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Survival benefit with erlotinib maintenance therapy in patients with advanced non-small-cell lung cancer (NSCLC) according to response to first-line chemotherapy
Abstract
In the placebo-controlled phase III SATURN study, maintenance erlotinib after first-line chemotherapy demonstrated significantly prolonged progression-free survival (PFS) and overall survival (OS) in the overall study population of patients with advanced non-small-cell lung cancer (NSCLC).
After four cycles of platinum-based doublet chemotherapy, patients without progressive disease (PD) were randomised to erlotinib (150 mg/day) or placebo until PD or unacceptable toxicity. In this pre-planned analysis, data are assessed according to response to first-line chemotherapy (complete/partial response [CR/PR] or stable disease [SD]).
Following first-line chemotherapy, 889 non-PD patients were included in the intention-to-treat population (55% SD; 44% CR/PR; <1% unknown response). Erlotinib maintenance therapy significantly prolonged PFS in both the SD (hazard ratio [HR] = 0.68; P < 0.0001) and CR/PR (HR = 0.74; P = 0.0059) groups, while OS was significantly prolonged in the SD group only (HR = 0.72; P = 0.0019). The erlotinib-related OS benefit in the SD group remained significant across subgroups, irrespective of tumour histology and/or EGFR mutation status. The incidence of adverse events was similar in the SD group and the overall population, and erlotinib treatment did not negatively impact quality of life.
Patients with advanced NSCLC and SD following first-line platinum-based doublet chemotherapy derive a significant OS benefit from maintenance erlotinib therapy.
... In another study, Erlotinib was established as an option for second-line therapy in advanced NSCLC patients [37,41]. Survival was found to be improved significantly in many patients who were treated with Erlotinib and with a delayed time to the deterioration of main symptoms for the disease, without negatively affecting the QoL of patients [42]. The benefits are of particular importance, provided that the survival benefits with Erlotinib are comparable to those with the cytotoxic chemotherapeutic agents approved as second-line therapy, such as pemetrexed and docetaxel [43,44]. ...
... A significant increase in overall survival and progression-free survival was reported in the Erlotinib arm as compared to placebo in the overall intention-to-treat (ITT) population (all the patients who are randomized, are analyzed also, no patients are excluded) as well as in EGFR immunohistochemistry (IHC)-positive tumor patients. These benefits were found across molecular and clinical biomarker subgroups, without any impairment in QoL [42]. ...
Background:
Cancer is one of the significant causes of morbidity and mortality in patients globally. Lung cancer, among other cancers, remains to be one of the principal causes of deaths in both men and women. The most common type of lung cancer is the non-small-cell lung cancer (NSCLC). Apart from lung cancer, pancreatic cancer is also one of the common cancers currently.
Objective:
The assessment of QoL in erlotinib-treated patients can also prove to be very useful in the establishment of this drug as the main treatment option for the patients with pancreatic and lung cancer.
Methods:
Therapies that target EGFR-mediated signalling are the latest keystones for treating these two types of cancers. They comprise of two main treatment modalities: firstly, against the extracellular fields, that include monoclonal antibodies and secondly, mechanisms that create interferences in the signalling pathways, primarily the small molecule tyrosine kinase inhibitors.
Results:
Quality of life (QoL) is one of the key advantages in erlotinib therapy over chemotherapy.
Conclusion:
The present review reports the role of erlotinib in improving the quality of life of cancer patients especially in NSCLC and pancreatic cancers. The studies or trials establishing the relations between erlotinib and QoL are discussed in detail in this review.
... Tumors harboring activating mutations in EGFR are amenable for therapeutic intervention using tyrosine kinase inhibitors (TKIs) (8). First-generation EGFR TKIs include adenosine triphosphate (ATP)-competitive kinase inhibitors erlotinib and gefitinib and second-generation irreversible inhibitors afatinib and dacomitinib, both generations showing clinical benefit in patients with activating mutations in EGFR (9)(10)(11)(12). However, patients eventually develop resistance to these inhibitors, which is frequently accompanied by a gatekeeper mutation, T790M, in exon 20 (13)(14)(15)(16)(17). ...
