EGFR-activating mutations and treatment with tyrosine-kinase inhibitors (TKI) to revert poor-prognosis (PP) associated with liver metastases (LM) in stage IV non-small cell lung cancer (NSCLC) patients (pts).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e19106-e19106
Author(s):  
Eduardo Castanon ◽  
Maria D. Lozano ◽  
Juan Pablo Fusco ◽  
Estefania Arevalo ◽  
Omar Esteban Carranza ◽  
...  
Keyword(s):  
Survival Rate ◽  
Clinical Outcome ◽  
Kinase Inhibitors ◽  
Stage Iv ◽  
Egfr Mutations ◽  
Wild Type ◽  
Molecular Alterations ◽  
Activating Mutations ◽  
One Year ◽  
Egfr Tki

e19106 Background: LM appear in 20-30% of pts diagnosed with NSCLC and they confer PP. However, whether the clinical outcome of NSCLC pts with LM harboring molecular alterations in EGFR, KRAS and EML4-ALK genes is substantially different depending on their distinct status is still unknown. Methods: A total of 268 consecutive stage IV NSCLC pts were included. The tumor molecular analysis for EGFR, KRAS and EML4-ALK was available in 205 pts (76.5%), 136 pts (50.7%) and 31 pts (11.6%), respectively. An EGFR mutation was observed in 32 pts (15.6%), KRAS was mutated in 28 pts (20.6%) and EML4-ALK gene rearrangement was observed in 3 pts (9.6%). We aimed to determine whether the molecular status of EGFR, KRAS and EML4-ALK has an impact on the clinical outcome of stage IV NSCLC pts. Results: Most of the pts were men (71.3%). The most common histology was adenocarcinoma (59.3%). Overall, 34% of the pts showed LM at any time of the disease course. Among the whole cohort, median OS for LM pts was 16 months vs 42 months for pts with metastases other than LM (p<0.001). Among pts with LM and EGFR mutations, the one-year survival rate was 85.7% vs 54.3% for pts with LM and EGFR wild-type (p=0.03). We analyzed whether pts received EGFR TKI or standard chemotherapy (SC). For the subgroup of pts carrying EGFR mutations and receiving TKI, the 18-month survival rate was 75% for those showing LM vs 80% (p=0.44) for those without LM. In contrast, for the subgroup of EGFR wild-type pts receiving SC, the 18-month survival rate was 32.4% for those showing LM vs 74.9% for those without LM (p<0.001). No impact of KRAS or EML4-ALK molecular alterations on OS of pts with LM was observed. Conclusions: The presence of LM at any time of the disease curse negatively impacts on the clinical outcome of NSCLC pts. However, the presence of EGFR activating mutations significantly improves the OS of those with liver spread, reaching a similar OS to subjects with no LM. Pts with EGFR mutations and LM may revert the PP associated to LM when an EGFR TKI is prescribed.

Tyrosine kinase inhibitors (TKI) treatment of non-small cell lung cancer (NSCLC) patients (p) based on EGFR mutations (m) status in serum only.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e19088-e19088
Author(s):  
Laia Capdevila ◽  
Enric Carcereny ◽  
Itziar de Aguirre ◽  
Sara Cros ◽  
Cristina Queralt ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Complete Response ◽  
Phase Iii ◽  
Egfr Mutations ◽  
Molecular Alterations ◽  
Former Smokers ◽  
Tki Treatment ◽  
Ecog Ps ◽  
Egfr Mutated ◽  
Egfr Tki

