Efficacy Of Crizotinib In Patients Research Articles

Efficacy and safety of crizotinib in ALK-positive systemic anaplastic large-cell lymphoma in children, adolescents, and adult patients: results of the French AcSé-crizotinib trial

BackgroundThe French phase II AcSé-crizotinib trial aimed to evaluate the safety and efficacy of crizotinib in patients with ALK, ROS1, and MET-driven malignancies, including ALK-positive anaplastic large-cell lymphoma (ALK+ ALCL). MethodsALK+ ALCL patients 12 months or older with measurable disease and no standard care options available received crizotinib twice daily at 165 mg/m2 in children and adolescents and 250 mg in adults. The primary end-point was the response rate at 8 weeks. ResultsTwenty-eight patients were enroled between February 2014 and March 2018. Three patients who were not treated were excluded from the analysis. The median age was 19 years. The median previous line of chemotherapy was two. In the 24 patients with an evaluable response, the response rate at 8 weeks was 67% (95% CI: 47–82%). All patients discontinued crizotinib after a median treatment duration of 3.7 months: eight for progression, two for adverse events (AEs) related to prior treatments, and 15 by choice, including six for allogeneic stem-cell transplantation. The median follow-up was 45 months. Nine patients experienced an event: eight relapses (seven after crizotinib discontinuation and one after dose reduction), and one died in complete remission. The median duration of response was 43.3 months (95% CI: 8.3–not reached). The 3-year progression-free and overall survival rates were 40% (95% CI: 23–59%) and 63% (95% CI: 43–79%). Grade 3 or 4 treatment-related AEs occurred in 32% of patients. ConclusionCrizotinib shows efficacy and an acceptable safety profile in ALK+ ALCL relapsed/refractory patients. However, a large proportion of patients experience a relapse after crizotinib discontinuation. Future studies will assess if prolonged ALK inhibitor exposure has curative potential without consolidation.

Crizotinib in ROS1-rearranged lung cancer (EUCROSS): Updated overall survival.

9078 Background: ROS1 rearrangements are found in approximately 1% of non-small cell lung cancer (NSCLC) patients. Prospective clinical trials showed high efficacy of crizotinib in this molecular subset. Lately, we reported an overall response rate (ORR) of 70% and a median progression-free survival (PFS) of 19.4 months for patients treated within the EUCROSS trial (Michels et al. Clin Oncol, 37(15_suppl):9066-9066, 2019). Here we present an updated analysis of the overall survival. Methods: EUCROSS is a European multi-centre, single arm phase 2 trial (Clinicaltrial.gov identifier: NCT02183870). Key eligibility criteria were ≥18 years of age, advanced/metastatic lung cancer, centrally confirmed ROS1-rearranged (fluorescence-in situ hybridisation) and no or stable brain metastases at baseline. Crizotinib was given at a dose of 250 mg twice daily. Primary endpoint of the trial was investigator-assessed ORR in the response-evaluable population (Response Evaluation Criteria in Solid Tumors, version 1.1), with secondary endpoints of PFS and overall survival (OS). Results: Of the 34 patients who received at least one dose of crizotinib (intention-to-treat population, ITT), 30 were included the primary efficacy analysis set (PAS). After a median follow-up of 55.9 months, 13 (43%) patients in the PAS and 15 (44%) in the ITT had died. Median OS was not reached in either group (95% CI, 17.1-NR and 20.3-NR, respectively). OS was negatively correlated with the presence of brain metastases (Log-rank p = 0.1805) and TP53 mutations (Log-rank p = 0.015). Detailed listings of the survival rates are depicted in Table. No new safety signals were observed. Owing to the approval of crizotinib by the European Medicines Agency, all patients who were still on treatment by January 24th 2018 (n=8), were prescribed crizotinib outside the trial. Conclusions: Updated OS highlights the efficacy of crizotinib in patients with ROS1-rearranged lung cancer. Patients with co-occurring TP53 mutations or brain metastases had worse outcomes and represent challenging populations. Clinical trial information: NCT02183870. [Table: see text]

Crizotinib in Metastatic ALK mutant Non-small Cell Lung Cancer Patients: A Single Centre Experience

The goal of this study was to evaluate the efficacy of crizotinib in patients with ALK-positive metastatic lung cancer. The patients' data were analyzed retrospectively. Cox regression and Kaplan-Meier methods were used to perform survival analyses. A total of 25 patients were involved in the study. Thirteen (52%) patients were male, and the average age was 55 (range, 30-80). 23 (92%) of the patients were de-novo metastatic. Brain metastases were present in 32% and liver metastases in 20% of