Background:
Non-small cell lung cancer (NSCLC) harboring activating mutations in the gene encoding epidermal growth factor receptor (EGFR) is amenable for targeted therapy with tyrosine kinase inhibitors (TKIs). Eventually, resistance to TKI-therapy occurs resulting in disease progression. A substantial fraction of resistance mechanisms is unknown and may involve alterations in the RNA or protein landscape. MicroRNAs (miRNAs) have been frequently suggested to play roles in various forms of cancer including NSCLC. However, a role of miRNAs in acquired resistance to EGFR TKIs remains elusive. In this work, we aimed to investigate the potential involvement of miRNAs in acquired resistance to the third-generation EGFR TKI osimertinib in NSCLC.
Methods:
We combined miRNA expression profiling with miRNA-inhibitory screening to identify miRNAs involved in conferring resistance to osimertinib. Finally, we validated our top miRNA candidate by profiling longitudinal plasma exosomal RNA from patients receiving osimertinib as second-line therapy in a clinical trial.
Results:
Various miRNAs displayed differential expression in parental versus osimertinib-refractory NSCLC cells. miRNA-inhibitory screening revealed miR-494-3p to partially confer resistance to osimertinib in vitro. Expression of miR-494-3p was significantly elevated in plasma sampled at disease progression compared to plasma sampled at treatment baseline in a cohort of 21 EGFR T790M-mutation positive NSCLC patients receiving osimertinib.
Conclusions:
Our results highlight the need for further therapeutic exploration of miR-494-3p in in vivo models of EGFR-mutant NSCLC.
... In patients with EGFR mutation as well as wild-type tumors, survival advantages with erlotinib were obtained after first/second-line chemotherapy and maintenance treatment. [14,15] The survival benefit of erlotinib does not only depend on the presence of EGFR-sensitizing mutations but additionally other molecular mechanisms and pathogenetic factors probably contribute to its therapeutic effect. [16] Phase III, placebo-controlled trial assessing the effect of gefitinib on survival as after first-line therapy in progressive NSCLC patients with unknown EGFR status revealed significantly better survival in the gefitinib group compared to the placebo group in no-smokers (median OS 8.9 vs. 6.1 months, P = 0.012) and Asian patients (median OS 9.5 vs. 5.5 months, P = 0.01). ...
Background: Adenocancer pathologic subtype, smoking history, and women gender have been known to predict the parameters such as the sensitivity to epidermal growth factor receptor tyrosine kinase inhibitors in advanced non-small cell lung cancer (NSCLC); however, we need new predictive markers as well as driver mutations for better treatment options. The aim of this study is to investigate the predictive role of sarcopenia in lung adenocancer patients treated with erlotinib. Materials and Methods: This study was designed as retrospectively. Skeletal muscle index (SMI) was measured with a single cross-sectional area of the muscle at the third lumber vertebra (L3, cm 2)/(height × height)(m 2). Sarcopenia was defined by median cutoff values of SMI of women (<28.2 cm 2 / m 2) and men (<32.7 cm 2 /m 2). The predictive role of sarcopenia and other parameters was assessed by the cox-regression model. Results: The median age was 56 years (range, 36-84). Median progression-free survival (PFS) was 38 (95% confidence interval [CI]: 21.3-54.6) weeks in the sarcopenic group and 49 (95% CI: 0-101.4) weeks in the nonsarcopenic group (P = 0.053). In multivariate analysis, the presence of sarcopenia and number of metastatis were the independent predictive factors for PFS. Disease control rate and overall survival were not significantly different between sarcopenic and nonsarcopenic groups. Conclusion: We found that the presence of sarcopenia and number of metastasis were a predictive marker in NSCLC patients treated with erlotinib. It is important to recognize sarcopenia early and manage patients accordingly.
... En el ensayo clínico SATURN se demuestra que erlotinib mejora la supervivencia en ambos grupos de pacientes con enfermedad estable, con una mediana de 12,4 meses. (33) En otro estudio, fase III (JMEN), se evalúa la terapia de mantenimiento con pemetrexed con mediana de SG de 13,4 meses también inferior a la alcanzada por el grupo de mantenimiento de CIMAvax-EGF. Otro ensayo fase 3, evalúa la terapia de mantenimiento con bevacizumab/pemetrexed vs bevacizumab solo en CPCNP avanzado no escamoso, y la SV alcanzada es 17,1 meses en el brazo de la combinación versus 13,2 meses con bevacizumab solo. ...