e19088 Background: Treatment of EGFR mutated NSCLC p with EGFR TKIs in phase III trials has shown improved efficacy to standard chemotherapy. However, it can be difficult to obtain sufficient tumor tissue for analysis of EGFR m status in a large proportion of p. Nevertheless, so far, no data exists for NSCLC p treated according to EGFR m status in serum alone. Methods: We reviewed our database to identify EGFR mutated p, excluding those for whom status was available in both serum and tissue. We analyzed p treated with an EGFR TKI for whom EGFR m status was known in serum only (status in tissue unknown due to insufficient material). At the same time, we reviewed p in whom EGFR m status in tissue was available over the same period in order to compare clinical characteristics and efficacy parameters: PFS, ORR and overall survival (OS). EGFR m analysis was performed in cell free circulating DNA (cfDNA)isolated from serum and plasma using the QIAmp DNA blood mini kit. Results: 9 p with EGFR m detected in serum and 33 p with EGFR m in tissue were included. In EGFR mutated p in serum, median age 63; male 55.6%; non-smokers 33.3%; former smokers 44.4%; ECOG PS 0-1 66.7%; adenocarcinoma 77.8%; deletion19 33.3%, L858R 66.7%; EGFR TKI treatment in 1st line 44.4%; 2nd or 3rd line 55.6%. ORR: complete response (CR) 22.2%; partial response (PR) 22.2%; stable disease (SD) 22.2%; progressive disease (PD) 11.1%. 2p had poor PS and died prior to evaluation. mPFS 4.7 months (mo). mOS 18 mo. In p with EGFR m in tissue, median age 61; male 36.4%; non-smokers 75.8%; former smokers 24.2%; adenocarcinoma 87.9%; deletion19 75.8%; L858R 24.2%; 1st line 54.5%; 2nd or 3rd line 45.5%. ORR: CR 15.2%; PR 57.6%; SD 12.1%; PD 15.2%. mPFS 8.9 mo. mOS 32.7 mo. The multivariate analysis for OS considering EGFR m in serum differed according to PS (PS 0-1 16.6 mo vs PS > 2 5.2 mo). Conclusions: Obtaining sufficient tissue from NSCLC p for analysis of EGFR m status and other molecular alterations can be difficult. Determination of EGFR m in serum alone is feasible, yields similar results to mutation status in tissue, and could permit us to take treatment decisions.

scholarly journals EGFR-Mutated Squamous Cell Lung Cancer and Its Association With Outcomes

2021 ◽  
Vol 11 ◽  
Author(s):  
Rui Jin ◽  
Ling Peng ◽  
Jiawei Shou ◽  
Jin Wang ◽  
Yin Jin ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Squamous Cell ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Lung Squamous Cell Carcinoma ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Wild Type ◽  
Egfr Tki ◽  
Egfr Tkis

BackgroundThe therapeutic efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in advanced EGFR-mutant lung squamous cell carcinoma (SCC) patients remains uncertain. Furthermore, the factors underlying the responsiveness have not been fully investigated. We therefore investigated the link between genomic profiles and EGFR-TKI efficacy.Material and MethodsWe consecutively enrolled stage IV, EGFR-mutant, and EGFR-TKI–treated patients with SCC. Patients with EGFR wild-type lung SCC and EGFR-mutant lung adenocarcinoma were consecutively enrolled as controls, and next-generation sequencing (NGS) was performed.ResultsIn total, 28 EGFR-mutant lung SCC, 41 EGFR-mutant lung adenocarcinoma, and 40 EGFR wild-type lung SCC patients were included. Among the patients with EGFR mutations, shorter progression-free survival (PFS) was observed in SCC compared to adenocarcinoma (4.6 vs. 11.0 months, P&lt;0.001). Comparison of the genomic profiles revealed that EGFR-mutant SCC patients had similar mutation characteristics to EGFR-mutant adenocarcinoma patients, but differed from those with EGFR wild-type SCC. Further exploration of EGFR-mutant SCC revealed that mutations in CREBBP (P = 0.005), ZNF217 (P = 0.016), and the Wnt (P = 0.027) pathway were negatively associated with PFS. Mutations in GRM8 (P = 0.025) were associated with improved PFS.ConclusionsEGFR-mutant lung SCC has a worse prognosis than EGFR-mutant adenocarcinoma. Mutations in other genes, such as CREBBP, ZNF217, GRM8, or Wnt that had implications on PFS raise the possibility of understanding mechanisms of resistance to EGFR-TKI in lung SCC, which will aid identification of potential beneficial subgroups of patients with EGFR-mutant SCCs receiving EGFR-TKIs.

scholarly journals EGFR Mutation Analysis of Circulating Tumor DNA Using an Improved PNA-LNA PCR Clamp Method

