: May 2020

e21698

Background: Advanced NSCLC is a heterogeneous disease, a large number of retrospective studies suggested that patients with oligometastases may achieve long-term survival from aggressive local treatment. However, relevant prospective studies were limited. Therefore, we prospectively evaluated the role of local treatment in synchronous oligometastatic NSCLC. Methods: We prospectively identified 50 NSCLC patients newly diagnosed with synchronous oligometastases (≤5)in two centers between 11/2017 and 12/2019, among whom there were 24 patients from a randomized clinical trial NCT03119519. Patients were given first-line systemic therapy according to the latest NCCN guidelines with either local radiotherapy or surgery to thoracic primary tumor and/or radiotherapy to metastases. They were divided into combined therapies (Tx), systemic Tx and untreated groups. Kaplan Meier Survival analysis was used to compare progression free survival (PFS) and overall survival (OS) among the groups. Results: Median age of all patients was 61 years old (range: 27-80 years) and median follow up was 5.7 months (range: 0.5-23.3 months). A total of 10 deaths were observed. In the combined Tx group, 23 patients received radiotherapy, and 2 patients received primary surgical resection. The median OS of the combined Tx group (n = 25), the systemic Tx group (n = 19) and the untreated group (n = 6) was 18.47 months, not reached, 3.27 months, respectively. Compared with the untreated group, the combined group and the systemic Tx group had better OS (hazard ratio [HR] = 0.1047, p = 0.0001; HR = 0.1125, p= 0.0006). However, the patients in the combined group did not show significant OS advantage compared with those in the systemic Tx group (HR = 1.376, p= 0.667). In addition, we conducted an ITT analysis in clinical trial NCT03119519, in which 8 progression events were observed. There was no significant difference in PFS between the combined group (n = 13) and the systemic Tx group (n = 11) (13.2 months vs. not reached, HR = 1.317, p= 0.7015; 1-year PFS: 74% vs. 54%, p = 0.7015, respectively). Conclusions: Current analysis shows that the addition of local treatment to first-line systemic Tx does not improve PFS and OS. More samples, further updated data and selection of potential beneficer are necessary. Funding: 81972853, 81572279, 2016J004, LC2019ZD009, 2018CR033. Clinical trial information: NCT03119519.
Immunotherapy efficacy of strong positive PD-L1 expression non-small cell lung cancer (NSCLC) patients: A systematic review and meta-analysis.
Authors: Lu Hongmin , Cui Longgang , Bai Yuezong , Zhang Yuzi , Zhao Zhengyi
Published: May 2020

e21701

Background: Immune-checkpoint inhibitors (ICIs) based therapy has been approved as the new 1L standard of care in advanced PD-L1 strong positive (>=50%) non-small cell lung cancer (NSCLC). However, little is known about the differences of efficacy between monotherapy and combined therapy of checkpoint inhibitors. We did a systematic review and meta-analysis to assess the heterogeneity of efficacy between monotherapy and combined therapy in 1L PD-L1 strong positive NSCLC patients. Methods: We systematically searched PubMed, Cochrane library, Embase and and major conference proceedings from January 2000 to November 2019 for randomized controlled trials that had available hazard ratios (HRs) for death according to PD-L1 expression (>=50%). The primary outcome was the difference in overall survival (OS). We calculated the pooled overall survival HR and 95% CI in monotherapy and combined therapy in 1L PD-L1 strong positive NSCLC patients using a random-effects model. Results: A total of 2211 publications were retrieved through initial literature search, 10 randomized controlled trials were included for this meta-analysis. No statistical differences were found between ICIs monotherapy and combined therapy (HR 1.09, 95% CI 0.88- 1.35). Subgroup analysis showed that immune monotherapy has similar effects to immune combined chemotherapy (HR 1.24, 95% CI 0.90-1.71) and immune combined immunotherapy (HR 1.01, 95% CI 0.81-1.27). Conclusions: For PD-L1 strong positive (>=50%) NSCLC patients, ICIs monotherapy had similar efficacy when compared with ICIs combination therapy.
A randomized phase II multi-institutional trial of anlotinib plus docetaxel versus docetaxel in EGFR-wild-type non-small cell lung cancer (NSCLC) patients after progression on first-line platinum-base chemotherapy: ALTER-L018.
Authors: Wu Lin , Wu Zhijun , Xiao Zemin , Weng Jie , Ma Zhongsha , Chen Yanhua , Xiao Maoliang , Cao Yongqing , Duan Huaxin , Cao Peiguo , Zhang Hui , Wang Qianzhi , Li Jia , Xu Yan , Pu Xingxiang , Li Kang
Published: May 2020