Introducción: Cuba ha desarrollado dos inmunoterapias dirigidas al receptor del factor de crecimiento epidérmico (R-EGF), que han sido registradas como terapia de mantenimiento en pacientes con cáncer de pulmón no microcítico avanzado.
Objetivo: Evaluar la supervivencia de pacientes con cáncer de pulmón no microcítico en estadios avanzados en tratamiento de mantenimiento con CIMAvax-EGF o Nimotuzumab.
Métodos: Se realizó un estudio observacional, longitudinal, prospectivo, entre enero 2017 a enero 2020, en el Hospital Clínico Quirúrgico Hermanos Ameijeiras. La muestra estuvo conformada por 77 pacientes divididos en dos grupos: CIMAvax-EGF (31 pacientes) y Nimotuzumab (46 pacientes). Se evaluó supervivencia global, libre de enfermedad y toxicidad. Se realizó una regresión logística de Cox, y se construyó el gráfico Forest Plot. Se utilizó el sistema RevMan 5.0.Resultados: En ambos grupos de tratamiento predominaron los pacientes mayores de 65 años, color de piel blanca, buen estado general y adenocarcinoma. La supervivencia global y libre de progresión fue de 18,0 y 7,2 meses, en el grupo de vacuna fue superior a los pacientes que recibieron Nimotuzumab, con 11,3 y 5,3 meses, respectivamente. Las toxicidades más frecuentes registradas en los pacientes inmunizados fueron: dolor en el sitio de inyección, fiebre y cefalea en el grupo de vacuna, mientras que la fatiga, náuseas y vómitos, lo fueron en el grupo tratados con Nimotuzumab.
Conclusiones: Los pacientes que recibieron tratamiento de mantenimiento con vacuna Cimavax-EGF obtuvieron mayor supervivencia global y libre de progresión que los pacientes tratados con Nimotuzumab.
Palabras clave: supervivencia; cáncer de pulmón; mantenimiento; CIMAvax-EGF; Nimotuzumab.
... En el ensayo clínico SATURN se demuestra que erlotinib mejora la supervivencia en ambos grupos de pacientes con enfermedad estable, con una mediana de 12,4 meses. (33) En otro estudio, fase III (JMEN), se evalúa la terapia de mantenimiento con pemetrexed con mediana de SG de 13,4 meses también inferior a la alcanzada por el grupo de mantenimiento de CIMAvax-EGF. Otro ensayo fase 3, evalúa la terapia de mantenimiento con bevacizumab/pemetrexed vs bevacizumab solo en CPCNP avanzado no escamoso, y la SV alcanzada es 17,1 meses en el brazo de la combinación versus 13,2 meses con bevacizumab solo. ...
Primer estudio en Cuba que compara la supervivencia en cáncer de pulmón no células pequeñas tratados con inmunoterapia en mantenimiento: CIMAvax y Nimotuzumab.
... The results of our study concur with those of other research that suggest that EGFR-TKI maintenance could be more efficient in wild-type EGFR NSCLC controlled by initial platinum-based therapy (31)(32)(33). Our experiments also show that cisplatin resistance is associated with abnormal activation of EGFR. ...
Background:
Gefitinib is a first-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) that has become first-line treatment for patients with mutant EGFR non-small cell lung cancer (NSCLC). Despite its anti-tumor activity, the benefit of gefitinib in patients with wild-type EGFR NSCLC is debated. This work aimed to evaluate the effects of gefitinib on cisplatin-resistant wild-type EGFR NSCLC cells in in vitro and in vivo animal xenografts.
Methods:
We established a cisplatin-resistant wild-type EGFR NSCLC cell line, H358R, to evaluate the cells' sensitivity to gefitinib compared with that of parental cell line H358. We first tested the p-EGFR of gefitinib's target in H358R and H358 cell line by western blot and immunofluorescence. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), clone formation assay, flow cytometry and annexin V-fluorescein/propidium iodide staining were used to investigate cellular proliferation and apoptosis of H358R/H358 cells treated with gefitinib, and the anti-tumor effect was evaluated in female BALB/c nude mice models of xenografts in vivo.
Results:
EGFR and the downstream node molecules ERK and AKT were significantly more phosphorylated in H358R than in the parental cells and were inhibited by gefitinib. In H358R cells, gefitinib increased the inhibition of cell survival/proliferation, and the promotion of apoptosis in vitro. The increased anti-tumor effect was present also in H358R xenografts in vivo.