ICREATE: imaging features of primary and metastatic alveolar soft part sarcoma from the EORTC CREATE study

BackgroundAlveolar Soft Part Sarcoma (ASPS) is a rare, slow-growing, but highly vascular soft tissue sarcoma, characterised by a high rate of metastases at presentation. Although imaging features of the primary are well described, less detail is available on the imaging pattern of metastatic ASPS. The EORTC 90101 (CREATE) study assessed the efficacy of Crizotinib in patients with metastatic ASPS and presents a unique opportunity to describe the imaging phenotype of primary and metastatic ASPS, based on prospectively collected imaging.MethodsA retrospective review of the staging CT scans of 32 patients with ASPS from the CREATE study was undertaken and the imaging features of primary and metastatic disease were assessed.ResultsImaging of the primary tumour was available in 7/32 cases (28%). All primary tumours demonstrated marked vascularity with prominent feeding vessels (7/7, 100%). The most frequent sites of metastases included lung (30/32, 94%), nodal (7/32, 22%), bone (5/32, 16%) and muscle/subcutaneous (5/32, 16%). Features of hypervascularity were identified at all sites, more appreciable in the lungs, with feeding vessels frequently demonstrated in pulmonary metastases (21/32, 66%).ConclusionAnalysis of imaging from the CREATE cohort of patients with metastatic ASPS demonstrates that metastases from ASPS are predominantly hypervascular and demonstrate feeding vessels comparable to primary ASPS, suggesting potential sensitivity of this rare sarcoma for antivascular/antiangiogenic treatment approaches.

Efficacy and Safety of Crizotinib in the Treatment of Advanced Non-Small-Cell Lung Cancer with ROS1 Rearrangement or MET Alteration: A Systematic Review and Meta-Analysis.

Crizotinib has been approved for the treatment of non-small-cell lung cancer (NSCLC) with ROS proto-oncogene 1 (ROS1) gene fusion. This drug has also been granted breakthrough designation for NSCLCs with MET exon 14 alterations. This systematic review and meta-analysis aimed to investigate the efficacy and safety of crizotinib in patients with these diseases. We searched PubMed and Web of Science for relevant studies. Meta-analysis of proportions was conducted to calculate the pooled rate of complete response, partial response, stable disease, progressive disease, disease control rate (DCR), objective response rate (ORR), and drug adverse effects (AEs) of crizotinib in NSCLCs with ROS1 rearrangement or MET alterations. A total of 20 studies were included for meta-analysis. Among patients with ROS1-positive NSCLC, crizotinib exhibited a pooled DCR of 93.2% (95% confidence interval [CI] 90.8-95.5) and a pooled ORR of 77.4% (95% CI 72.8-82.1). The median progression-free survival (PFS) and overall survival (OS) of patients in this group was 14.5 and 32.6months, respectively. For NSCLC with MET alterations, crizotinib was associated with a lower efficacy (DCR 78.9% [95% CI 70.3-87.4] and ORR 40.6% [95% CI 28.3-53.0]). The median PFS was 5.2months, and median OS was 12.7months. The most common drug AEs were vision impairment (43.7%), edema (42.9%), and fatigue (40.1%). Our study highlighted and confirmed the efficacy of crizotinib in patients with NSCLC with ROS1 or MET genetic alterations. Crizotinib had remarkable effects on advanced NSCLC with ROS1 fusion, as previously reported. However, the role of this targeted therapy in MET-altered NSCLC remains investigational.

Phase II, open-label, multicenter trial of crizotinib in Japanese patients with advanced non-small cell lung cancer harboring a MET gene alteration: Co-MET study

BackgroundMET-deregulated non-small cell lung cancer represents an urgent clinical need because of the lack of specific therapies. Although recent studies have suggested a potential role for crizotinib in patients harboring MET gene alterations, no conclusive data are currently available. Therefore, we designed the Co-MET study, a single-arm phase II study to assess the efficacy and safety of crizotinib in patients with advanced non-small cell lung cancers harboring MET gene alterations.MethodsCo-MET is an open-label, multi-center, single-arm, phase II trial to assess the safety and efficacy of oral crizotinib in patients with advanced non-small cell lung cancer harboring MET exon 14 skipping mutation (cohort 1) or a high MET gene copy number of ≥ 7 (cohort 2). We will identify MET gene alterations using RT-PCR and/or next-generation sequencing. Oral crizotinib 250 mg BID will be administered until disease progression or unacceptable toxicity. A radiology committee will review tumor scans according to the RECIST criteria. The primary endpoint is the objective response rate. Assuming a null hypothesis of 20% objective response rate and an alternative hypothesis of 50% objective response rate for cohort 1, and a one-sided alpha error of 0.05 and 80% power based on the exact binomial distribution, the required number of evaluable patients is 19. We set the exploratory sample size for cohort 2 at 10 patients.DiscussionThe results of this study are expected to provide evidence regarding the usefulness of oral crizotinib for advanced MET exon 14 skipping mutation-positive or MET high gene copy number-positive non-small cell lung cancer.Trial registrationThis study was registered with the University Hospital Medical Information Network Clinical Trials Registry as UMIN000031623 on 3 March 2018.