e21703

Background: Anlotinib is an oral VEGFR, FGFR, PDGFR and c-Kit tyrosine kinase inhibitor, which can prolong both PFS and OS of refractory advanced NSCLC patients in phase III trial: ALTER0303. The combination of docetaxel and ramucirumab/nintedanib had been demonstrated activity in the second line therapy setting for NSCLC. We performed ALTER-L018 to assessed the safety and efficacy of anlotinib with docetaxel in EGFR-wild type refractory advanced NSCLC (NCT03624309). Methods: Patients (pts) with EGFR-wild type refractory advanced NSCLC, who failed to first-line platinum-based chemotherapy, were randomized to group A(anlotinib: 12mg QD from day 1 to 14 of a 21-day cycle +docetaxel: 75mg/m2 Q3W) and group B(docetaxel: 75mg/m2 Q3W). The primary end points is PFS, and secondary end points include OS, ORR, DCR and safety. Results: Between January and December 2019, 36 pts were enrolled at 10 institutions in Hunan China, with 31(15 in group A, 16 in group B) of these individuals being evaluable for treatment efficacy and safety. Pt characteristics(group A/ group B): median age: 55(39-70)/57(44-67); male: 73%/81%; non-squamous NSCLC: 86%/75%. Median PFS were 5.3 months (95%CI:2.76-7.85) in group A and 2.3 months (95%CI, 1.14-3.46) in group B (HR 0.42; 95% CI:0.16-1.13; p = 0.047); In group A and B, ORR and DCR were 26.67% versus 0%(p = 0.043), 60.00% versus 31.25%(p = 0.16), respectively. Among 31 pts, 89% of treatment-related AEs (TRAEs) were grade 1 or 2, and the most common TRAEs in group A were hand-foot syndrome, pruritus and insomnia of 13%(2/15) each; in group B were alopecia, constipation and anemia of 12%(1/16) each. Toxicities≥grade 3(TRAEs) included: neutropenia, leukopenia, diarrhea and hrombocytopenia, 6.6%(1/15) each in group A. There was 1 grade 5 AE in group A. Conclusions: This combination of anlotinib and docetaxel with significant difference PFS prolonging and manageable safety profile, is a viable option in relapsed NSCLC, should be considered following progression on platinum-based chemotherapy. It will be further explored in a randomized phase III trial. Clinical trial information: NCT03624309.
Impact of chemoradiotherapy (CRT) on immune-related tumor microenvironment and the efficacy of anti-PD-1 therapy after the recurrence of CRT in unresectable locally advanced NSCLC patients.
Authors: Shirasawa Masayuki , Yoshida Tatsuya , Motoi Noriko , Matsumoto Yuji , Shinno Yuki , Okuma Yusuke , Goto Yasushi , Horinouchi Hidehito , Yamamoto Noboru , Watanabe Shun-ichi , Ohe Yuichiro
Published: May 2020

e21719

Background: Chemoradiotherapy (CRT) followed by durvalumab as maintenance therapy prolonged progression-free survival (PFS) and overall survival (OS) in unresectable locally advanced NSCLC (LA-NSCLC). Additionally, the history of radiotherapy and CRT has been reported to increase the efficacy of PD-1 blockade in advanced NSCLC patients. We evaluated the efficacy of anti-PD-(L)1 antibody therapy after CRT failure, and how CRT changes the status of PD-L1 expression on tumors and tumor infiltrated lymphocytes (TILs) in tumor microenvironment (TME) in unresectable LA-NSCLC patients. Methods: We retrospectively reviewed unresectable LA-NSCLC patients treated with CRT between December 2007 and December 2018, and evaluated the efficacy of PD-1 blockade after CRT failure. We also analyzed PD-L1 (clone: 22C3) expression on tumor cells, and CD8 positive TILs using the paired specimens that had been obtained pre-CRT and post-CRT failure. Results: We identified 422 patients who received CRT. Median follow-up was 36.1 months (range 2.7–138.1 months). Among these patients, sixty-five patients who had progressed post-CRT received anti-PD- (L)1 therapy (PD-1 therapy: 61 patients, PD-L1 therapy: 4 patients). Response rate (RR) and PFS of anti-PD-(L)1 therapy were 48% (95% CI, 35–60) and 8.7 (95% CI, 4.5–13.0) months. The RR and PFS did not differ according to PD-L1 expression levels (Table). Of the 18 patients, 9, 7, and 2 showed upregulation in PD-L1 expression or down- or no change, respectively, post-CRT. In contrast, the density of CD8 positive TILs in TME increased by CRT treatment ([pre-CRT]: median, 110 ± 239 /mm2 vs. [post-CRT]: median, 470 ± 533 /mm2, p = 0.025). Conclusions: The clinical outcome of anti-PD-(L)1 therapy after CRT failure in LA-NSCLC patients could be better than advanced NSCLC patients, but did not differ according to PD-L1 expression levels. The efficacy of PD-(L)1 therapy enhanced by CRT treatment could be due to the infiltration of CD8 T-cells into TME. [Table: see text]
Retrospective analysis of clinical outcomes of patients with advanced non-small cell lung cancer (NSCLC) exposed to immunotherapy: The experience of the Oncology Center of Hospital Moinhos de Vento.
Authors: Venero Fernando Castilho , Andrade Helena , Roithmann Sergio , Casarotto Fernanda Cano , Lima Geraldine Eltz de , Geib Guilherme
Published: May 2020