Conclusions:
Abnormal activation of EGFR in H358R cells results in enhanced sensitivity to gefitinib. The improved efficacy of gefitinib on cisplatin-resistant wild-type EGFR NSCLC cells suggests that gefitinib as sequential therapy for patients with cisplatin-resistant wild-type EGFR NSCLC should be considered.
... The information about its safety is also generally reported and well-known. Skin rash and diarrhea are the most common adverse events of erlotinib and the event rates were reported as 49.2% for skin rash and 20.3% for diarrhea in the SATURN study [4]. Dose reductions or delays due to these adverse effects may be required, but the first-line therapy remains erlotinib followed with monitoring and appropriate supportive care in many cases. ...
Background
Erlotinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors used to treat EGFR mutation positive non-small-cell lung cancer (NSCLC). Skin rash and diarrhea are well-known and common adverse events in patients receiving erlotinib, whereas other adverse events, including eye, liver, or renal disorders have not been evaluated adequately. This meta-analysis aimed to evaluate the ocular, hepatobiliary, and renal toxicities of erlotinib in patients with NSCLC cancers.
Methods
In total, sixty studies were assessed, and the results of the included studies were quantitatively integrated using meta-analysis. The incidence of ocular, hepatobiliary (alanine aminotransferase [ALT] and bilirubin elevations; other hepatic adverse events), and renal adverse events were estimated. Additionally, the erlotinib-treated groups and the control groups (placebo or other treatment) were compared with respect to ocular disorders and ALT elevation. The study protocol has been registered in the International Prospective Register for Systematic Reviews (PROSPERO) CRD42018093758.
Results
The overall incidence of ocular disorders was 3.30% (95% confidence interval [CI] 2.20%–5.00%). The incidence of ALT elevation, bilirubin elevation, and other hepatobiliary disorders was 6.40% (95% CI 3.90%–10.4%), 3.80% (95% CI 2.30%–6.10%), and 1.00% (95% 0.60%–1.80%), respectively. The incidence of renal disorder was 3.10% (95% CI 1.90%–5.00%). The risk of ocular toxicity in the erlotinib treatment group was significantly increased (risk ratio = 2.91; 95% CI 1.70–4.98) compared to that in the control group. ALT elevation was not significantly different between the two groups.
Conclusion
Based on the results, careful monitoring of ocular toxicity in patients receiving erlotinib should be recommended and closer monitoring of hepatic toxicity should be also recommended in patients with liver-related risk factors.
Terapia de alto costo en el tratamiento del cáncer de pulmón metastásico
CRA8000
Background: Pemetrexed's efficacy, favorable tolerability profile, and ease of administration provided a strong rationale for evaluation as maintenance therapy in patients (pts) with advanced NSCLC. We present the final analyses for all outcomes, including overall survival (OS), from a phase III study of Pem vs. Plac (Ciuleanu, J Clin Oncol 26, 2008, A 8011) in pts with stage IIIB/IV NSCLC who had not progressed on four cycles of platinum-based chemotherapy. Methods: In this double-blind trial, pts were randomized 2:1 to receive Pem (500 mg/m ² , day 1) plus BSC or Plac plus BSC in 21-day cycles until disease progression. All pts received vitamin B 12 , folic acid, and dexamethasone. The final OS analysis was performed using an unadjusted Cox model. Overall α = 0.05 for PFS and OS. Results: In the 663 randomized pts (Pem 441: Plac 222), Pem resulted in significantly better OS (13.4 vs. 10.6 mos [HR 0.79, 95% CI: 0.65–0.95, P = 0.012]). As reported earlier, Pem also had better PFS (P <0.00001) and response (P <0.001) ( Table ). The improvements in PFS and OS were observed primarily in patients with non-squamous histology (PFS HR = 0.47 and OS HR = 0.70). Treatment by histology interaction for OS was significant (P = 0.038). Drug-related grade 3/4 toxicities were higher for Pem (16% vs 4%; P <0.001); specifically, fatigue (5% vs 0.5%) and neutropenia (2.9% vs. 0%). Grade 3/4 toxicities did not increase significantly in pts who received ≥6 and ≥10 cycles of Pem. There were no Pem-related deaths. Fewer pts in the Pem arm (51.5% vs 67.1%; P <0.001) received systemic post-discontinuation therapy. Conclusions: Pem maintenance therapy is well tolerated and offers superior OS and PFS compared with Plac, making it a new treatment paradigm for patients with advanced NSCLC who respond to initial therapy. This trial further validates that Pem has greater efficacy in patients with non-squamous histology.