Clinical observation of crizotinib in the treatment of ALK-positive advanced non-small cell lung cancer

BackgroundALK is a prognostic and predictive tumor marker in non-small cell lung carcinoma (NSCLC), and is more often found in lung adenocarcinomas. MethodsThe clinical and pathological data of 87 patients confirmed to have NSCLC by pathology or cytology were selected from April 2014 to January 2017 at the Tumor Hospital of Hebei Province. ResultsOf the 87 ALK-positive-patients, 47 patients were treated with oral administration of crizotinib. The objective response rate (ORR) was 61.7%, the disease control rate (DCR) was 93.6%, and the mPFS was 19 months. In an analysis of the number of metastatic sites, the patients who had more than three metastatic sites, the ORR, DCR, and mPFS were 63.9%, 94.5%, and 19 months, compared with the 45.5%, 91%, and 11 months in the patients with less sites (P = 0.040). For patients of 60 years or older, ORR and DCR were 40% and 100%, the other group was 71.9% and 90.6%, respectively(P = 0.036). The timing of treatment was analyzed. At the first application of crizotinib, ORR and DCR were 78.2% and 100% corresponding 45.8% and 87.5% at the second and final application of crizotinib group (P = 0.022). Baseline brain metastases were present in 25.5% (12/47) of patients in this study. 9 of the patients who developed disease progression during crizotinib treatment had new brain metastases or increased preexisting cranial foci. Most of them took the treatment strategy of continuing crizotinib or replacing the second/third generation ALK-TKI treatment combined with local radiotherapy for brain metastases. ConclusionsThe efficacy of crizotinib in patients with advanced NSCLC is related to the number of metastatic organs, age and timing of treatment. The use of crizotinib is prone to intracranial progression, and progression of simple brain metastases is not an indication that crizotinib is discontinued. Patients will continue to benefit from combination of local radiotherapy.

Safety and Efficacy of Crizotinib in Patients With Advanced or Metastatic ROS1-Rearranged Lung Cancer (EUCROSS): A European Phase II Clinical Trial

IntroductionROS1 rearrangements are found in 1% of lung cancer patients. Therapeutic efficacy of crizotinib in this subset has been shown in early phase trials in the United States and East Asia. Here we present data on efficacy and safety of a prospective phase II trial evaluating crizotinib in European ROS1-positive patients (EUCROSS). Patients and MethodsThe trial was a multicenter, single-arm phase II trial (Clinicaltrial.gov identifier: NCT02183870). Key eligibility criteria included patients who were 18 years of age or older with advanced/metastatic lung cancer and centrally confirmed ROS1-rearranged lung cancer (fluorescence-in situ hybridization). Treatment included 250 mg crizotinib twice daily. The primary endpoint was investigator-assessed objective response rate (ORR) (Response Evaluation Criteria in Solid Tumors, version 1.1). Key secondary endpoints were progression-free survival (PFS), overall survival, efficacy by independent radiologic review, safety, health-related quality of life, and molecular characterization of tumor tissue. ResultsThirty-four patients received treatment. Four patients were excluded from efficacy analysis. Investigator ORR was 70% (95% confidence interval [CI]: 51–85; 21 of 30 patients) and median PFS was 20.0 months (95% CI: 10.1–not reached). Two patients with ROS1 wild-type sequences assessed by DNA sequencing had progression as best response. CD74-ROS1-positive patients had a trend towards a higher ORR and longer median PFS. TP53-co-mutant patients had a significantly shorter median PFS than wild-type patients (7.0 months, 95% CI: 1.7–20.0 versus 24.1 months, 95% CI: 10.1–not reached; p = 0.022). Treatment-related adverse events were documented in 33 of 34 patients (97%). ConclusionsCrizotinib is highly effective and safe in patients with ROS1-rearranged lung cancer. ROS1-/TP53-co-aberrant patients had a significantly worse outcome compared to TP53 wild-type patients.

Clinicopathological features and clinical efficacy of crizotinib in Chinese patients with ROS1-positive non-small cell lung cancer.