e21720

Background: Lung cancer has the highest mortality rate among malignant neoplasms worldwide. Most cases present an advanced stages. From the last few years, the target drugs and immunotherapy (IO) have emerged as important therapeutic options in this scenario. In Brazil, in 2018, this disease was responsible for 8.7% of cases of malignant neoplasms in men and 6.2% of cases in women. When looking at data from our state, Rio Grande do Sul, the highest rates in the country are noted, with an estimated rate of 40.22 cases for every 100 thousand men and 20.49 cases for every 100 thousand women. Although the available trials point to significant improvements in the clinical outcomes, the real impact of using such treatments on patients in our community practice, real-world scenario, is unknown. Methods: Through the detailed analysis of the institutional electronic medical record, we included patients with metastatic NSCLC, followed up on an outpatient basis at the Oncology Center of Hospital Moinhos de Vento, who had received at least one dose of nivolumab, pembrolizumab or atezolizumab, either as monotherapy or in combination therapy with chemotherapy, in any line of cancer treatment, in the period from January 2015 to June 2019. Primary endpoint was overall survival (OS) and secondary endpoints were time-to-treatment discontinuation (TTD) and treatment-related toxicity (TRT). Results: 41 patients met criteria. The sample consisted of patients with a mean age at diagnosis of 67.7 years, the majority being male (53.7%), stage IVB disease (53.7%), previously smokers (61%) and with non-squamous NSCLC (75.6%). Central nervous system (CNS) metastases were present in 26.8% of patients. About 51.3% (n = 21) received IO as second line or later treatment. At this group, nivolumab was the main IO (81%). The median OS in the first line (1L) of treatment was not reached while in second line and beyond was 10.0 months (3.4 - 16.5), with no statistical difference (p = 0.071). The median TTD was higher in patients whose received IO at 1L (17.0 months vs 7.0 months, p = 0.045). Pneumonitis was the main toxicity being present in 7.1% of patients. Colitis, thyroiditis and hepatitis were seen in one patient each. Conclusions: in general, we were able to observe that in our real-world scenario, IO is well tolerated, regardless of the treatment line. In addition, OS met the findings of the landmark clinical trials.
Impact of adherence to National Comprehensive Cancer Network (NCCN)-recommended first-line therapy on treatment duration for patients with advanced non-squamous non-small cell lung cancer (NSCLC).
Authors: John Ani K , Yang Baiyu , Shah Roma
Published: May 2020

e21727

Background: Identification of molecular alterations can provide essential information to guide personalized treatment selection for advanced non-small cell lung cancer (aNSCLC) patients. However, in routine oncology practice, not all eligible patients receive biomarker testing and receive treatment according to the testing results following the National Comprehensive Cancer Network (NCCN) guideline. We aim to examine the impact of adherence to guideline-recommended therapy on the duration of treatment in a real-world setting. Methods: Patients diagnosed with non-squamous aNSCLC (stage IIIB and above) and received the first-line of therapy (FLOT) between 2011 and 2019 from the nationwide Flatiron Health electronic health record-derived de-identified database were included in this analysis. Adherence was defined as using any NCCN guideline-recommended FLOT consistent with a patient’s biomarker testing results (EGFR, ALK, ROS1, BRAF and PD-L1) assessed up to 90 days before and/or 14 days after the FLOT start date. Non-adherence was defined as not receiving guideline-recommended FLOT based on the above-mentioned biomarker results, or patients treated without evidence of biomarker testing. Median time to treatment discontinuation (TTD) of FLOT was calculated using Kaplan-Meier analysis. Unadjusted and adjusted Cox proportional hazards regression models were used to evaluate the association between guideline adherence and TTD. Results: A total of 17,137 eligible patients were included (67.5% adherent, 32.5% non-adherent). Mean age at diagnosis was 67 years (SD: 10 years). The majority of patients (92%) received care at a community clinic, and 73% reported having insurance plans. Overall, 87.2% had discontinuation of FLOT, including 84.9% in the adherent group and 92.0% in the non-adherent group. The median TTD was 155 days (95% CI 153-159) in the adherent group and 128 days (95% CI 125-132) in the non-adherent group. Adherent patients had a lower risk of FLOT discontinuation in the unadjusted analysis (hazard ratio [HR] 0.78, 95% CI 0.76-0.81), which remained significant after adjusting for potential confounders including age at FLOT start, sex, history of smoking, and stage at initial diagnosis (HR 0.76, 95% CI 0.74-0.79). Conclusions: Among non-squamous aNSCLC patients, the majority of patients were adherent to NCCN guidelines. Adherence was associated with lower risk of discontinuation and longer duration of FLOT.
Brain metastasis in lung cancer: Are there any predictive risk factors?
Authors: Ait Batahar Salma
Published: May 2020