[Table: see text]
[Table: see text]
Purpose: The primary objective of this randomized phase III study was to show significant difference in median time to progression (TTP) in patients with advanced NSCLC treated with single-agent gemcitabine maintenance therapy versus best supportive care following gemcitabine plus cisplatin initial first-line therapy. Patients and methods: Chemonaive patients with stage IIIB/IV NSCLC received gemcitabine 1250 mg/m(2) (days 1 and 8) plus cisplatin 80 mg/m(2) (day 1) every 21 days. Patients achieving objective response or disease stabilization following initial gemcitabine plus cisplatin therapy were randomized (2:1 fashion) to receive maintenance gemcitabine (1250 mg/m(2) on days 1 and 8 every 21 days) plus best supportive care (GEM arm), or best supportive care only (BSC arm). Results: Between November 1999 and November 2002, we enrolled 352 patients (median age: 57 years; stage IV disease: 74%; Karnofsky performance status (KPS) >80: 41%). Following initial therapy, 206 patients were randomized and treated with gemcitabine (138) or best supportive care (68). TTP throughout the study period was 6.6 and 5 months for GEM and BSC arms, respectively, white values for the maintenance period were 3.6 and 2.0 months (for p < 0.001 for both). Median overall survival (OS) throughout study was 13.0 months for GEM and 11.0 months for BSC arms (p=0.195). The toxicity profile was mild, with neutropenia being most common grade 3/4 toxicities. Conclusion: Maintenance therapy with gemcitabine, following initial therapy with gemcitabine plus cisplatin, was feasible, and produced significantly longer TTP compared to best supportive care alone. Further studies are warranted to establish the place of maintenance chemotherapy in patients with advanced NSCLC.
7507 Background: NSCLC patients (pts) whose tumors have not progressed following platinum-based chemotherapy (CT) obtain PFS and OS benefits with maintenance CT or erlotinib (E). We investigated maintenance gemcitabine (G) or E vs observation (O), following induction CT. Unlike previous maintenance trials, we included a predefined second-line therapy in all arms (pemetrexed [P]). Methods: Stage IIIB/IV pts with an ECOG PS of 0-1 whose tumors did not progress following four cycles of cisplatin-gemcitabine were randomized (stratified by center, gender, histology, response to induction CT and smoking status) to O, or to receive as maintenance therapy either G (1,250 mg/m2, days 1 and 8 of a 3 week cycle) or E 150 mg/day until disease progression. The primary endpoint was PFS by independent review with an 80% power to detect a 50% improvement in the median PFS (HR 0.66) for each comparison (G vs O and E vs O) at a two-sided 5% alpha level. Results: Of the 834 pts who received induction CT, 464 were randomized...
Background: Lung cancer is the leading cause of cancer related mortality world-wide and amongst males in India. The discovery of tyrosine kinase inhibitors holds a ray of hope for a subset of lung cancer patients, which have activating epidermal growth factor receptor (EGFR) mutations. Much of the preliminary data on frequency of EGFR mutations emanated from Western studies, which reported EGFR mutation rates of 10-15%. However, studies from Asian countries report a much higher frequency of EGFR mutations, not only in the male population, but also in females.
The object of this study was to share the author's experience of EGFR mutation testing in 402 lung cancer patients as no large-scale study addressing the issue has been published from India. Materials and Methods: Formalin fixed paraffin embedded tissues were analyzed for EGFR exon 19 deletions and exon 21 point mutation by length analysis of fluorescently labeled polymerase chain reaction products on Applied Biosystems Inc. 310 genetic analyzer. Results: Out of 402 samples, 35 samples could not be analyzed because of poor deoxyribonucleic acid material. Thus of the remaining 367 cases analyzed, EGFR mutations were found in 118 patients (32%). Mutations were equally distributed between males (50%) and females (50%). Majority of the mutations were seen in adenocarcinoma subtype (90%). Exon 19 mutations accounted for 76% while exon 21 mutations accounted for 24% of the mutations. Summary: EGFR mutation frequency is higher in Indian population vis-à-vis Caucasian population, but lower than that reported in the East Asian population. A significantly higher number of males also harbor EGFR mutations.