C-ros oncogene 1 receptor tyrosine kinase (ROS1) rearrangement forms a novel molecular subgroup of non-small cell lung cancer (NSCLC). The present study explored the clinicopathological features and clinical efficacy of crizotinib in patients with ROS1-positive NSCLC. A retrospective analysis of 2,617 cases of NSCLC diagnosed between January 2013 and December 2016 was performed. ROS1 fusion genes were detected by reverse transcription-quantitative polymerase chain reaction, fluorescence in situ hybridization or next-generation sequencing techniques, and patients positive for the ROS1 fusion gene received oral treatment with crizotinib. The ROS1 fusion was identified in 67 out of 2,617 cases (2.56%), including 21 cases that were male and 46 cases that were female. The median age was 68 years. Among these cases, 59 (88.06%) were adenocarcinoma and 8 were non-adenocarcinoma. According to Tumor-Node-Metastasis (TNM) staging, 4 cases were stage I-IIIa and 63 (94.02%) were stage IIIb-IV. The epidermal growth factor receptor (EGFR) gene status included 60 cases of wild-type, 1 case of co-mutation and 6 unknown cases. Statistically significant differences were identified for sex, TNM staging and EGFR gene status between ROS1 fusion gene-positive and -negative patients (P<0.001). A total of 23 patients received oral treatment with crizotinib, of which 13 (56.52%), 5 (21.74%) and 5 (21.74%) patients demonstrated a partial response, stable disease and progressive disease, respectively. The objective response rate was 56.52% and the disease control rate was 78.26%. Among all patients, the median progression-free survival (mPFS) time was 14.5 months. No differences were revealed in the mPFS time with regard to age, sex, smoking history, performance status score, histopathological type, TNM staging, tumor protein p53 gene status, EGFR gene status and first-line crizotinib treatment, whether by single or multiple factor analysis. The grade 3/4 treatment-associated adverse events included gastrointestinal disturbance, followed by increased transaminase concentration. In conclusion, the rate of ROS1 fusion in NSCLC among the patients is low, and crizotinib is an effective and safe drug for the treatment of ROS1-positive advanced NSCLC.

Efficacy of Crizotinib among Different Types ofROS1 Fusion Partners in Patients with ROS1-Rearranged Non-Small Cell Lung Cancer.

ROS1 rearrangement-positive NSCLC can be treated effectively with an anaplastic lymphoma kinase/ROS1/mesenchymal-epithelial transition factor inhibitor such as crizotinib; however, the rate of response remains variable. Although several ROS1 fusion partners have been identified, the efficacy of crizotinib in patients with different types of ROS1 fusion partners is poorly understood. We reviewed clinicopathological data of patients with ROS1 rearrangement who received crizotinib therapy at our institution between April 2014 and December 2016. ROS1 fusion partners were evaluated by using Sanger sequencing for available tumor tissue. During the study, 49 patients were found to have ROS1 rearrangement and were subsequently treated with crizotinib. Tumor specimens were available for 36 patients, of whom 19 were found to have CD 74 molecule gene (CD74)-ROS1 fusion partners. Before therapy, those in the CD74-ROS1 group were found to have a higher rate of brain metastases (six versus 0 [p= 0.020]). The objective response rate for crizotinib was 83.3% in all patients, whereas it was 94.11% and 73.68% in the non-CD74-ROS1 and CD74-ROS1 groups, respectively. As compared with the CD74-ROS1 group, the non-CD74-ROS1 group had both a significantly longer progression-free survival (17.63 months versus 12.63 months [p= 0.048]) and a significantly longer overall survival (44.50 months versus 24.33 months [p= 0.036]). On multivariable analysis, the only factor associated with overall survival was presence of brain metastases before therapy (p= 0.010). There were no significant factors associated with progression-free survival in the multivariable analysis. These findings suggests that patients with CD74-ROS1 fusion partners are more likely to present with brain metastases. Although not independently significant, a trend toward improved survival was observed in patients in the non-CD74-ROS1 group when they were treated with crizotinib.