e21740

Background: Lung cancer is the first cause of death by cancer worldwide. Brain metastases in lung cancer are associated to an even poorer prognosis of this cancer. Identifying patients with a higher risk of developing brain cancer may help their prognosis by including systematic brain radiotherapy to their treatment. But what are risk factors of brain metastasis occurrence in lung cancer patients? Methods: To answer this question, we conducted a case control study comparing two groups of lung cancer patients. The cases group included 35 lung cancer patients with brain metastasis at the moment of diagnosis while the control group was made of 49 lung cancer patient with no brain metastasis at the moment of diagnosis. Many parameters were compared between the two groups such as: professional exposure, type and duration of smoking, medical history, clinical and radiological presentation as well as the histological type of the carcinoma. Results: The mean age was 56 for the cases group and 61 for the control group. Nonsmokers represented 14% in the cases group and 4% in the control group. The average smoking was 34 pack-year for the cases group and 31 pack-year for the control group and in both groups 51% of patients smoked a mixture of tobacco and Cannabis. 36% of the control group patients had an exposure to a professional carcinogen while 48% of the cases group patients had one. Digital clubbing was found in 62% of cases group patients and in 51% of the control group patients. 17% of the cases group patients had two more metastases outside the lungs and other than the brain ones while this rate was only 6% for the control group patients. The mean level of LDH (Lactate Dehydrogenase) was 340 U/L for the cases group and 342 U/L for the control group while the CRP (C- reactive protein) one was 78 mg/L for the cases group and 59 mg/L for the control group. The main histological type found in both groups was Adenocarcinoma (25% in the cases group and 18% in the control group) followed by the poorly differentiated carcinoma in the cases group and the squamous cell carcinoma in the control group. Small cell carcinoma was found in 5% of the patients with brain metastases and in 8% of the patients without brain metastases. Conclusions: Patients with brain metastases have a higher professional carcinogens exposure, a higher percentage of nonsmokers, more digital clubbing, and higher CRP levels than patients with no brain metastases. They also have more than one metastasis at the moment of the diagnosis and the predominant histological types are Adenocarcinoma and poorly differentiated carcinoma.
Interim results of prospective pilot phase II trial of concurrent anti-PD-1 and stereotactic radiosurgery (SRS) for melanoma and NSCLC patients with brain metastases (NCT02858869).
Authors: Khan Mohammad Khurram , Nasti Tahseen , Yushak Melinda Lynne , Lawson David H. , Switchenko Jeffrey M. , Wallington David , Kleber Troy , Kirmani Khadija , Owonikoko Taofeek Kunle , Ramalingam Suresh S. , Ahmed Rafi
Published: May 2020

e22002

Background: The safety and efficacy of concurrent radiotherapy (SRS) and single agent (anti-PD-1) checkpoint inhibitor have not been established. We report the first results of an interim analysis from a prospective pilot phase II trial of cocurrent anti-PD-1 (pembrolizumab) and SRS for brain metastases Methods: Food and Drug Administration (FDA) and Institutional Review Board (IRB) approval were obtained to conduct a prospective trial with three different radiation dose arms (Arm A: 6 Gray (Gy) in 5 fractions (fx), 9 Gy in 3 fractions, and 18-21 Gy in single fraction) in combination with Pembrolizumab. Patients with not more than 10 brain metastasis who have not received prior brain radiation were eligible. Routine statistical methods were used to estimate control of brain metastases within the irradiated volume (local control, LC), anywhere intra-cranial control (AICC), progression free survival (PFS), and overall survival (OS). RECSIST 1.1 criteria were used to assess. Safety was monitored using NCI CTCAE v 4.0 criteria for toxicity assessment while intracranial and extracranial treatment response was assessed according to RECIST 1.1 criteria. Patients were enrolled from 2017-2020. Results: We report interim analysis from the first 18 patients of planned 36 patients who have completed treatments on each of the three different radiation dose arms (12 patients per arm). All patients received PD1 on day 0, immediately followed by SRS within 2-3 days. At 6 months, the LC (94.0% [CI: 65-99.1]), AICC (70.6% [CI: 43.1-86.65]), PFS (50% [24.5-71]), and OS (77.4% [50.3-90.9]) were higher than expected with either SRS alone or PD1 alone, and appear to be comparable to dual checkpoint, but with much less toxicity. No grade 4 or grade 5 toxicity was noted. The primary endpoint of safety, based on the absence of grade 3 CNS toxicity at 3 months was met with all three radiation dose arms. Overall rate of grade 1-3 toxicity was also within acceptable range. Conclusions: Preliminary prospective results of concurrent SRS and single agent pembrolizumab for brain metastases in melanoma and NSCLC supports this strategy as a safe and promising option compared with dual agent therapy. Clinical trial information: NCT02858869.
Correlation of nivolumab 480 mg Q4W with better survival than other nivolumab monotherapy schedule in metastatic melanoma patients.
Authors: Simeone Ester , Mallardo Domenico , Giannarelli Diana , Festino Lucia , Vanella Vito , Trojaniello Claudia , Vitale Maria Grazia , Palla Marco , Scarpato Luigi , Capone Mariaelena , Madonna Gabriele , Curvietto Marcello , Esposito Assunta , Hauber Federica , Sandomenico Fabio , Cavalcanti Ernesta , Caraco Corrado , Mainardi Paolo , Grimaldi Antonio Maria , Ascierto Paolo Antonio
Published: May 2020