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Kana Watanabe ◽  
Tatsuro Fukuhara ◽  
Yoko Tsukita ◽  
Mami Morita ◽  
Aya Suzuki ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Egfr Mutation ◽  
Resistance Mutation ◽  
Biological Data ◽  
Egfr Mutations ◽  
Plasma Samples ◽  
Wild Type ◽  
T790m Mutation ◽  
Activating Mutations ◽  
Tki Treatment

Introduction. Rebiopsies have become more crucial in non-small cell lung cancer (NSCLC). Instead of invasive biopsies, development of collecting biological data of the tumor from blood samples is expected. We conducted a prospective study to assess the feasibility of detection of epidermal growth factor receptor (EGFR) mutation in plasma samples.Method. NSCLC patients harboring EGFR activating mutations, who were going to receive EGFR-tyrosine kinase inhibitors (TKIs) as first-line treatment, were enrolled in this study. Plasma EGFR activating mutations and the T790M resistance mutation were analyzed by an improved PNA-LNA PCR clamp method, characterized by a 10-fold or more sensitivity compared with the original methods.Result. Six patients with wild-type EGFR and 24 patients with EGFR mutations were enrolled in this study. Pretreatment plasma samples achieved sensitivity of 79%. The 6 patients with wild-type EGFR were all negative for plasma EGFR mutations. At the time of disease progression, plasma T790M mutation was detected in 8 of 16 cases. Absence of T790M before and during TKI treatment and disappearance of activating mutations during TKI treatment were considered as predictors of EGFR-TKIs efficacy.Conclusion. We were able to detect EGFR mutations in plasma samples by using an improved PNA-LNA PCR clamp method.

scholarly journals Better Progression-Free Survival in Elderly Patients with Stage IV Lung Adenocarcinoma Harboring Uncommon Epidermal Growth Factor Receptor Mutations Treated with the First-line Tyrosine Kinase Inhibitors

Cancers ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 434 ◽  
Author(s):  
Ming-Ju Tsai ◽  
Jen-Yu Hung ◽  
Mei-Hsuan Lee ◽  
Chia-Yu Kuo ◽  
Yu-Chen Tsai ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Egfr Mutations ◽  
First Line ◽  
Free Survival ◽  
Younger Patients ◽  
Epidermal Growth

Patients with lung adenocarcinoma harboring common epidermal growth factor receptor (EGFR) mutations usually have a good response rate (RR) and longer progression-free survival (PFS) to EGFR tyrosine kinase inhibitors (TKIs). However, the treatment efficacy to uncommon EGFR mutations remains controversial. We, therefore, performed a retrospective study, screening 2958 patients. A total of 67 patients with lung adenocarcinoma harboring uncommon EGFR mutations were enrolled and 57 patients with stage IV diseases receiving a first-line EGFR TKI were included for further analyses. The patients were classified into 27 (47%) “a single sensitizing uncommon mutation”, 7 (12%) “multiple sensitizing mutations”, 5 (9%) “a sensitizing mutation and a resistant uncommon mutation”, and 18 (32%) “other resistant uncommon mutations”. No significant difference was noted in PFS or overall survival (OS) between groups. Patients receiving different first-line EGFR TKIs had similar PFS and OS. The elder patients had a significantly poorer performance status than the younger patients but a significantly longer PFS than the younger patients (median PFS: 10.5 vs. 5.5 months, p = 0.0320). In conclusion, this is the first study to identify that elderly patients with stage IV lung adenocarcinoma harboring uncommon EGFR mutation might have a longer PFS. Large-scale prospective studies are mandatory to prove our findings.

scholarly journals Mutation status and immunohistochemical correlation of EGFR mutations in gastrointestinal stromal tumors

2021 ◽  
Vol 24 (1) ◽  
pp. 67-72
Author(s):  
H Ozkayalar ◽  
MC Ergoren ◽  
G Tuncel ◽  
S Kurt ◽  
E Cevik ◽  
...  
Keyword(s):  
Gastrointestinal Stromal Tumors ◽  
Kinase Inhibitors ◽  
Treatment Options ◽  
Growth Factor Receptor ◽  
Egfr Mutations ◽  
Stromal Tumors ◽  
Molecular Alterations ◽  
Treatment Regimes ◽  
Research Areas ◽  
Turkish Patients