e22008

Background: Nivolumab (nivo) 480 mg (Q4W) flat dose has already been assessed for safety compared to other drug dose regimens in clinical trials [1]. However, few data about melanoma patients treated in real life are available. The aim of our study was to evaluate safety and efficacy in metastatic melanoma pts treated with different schedules of nivo in clinical practice. Methods: We analyzed data from n.124 metastatic melanoma patients who were treated from Jun 2016 to Oct 2019 at NCI of Naples. 83/ 124 (67%) were treated with nivo 480 mg Q4W, and 41/124 (33%) with other schedules (n.26 [63%] with 3 mg/kg, and 15 [37%] with 240 mg Q2W). All patients were stage IV, and n.44/124 (35%) were B-RAF mutated. Nivo was administered as first line in n.95 patients (77%), n. 24 [19%] as second line, and 5 (4%) as third line. Among B-RAF mutated patients, n.23/44 [52%] received a first line with a target-based regimen. According to our previous work [2] we calculated Body Mass Index (BMI). In 93/124 pts the BMI was < 25 (75%), while in 31/124 (25%) BMI was ≥ 25. In the table are summarized other clinical characteristics. Hazard Ratios and their 95% confidence intervals (95% CI) were estimated with the Cox model. Association between factors was evaluated with the chi-square test. Results: Our data suggests that nivo 480 mg (Q4W) correlates with a better OS compared with other regimens (HR = 0.48; [95% CI: 0.24-0.96; p = 0.04]). Moreover, better OS trend was also observed in pts with BMI > 25 (HR = 0.48; [95% CI: 0.33-1.74]; p = 0.51) and with B-RAF mutation (HR = 0.53; [95% CI: 0.25-1.14); P = 0.10]). The incidence of any grade toxicities did not differ according the dosage. Conclusions: This retrospective analysis showed a trend of better outcome with nivo 480. This observation warrants further investigation in a larger cohort of pts. [Table: see text]
Role of AXL in metastatic melanoma and impact of TP-0903 as a novel therapeutic option for melanoma brain metastasis.
Authors: Tizpa Eemon , Young Hannah J , Bonjoc Kimberley-Jane C. , Chang Chou-Wei , Liu Yilun , Foulks Jason M , Chaudhry Ammar
Published: May 2020