Abstract Being one of the leading causes of cancer deaths worldwide and their resistance to conventional treatment methods, made gastrointestinal stromal tumors (GISTs) one of the hot topics in medical research areas in the past decade. To investigate molecular alterations underlying the tumor is of great importance to be able to develop new, targeted treatment options. In this study, GIST samples obtained from 40 Turkish patients were analyzed for actionable epidermal growth factor receptor (EGFR) mutations that are related to treatment regimes in non small cell lung cancer (NSCLC) to understand whether EGFR expression is altered in GISTs. Established alterations in EGFR can make the use of tyrosine kinase inhibitors possible, which are currently used in cancer therapy, especially in NSCLC. Our results indicated that EGFR mutations are rare in GISTs. Further research is needed to sequence whole coding regions of the gene to investigate new actionable mutations in EGFR in an increased sample size.

scholarly journals Targeting Oncogenic BRAF: Past, Present, and Future

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1197 ◽  
Author(s):  
Zaman ◽  
Wu ◽  
Bivona
Keyword(s):  
Kinase Inhibitors ◽  
Therapy Resistance ◽  
Resistance Mechanisms ◽  
Genetic Alterations ◽  
Therapeutic Strategies ◽  
Wild Type ◽  
Braf Mutations ◽  
Molecular Alterations ◽  
Mutant Braf

Identifying recurrent somatic genetic alterations of, and dependency on, the kinase BRAF has enabled a “precision medicine” paradigm to diagnose and treat BRAF-driven tumors. Although targeted kinase inhibitors against BRAF are effective in a subset of mutant BRAF tumors, resistance to the therapy inevitably emerges. In this review, we discuss BRAF biology, both in wild-type and mutant settings. We discuss the predominant BRAF mutations and we outline therapeutic strategies to block mutant BRAF and cancer growth. We highlight common mechanistic themes that underpin different classes of resistance mechanisms against BRAF-targeted therapies and discuss tumor heterogeneity and co-occurring molecular alterations as a potential source of therapy resistance. We outline promising therapy approaches to overcome these barriers to the long-term control of BRAF-driven tumors and emphasize how an extensive understanding of these themes can offer more pre-emptive, improved therapeutic strategies.

Lung Cancer in 2013: State of the Art Therapy for Metastatic Disease

2013 ◽  
pp. 339-346
Author(s):  
Frances A. Shepherd ◽  
Paul A. Bunn ◽  
Luis Paz-Ares
Keyword(s):  
Lung Cancer ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Stage Iv ◽  
Poor Performance ◽  
Initial Therapy ◽  
Egfr Mutations ◽  
Molecular Testing ◽  
Molecular Features ◽  
Platinum Doublet

Lung cancer is the leading worldwide cause of cancer death and the majority of patients present with metastatic stage IV disease. At diagnosis, clinical, histologic, and molecular features must be considered in therapeutic decision-making for systemic therapy. Molecular testing for at least epidermal growth factor receptor ( EGFR) and ALK should be performed in all patients before therapy. Platinum doublet chemotherapy may be considered for “fit” patients who do not have a molecular driver genetic abnormality. Bevacizumab can be considered for addition to the doublet in patients with nonsquamous cancers who have no contraindications. A pemetrexed combination is considered only in nonsquamous histology. Patients with EGFR mutations or ALK fusions should be treated with erlotinib or crizotinib, respectively, even in patients with tumor-related poor performance. The tyrosine-kinase inhibitors (TKIs) may be continued until multisite, symptomatic progression. For patients initially treated with a platinum doublet, maintenance chemotherapy with pemetrexed, erlotinib, gemcitabine, or possibly docetaxel is an option with selection based on clinical features, histology, type of initial therapy, and response to first-line therapy.

scholarly journals The Clinical Significance of RAS, PIK3CA, and PTEN Mutations in Non-Small Cell Lung Cancer Using Cell-Free DNA

2020 ◽  
Vol 9 (8) ◽  
pp. 2642
Author(s):  
Won Jin Chang ◽  
Jae Sook Sung ◽  
Sung Yong Lee ◽  
Eun Joo Kang ◽  
Nak-Jung Kwon ◽  
...  
Keyword(s):  
Clinical Significance ◽  
Stage Iv ◽  
Egfr Mutations ◽  
Sequencing Analysis ◽  
Downstream Signaling ◽  
Pathway Activation ◽  
Activating Egfr Mutation ◽  
Tki Treatment ◽  
Deep Sequencing Analysis ◽  
Egfr Tki

Mutations in the EGFR gene downstream signaling pathways may cause receptor-independent pathway activation, making tumors unresponsive to EGFR inhibitors. However, the clinical significance of RAS, PIK3CA or PTEN mutations in NSCLC is unclear. In this study, patients who were initially diagnosed with NSCLC or experienced recurrence after surgical resection were enrolled, and blood samples was collected. Ultra-deep sequencing analysis of cfDNA using Ion AmpliSeq Cancer Hotspot Panel v2 with Proton platforms was conducted. RAS/PIK3CA/PTEN mutations were frequently detected in cfDNA in stage IV NSCLC (58.1%), and a high proportion of the patients (47.8%) with mutations had bone metastases at diagnosis. The frequency of RAS/PIK3CA/PTEN mutations in patients with activating EGFR mutation was 61.7%. The median PFS for EGFR-TKIs was 15.1 months in patients without RAS/PIK3CA/PTEN mutations, and 19.9 months in patients with mutations (p = 0.549). For patients with activating EGFR mutations, the overall survival was longer in patients without RAS/PIK3CA/PTEN mutations (53.8 months vs. 27.4 months). For the multivariate analysis, RAS/PIK3CA/PTEN mutations were independent predictors of poor prognosis in patients with activating EGFR mutations. In conclusion, RAS, PIK3CA and PTEN mutations do not hamper EGFR-TKI treatment outcome; however, they predict a poor OS when activating EGFR mutations coexist.

Never-smoking women with lung cancer from the Spanish WORLD07 database.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 1531-1531 ◽  
Author(s):  
Dolores Isla ◽  
Mariano Provencio ◽  
Margarita Majem ◽  
Enriqueta Felip ◽  
Nuria Vinolas ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Contraceptive Use ◽  
Previous History ◽  
Stage Iv ◽  
Egfr Mutations ◽  
Malignant Tumours ◽  
Treatment Data ◽  
History Of ◽  
Egfr Tki ◽  
History Of Cancer

1531 Background: Gender differences in lung cancer (LC) have been reported, but with many unresolved issues yet. Tobacco causes the majority of women lung cancer (WLC), although the rate of never-smoking WLC is higher than in men. Several factors may play etiologic roles, and an in-depth understanding is needed. Methods: WORLD07 is a Spanish prospective, multicenter, epidemiologic female-specific LC database sponsored by ICAPEM, a professional association committed with WLC research. In order to improve the knowledge on never-smoking WLC, information has been extracted from WORLD07 database. Results: From October/2007 to October/2011, 1371 newly diagnosed WLC were included in an e-database from 32 centers, 539 (39.3%) never-smoking. Patient (p) characteristics: median age 71.1 years(y); median age of menarche 13y.; motherhood 91.2% (median 2.3 children, median age at first child 26.4y); oral contraceptive use 11.9%; postmenopausal 88.9% (median age of menopause 49y); HRT 5.2%; second-hand smokers 40% (work-exposure 17.1%, home-exposure 88.8%); obesity 16.3%; familiar history of cancer 39.9% (LC 29.8%); previous history of cancer 13% (breast/lung/cervix: 41.4/5.7/2.9%); current LC histology(%): adenocarcinoma/SqCC/LCC/SCLC: 83.4/6.2/5.5/3.9; EGFR mut+ (268 p analyzed): 55.5% (exon 19/20/21(%): 61.1/7.4/36.9); TNM NSCLC I/II/III/IV(%): 14/3.3/19.8/60.3. Treatment: EGFR-TKI in p EGFR mut+, stage IV(1st-/2nd-line)(%): 51.7/15.4; stage IV NSCLC (1st-line/2nd-line): platinum-based CT 42.5%, EGFR-TKI 33.5%, combinations with bevacizumab 2.9% / EGFR-TKI 15.8%. Overall survival: median 27 months(m), 1/2-y(%) 74.8/55.2; stage IV NSCLC: median 20.5m, 1/2-y(%) 67/46; EGFR-mut+ p: median 27.3m, 1/2-y(%) 75/54.3. Conclusions: According to our e-database, WLC showed high rates of never-smokers (39.3%), and of relatives diagnosed with malignant tumours (39.9%, ≅1/3 LC). Adenocarcinoma was the most frequent histology (76.1%), and more than half of the cases analyzed harboured EGFR mutations. Although 40% were second-hand smokers, further investigations are warranted. Survival outcomes remain satisfactory, as expected from this selected subgroup of p. Additional epidemiologic and treatment data will be presented.