e22021

Background: Melanoma brain metastases (MBM) are common with a median overall survival of 4-5 months. Although immunotherapies have improved clinical outcomes and have doubled overall survival in MBM, there is a high incidence rate of relapse caused by drug resistance. AXL, a receptor tyrosine kinase (RTK), is associated with drug resistance and metastasis in many cancers. The activation of AXL via trans-phosphorylation regulates multiple signaling pathways that induce tumor survival, metastasis, drug resistance, and epithelial-to-mesenchymal transition (EMT). In MBM, AXL is upregulated and associated with disease progression, promoting cell invasion and migration. This suggests that targeting AXL can be a novel strategy to overcome treatment-related resistance in MBM. TP-0903, an investigational small molecule inhibitor of AXL, has shown efficacy in reversing the mesenchymal phenotype and re-sensitizing resistant cancer cells to targeted therapies in heme malignancies, pancreatic, and breast cancer. We aim to investigate the efficacy of TP-0903 in MBM. Methods: The Cancer Genome Atlas (TCGA) data was utilized to investigate the signaling pathways downstream of AXL that are upregulated in advanced melanoma. Nine signaling molecules including AKT1, mTOR, and PAK4 were analyzed to identify any correlation between gene expression levels and overall survival. Four metastatic melanoma cell lines were used to evaluate the effect of TP-0903 on cell viability and active AXL downregulation was assessed in vitro through MTS cell viability assays and Immunoblotting. Wound closure assays were executed to understand the functional consequences of AXL downregulation. Results: In all nine genes, high expression levels confer poor survival probability. Cell viability assays of four malignant melanoma cell lines showed that TP-0903 treatment resulted in IC50 values ranging from 32 – 692 nM. Western blot analysis indicated that TP-0903 reduced the levels of phosphorylated AXL in malignant melanoma cell lines. In addition, increasing TP-0903 concentrations reduced the rate of cell migration in these malignant melanoma cell lines. Conclusions: AXL plays a role in EMT, treatment resistance, and metastasis in MBM, resulting in poor survival. Our findings suggest TP-0903 is effective in reducing cell migration, inhibit metastasis, and can be a potential therapeutic option in MBM.
Lack of evidence to support large-panel genomic testing in treatment selection for malignant melanoma.
Authors: Dimitrova Maya , Kim Min Jae , Donnelly Douglas M. , Giles Keith M. , Moran Una , Weber Jeffrey S. , Osman Iman , Jour George
Published: May 2020

e22027

Background: Genomic profiling informs clinical decision-making for malignant melanoma (MM) as specific tumor mutations can be treated with targeted therapy (TT). However, given the range of different panel sizes available and increasing use of immune checkpoint inhibitors (ICI), the clinical significance of upfront, large-panel genomic profiling in MM remains undetermined. Herein, we investigate the impact of panel size and targetable mutational status on first-line treatment selection and outcomes of MM patients from 9 different institutions. Methods: We analyzed data for 1,341 MM patients from 3 cohorts. Cohort 1 included 169 patients enrolled at NYULH and profiled with the 50 gene Ion Torrent panel (IT). Cohort 2 included 256 patients enrolled at MSKCC, profiled with the 400-gene MSK-IMPACT panel (MSK-I). Cohort 3 included 916 patients enrolled at 7 different sites, profiled with whole exome sequencing (WES). Data for cohorts 2 and 3 were extrapolated from publicly available data using cBioPortal. We tested associations between molecular data, treatment choice and overall survival (OS), adjusting for baseline characteristics when available. Results: Treatment information was available for 100%, 25%, and 0% of patients in cohort 1, 2 and 3, respectively. Stage was available for all of cohort 1 (III, n = 68; IV, n = 101) and cohort 2 (III, n = 2; IV, n = 254), but in only 23% of cohort 3 (III, n = 184; IV n = 25). For the IT and MSK-I, BRAF and NRAS were among the top 5 most commonly mutated genes, whereas for WES only BRAF was in the top 5. In cohort 1, 36% (16/45) of BRAF MUT patients received first-line TT vs 25% (66/256) in cohort 2. There was no significant difference for BRAF MUT patients treated with ICI vs. TT in cohort 1 in OS (P = 0.19), nor for BRAF MUT patients from cohort 1 treated with ICI vs. those from cohort 2 treated with TT (OS P = 0.762). Conclusions: Publicly available datasets provide population-level data, however the heterogeneity and deficiency of reported clinical information limits their value and calls for data standardization. Without evidence of clear clinical benefit of a larger panel size, there is a rationale for adopting smaller, more cost effective panels in MM.
Access to innovation through the French Expanded-Access Program and clinical trials in patients with malignant melanoma.
Authors: Christen Claire , Belgodere Laetitia , Guillot Bernard , Kerouani-Lafaye Ghania , Brunel Liora , Turcry Florence , Monard Adrien , Grude Francoise , Guyader Gaëlle , Boudali Lotfi , Albin Nicolas
Published: May 2020

e22030

Access to innovation through the French Expanded-Access Program and clinical trials in patients with malignant melanoma Background: The arrival of immunotherapy (IT) and targeted therapy (TT) has constituted a revolution in the treatment of metastatic melanoma (MM) since the 2010s. The major challenge was to allow these new treatments to make them available as soon as possible. France has effective tools such as clinical trials (CT) and an expanded-access program (EPA) (through temporary use authorizations (ATU) and temporary use recommendations (RTU)) allowing the use of innovative drug without marketing authorization (MA) in case of therapeutic “dead-end”. Methods: Real-time data collection of nominal and cohort ATU, RTU (between 01/09/2009 and 01/09/2019), and CT authorizations (from 01/12/2017 to 01/09/2019) filed and evaluated by the French national agency for medicines and health products safety (ANSM) in the MM from internal databases. Clinical data of the cATU come from the summary reports produced by the laboratory. Results: 45 CT were authorized in MM, including 51% in early phases and 44% in phase II/III, mainly in the metastatic stage (86%) and with an industrial promoter (73%). IT and TT (63% and 24% respectively) are the most used in experimental arms, mostly in combination. Through the EPA, 3 RTUs were authorized in the adjuvant treatment of MM, 14 drugs benefited of a nATU and 5 obtained a cATU. This has treated 6538 patients (28% of nATU and 72% of cATU). The anti-PD1 and combination therapy of BRAF and MEK inhibitors are the most used, mainly in combination. 80% of the indications are from the second line. The duration of availability of the ATU is 9,85 months before obtaining the MA. Efficacy data in patients receiving cATU of vemurafenib and combination of cobimetinib and vemurafenib showed respectively the following objective response rate (ORR): at 8 weeks of treatment, ORR = 57,7% and 54,7%; at 20 weeks, ORR = 36,7% and 54,7% (IR criteria). For pembrolizumab, at 12 weeks, ORR = 29,7% and at 24 weeks, ORR = 40% (irRC criteria). All of these drugs obtained a MA and an inscription on the reimbursement list after the health technology assessment. Conclusions: Thanks to CT and the French EPA, patients were able to benefit from innovative treatments at an early stage of MM.
Phase II study of apatinib combined with temozolomide in advanced melanoma patients after failure of anti-PD-1 therapy.
Authors: Zhou Li , Cui Chuanliang , Si Lu , Chi Zhihong , Sheng Xinan , LIAN BIN , Wang Xuan , Tang Bixia , Mao Lili , Yan Xieqiao , Bai Xue , Guo Jun
Published: May 2020

e22043

Background: Immunotherapy is first-line therapy in advanced melanoma. Because of different subtypes and gene alterations, the efficacy of immunotherapy in Asians, mostly comprised of acral and mucosal melanoma, is lower than Caucasians. There are no standard treatment strategies after immunotherapy failure. Chemotherapy and anti-angiogenesis combination showed emerging evidence of activity in mucosal and acral melanoma. This study was to evaluate the efficacy of apatinib combined with temozolomide in advanced immunotherapy refractory melanoma patients (pts). Methods: This prospective, single-arm, phase II study recruited unresectable or metastatic melanoma pts after failure of anti-PD-1 therapy. Other treatment including targeted therapy, chemotherapy, and clinical trials were allowed. Primary endpoint was progression-free survival (PFS), and secondary endpoints were objective response rate (ORR), disease control rate (DCR), and adverse events (AEs). According to the dose recommended from previous phase I study, pts were given apatinib 500 mg every day and temozolomide 300mg day 1-5, 28 days for one cycle. Results: 31 pts were enrolled between Feb 2018 and Dec 2018, with 8 males, average age 55 yrs (range 24 – 69 yrs). 13 pts (41.9%) were from mucosal primaries, 9 (29.0%) acral, 5 (16.1%) cutaneous (non-acral), and 4 (12.9%) unknown primaries. One had BRAF mutation, 1 CKIT, and 3 NRAS mutations. 9 pts (29.0%) were classified as IIIc/M1a, 9 (29.0%) M1b, and 13 (41.9%) M1c. 18 pts (58.1%) had elevated lactate dehydrogenase level. All pts progressed after anti-PD-1 therapy. In addition, 29.0% pts received dacarbazine based chemotherapy, 29.0% paclitaxel or albumin-bound paclitaxel, and 3.2% had dabrafenib with trametinib. Up to Dec 2019, 30 pts can be evaluated for efficacy. Median follow-up time was 10.2 mos (2.0-23.1 mos). There were 5 confirmed PRs and 20 SDs. ORR was 16.7%, DCR 83.3%, and median PFS was 5.0 mos (95%CI 1.9-8.1 mos). Median overall survival was 10.1 mos (95%CI 4.7-15.5 mos). Common AEs were hypertension (51.6%), proteinuria (41.9%), elevated transaminase (25.8%), thrombocytopenia (16.1%), and hand-foot syndrome (16.1%). Most were grade 1-2. Grade 3-4 AEs included proteinuria (12.9%), hypertension (6.4%), and thrombocytopenia (6.4%); 10 pts required a dose reduction, and 1 had to discontinue. No treatment-related deaths were observed. Conclusions: In pts progressed after anti-PD-1 therapy, apatinib in combination with temozolomide demonstrated promising efficacy and favorable safety profile. Clinical trial information: NCT03422445.
Patterns of hepato-pulmonary metastasis and their impact on clinical outcomes in uveal melanoma.
Authors: Javed Asad , Al Saleh Abdullah S. , Block Matthew Stephen , McWilliams Robert R. , Yan Yiyi , Kottschade Lisa A. , Markovic Svetomir
Published: May 2020