Phase II study of pemetrexed (Pem) and cisplatin (Cis) plus cetuximab (Cet) followed by Pem and Cet maintenance therapy in patients (Pts) with advanced nonsquamous non-small cell lung cancer (NSCLC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 7554-7554
Author(s):  
Gerald Schmid-Bindert ◽  
Vittorio Gebbia ◽  
Frank Mayer ◽  
Edurne Arriola ◽  
Diego Marquez-Medina ◽  
...  
Keyword(s):  
Survival Rate ◽  
Performance Status ◽  
Objective Response ◽  
Stage Iv ◽  
Study Drug ◽  
Progression Free Survival ◽  
Free Survival ◽  
Secondary Endpoints ◽  
Grade 3 ◽  
One Year

7554 Background: A prospective, nonrandomized, multicenter study was conducted to assess the effect of adding cet to pem and cis in pts with advanced nonsquamous NSCLC. Methods: 113 Caucasian performance status 0-1 pts received 1st line pem (500 mg/m2) and cis (75 mg/m2) on day 1 (21d cycle) for 4-6 cycles and cet (400 mg/m2 loading dose followed by 250 mg/m2) weekly. Non-progressive pts received pem 500 mg/m2 on day 1 (21d cycle) plus cet (250mg/m2 weekly) until progression. Pts received vitamin B12/folic acid and dexamethasone. Primary endpoint was objective response rate (ORR) (RECIST 1.0). Secondary endpoints were progression free survival (PFS), 1 year survival rate, translational research (TR) and safety. Results: Pts’ characteristics: median age 59.7 years, 64% male, 50% PS 0, 92% stage IV, and 78% adenocarcinoma. All pts completed ≥ 1 cycle of induction therapy and 45% and 43% completed ≥ 1 cycle of maintenance with pem and cet, respectively. ORR (n=109) was 38.5% (80% CI 32.2-45.1), all partial responses. Disease control rate (response/stable disease) was 59.6% (80% CI: 53.1-65.9). Median PFS was 5.82 months (80% CI: 4.40-6.70). One year survival rate was 0.45 (80% CI: 0.39-0.51). Significant associations were seen between high EGFR by IHC and increased PFS (cytoplasm: HR=0.46, p=0.035; membrane: HR=0.41, p=0.008), and between high nuclear TTF-1 and increased ORR (OR=7.73, p=0.021) / PFS (HR=0.21, p<0.001) / OS (HR=0.25, p=0.035). Of 113 pts evaluated for safety, 73 (64.6%) pts had drug related CTC Grade 3/4 adverse events (AE): most frequent were neutropenia (14.2%), rash (15%), and vomiting (8.8%). Drug related serious AEs were reported in 27.4% pts: most frequent were anemia (5.3%), neutropenia (5.3%), vomiting (3.5%), and rash, renal failure, diarrhea and fatigue (1.8% each). There were 2 potential on-study drug related deaths (sudden death and large intestinal perforation). Conclusions: Pem, cis and cet appeared efficacious and tolerable. These results support further evaluation in a randomized trial. The TR outcomes are hypothesis generating given the study’s size and nonrandomized nature.

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