e22052

Background: Metastatic Uveal Melanoma (MUM) is a rare tumor with poor prognosis following development of liver metastasis. We hypothesized that patterns of metastasis in Uveal Melanoma correlate with clinical outcomes. Methods: We retrospectively reviewed patients with MUM at Mayo Clinic, Rochester from January 1999 to August 2019. Patients were stratified into two groups based on the pattern of hepatic and pulmonary metastasis at the time of diagnosis of metastatic disease: Group 1 (≤5 liver metastasis or lung metastasis) and Group 2 ( > 5 liver metastasis without lung metastasis). Baseline characteristics were compared between both groups. Survival analysis was performed using the Kaplan Meier method. Univariate and multivariate analysis were performed for Overall Survival (OS). Results: 147 patients were included in the study (n = 67 Group 1; n = 80 Group 2). In Group 1, 49/67 patients presented with ≤5 liver metastasis and 18/67 had lung metastasis without liver metastasis. Median OS for Group 1 was significantly longer than Group 2 (38 vs. 15 months; p < 0.0001) (Table). On univariate analysis, predictors for OS were: Pattern of Metastasis, ECOG PS > 0, Time to metastasis > 60 months, and Surgical metastatectomy. Pattern of Metastasis was an independent predictor for OS in a multivariate model that included these predictors (p = 0.0004). Group 1 patients were more likely to undergo surgical metastatectomy compared to group 2 (21.5% vs. 1.3%; p < 0.0001). Interestingly, the median time to metastasis from diagnosis of UM was significantly longer for Group 1 as compared to Group 2 (67 vs. 24.5 months; p < 0.0001). Conclusions: Limited (≤5) liver metastasis or lung metastasis (without liver metastasis) at diagnosis predict favorable clinical outcomes in MUM. The occurrence of such metastasis following a significantly longer time from primary diagnosis suggests the existence of a distinct sub-type of metastatic disease with relatively indolent behavior. [Table: see text]
Patient-reported outcomes among patients with resected high-risk melanoma (AJCC7 IIIB, IIIC, M1a, M1b) randomized to low- or high-dose adjuvant Ipilimumab (ipi) versus high-dose interferon alfa-2b (HDI): Health-related quality of life (HRQL) analysis of ECOG-ACRIN E1609.
Authors: Tarhini Ahmad A. , Zheng Yue , Lee Sandra J. , Hodi F. Stephen , Rao Uma , Cohen Gary Irvin , Sondak Vernon K. , Kirkwood John M. , Wagner Lynne I.
Published: May 2020

e22078

Background: The primary objective of the patient-reported outcomes (PRO) study of E1609 patients (pts) was to compare overall HRQL among pts receiving ipi (ipi10, ipi3) or HDI. We hypothesized that ipi would be superior to HDI in HRQL. Secondary analyses compared HRQL and GI distress between ipi10 and ipi3. Methods: PROs were administered among pts enrolled from NCI Community Oncology Research Program (NCORP) sites at baseline, every 12 weeks (wks) during treatment, and every 24 wks off-treatment for one year. Differences between ipi arms and HDI in overall HRQL at 12 wks (completion of ipi induction) was defined a priori as the primary outcome. HRQL was assessed using the 27-item Functional Assessment of Cancer Therapy –General (FACT-G) total score. GI toxicity was a secondary outcome measured by the 11-item FACIT-Diarrhea (FACIT-D) scale. Two sample t-test was used to compare scores between arms. Results: 548 pts completed PROs at baseline and 334 at 12 wks. Among 322 (59%) pts with PRO data at both time points, mean FACT-G total change scores from baseline to 12 wks were significantly lower (indicating less decline in HRQL) among pts randomized to ipi10 (-4.9,SD:14.1) or ipi3 (-3.4 points,SD:13.2) vs. HDI (-12.9, SD:14.1), p < 0.05 for both ipi10 vs. HDI and ipi3 vs. HDI. Mean FACIT-D change scores indicated higher GI distress from baseline to 12 wks among pts randomized to ipi10 (-3.7, SD:6.9) or ipi3 (-2.2, SD:5.1) vs HDI (-0.7, SD:2.7), p < 0.05 for both comparisons. In comparing ipi10 to ipi3, FACT-G total and FACIT-D total change scores from baseline to wk 12 were comparable. Conclusions: Overall decline in HRQL from baseline to completion of ipi induction was less among pts receiving ipi compared to HDI. Pts randomized to ipi reported a greater increase in diarrhea compared to HDI. HRQL and diarrhea were comparable between ipi3 and ipi10. Our findings are based on PRO data, thus increase our confidence in capturing pts’ experience with treatment from the pt’s perspective. Clinical trial information: NCT01274338. [Table: see text]