P3.02a-026 Crizotinib in Clinical Practice and in Clinical Trials - How Much the Results Differ?: Topic: ALK Clinical

In Slovakia, since October 2012, crizotinib has been available for the treatment of adults with previously treated ALK-positive advanced NSCLC, based on the therapeutic indication approved by the European Medicines Agency. The purpose of this study was to assess the results achieved with crizotinib in the treatment of NSCLC in clinical practice in Slovakia, and to compare them with the results from the key clinical trial PROFILE 1007. In the multicenter retrospective study, approved by the Ethical Committee of the Specialized Hospital of St Zoerardus Zobor, the data of 34 ALK-positive patients from 8 centers were reviewed. Data regarding ALK testing and results were obtained from the central laboratory database (Comenius University Jessenius Medical Faculty and Martin's Biopsy Centre). Data regarding patients were obtained from the databases of participating institutions and patient files. Fluorescence in situ hybridization (FISH) with break-apart probes was used for the confirmation of ALK rearrangement in all cases. Response to treatment was evaluated using RECIST criteria v. 1.1. Statistical analyses were performed using MedCalc® software. PFS and OS were estimated using the Kaplan–Meier method. Between October 2012 and December 2015, 34 ALK-positive patients with locally advanced or metastatic NSCLC were treated with crizotinib, 31 of them after the first-line chemotherapy. Characteristics of patients: median age, years (range): 58 (23-77), ECOG/WHO PS: 0, 1, 2, 3 in 1, 23, 6, and 4 patients, respectively. Histology: adenocarcinoma in 33 cases, NSCLC, NOS in one. Patients with locally advanced disease: 2, with metastatic disease: 32. Median PFS was 18 months (95% CI: 13 - 22), median OS (number of events: 13, 38,24%): 32 months (95% CI: 18 - 32), response rates: CR + PR: 3 + 23, 76,5% (95% CI 50-100%), SD: 7, 21,5%, PD: 3, 8,8%, not stated: 1. There was a significant improvement in PS within 2 month, mean difference: - 0,62, p = 0,0025. Grade 3/4 toxicities occurred in 15/2 patients. Crizotinib was permanently discontinued due to AEs in 2 patients only. PFS and OS in our study were numerically better in comparison with PROFILE 1007. On the other hand, common grade 3 toxicities occurred also more often. Our study provides real-world evidence of the efficacy of crizotinib in patients with ALK-positive NSCLC, treated outside of clinical trials.

Differential Crizotinib Response Duration Among ALK Fusion Variants in ALK-Positive Non-Small-Cell Lung Cancer.

Anaplastic lymphoma kinase (ALK) rearrangement-positive non-small-cell lung cancers can be effectively treated with an ALK tyrosine kinase inhibitor (TKI) such as crizotinib, but the response magnitude and duration are heterogeneous. Several ALK variants have been identified, but few studies have focused on the effects of different ALK variants on the efficacy of crizotinib. Among 55 patients treated with crizotinib as the initial ALK-TKI between January 2007 and December 2014, we identified 35 patients with tumor specimens that could be evaluated for ALK variants by reverse transcription polymerase chain reaction. We retrospectively evaluated the efficacy of crizotinib on the basis of the objective response rate and progression-free survival (PFS) according to the ALK variants. The most frequent ALK variant was variant 1 in 19 patients (54%), followed by variant 2 in five patients (14%), variant 3a/3b in four patients (12%), and other variants in seven patients (20%). Objective response rate was 69% in all patients, whereas it was 74% and 63% in the variant 1 and non-variant 1 groups, respectively. The median PFS time was significantly longer in patients with variant 1 than in those with non-variant 1 (median PFS, 11.0 months [95% CI, 6.5 to 43.0 months] v 4.2 months [95% CI, 1.6 to 10.2 months], respectively; P < .05). Multivariable analysis identified two significant factors associated with PFS duration, ALK variant 1 (hazard ratio, 0.350; 95% CI, 0.128 to 0.929; P < .05) and advanced stage (hazard ratio, 4.646; 95% CI, 1.381 to 21.750; P < .05). Our results indicate the better efficacy of crizotinib in patients with ALK variant 1 versus non-variant 1. The ALK variant status might affect the efficacy of ALK-TKIs.

The efficacy of crizotinib in patients with ALK-positive nonsmall cell lung cancer.

Molecular profiling of nonsmall cell lung cancer (NSCLC) contributes to better understanding the different molecular subtypes of this heterogeneous group of diseases. The discovery of oncogenic ALK rearrangements in NSCLC and the subsequent success in their therapeutic targeting with crizotinib reinforces the benefits of a precision approach to systemic anticancer therapy. In addition, the rapid development of crizotinib from first discovery thorough accelerated US Food and Drug Administration approval, and late stage confirmatory clinical trials, exemplifies the success of the drug development strategy of close collaboration between clinicians, industry and regulatory authorities. In this review we describe the identification of ALK rearranged NSCLC, clinical characteristics of such patients, and clinical outcomes when treated with crizotinib.

Efficacy and safety of crizotinib among Chinese EML4-ALK-positive, advanced-stage non-small cell lung cancer patients.

IntroductionWe report the efficacy and safety of crizotinib treatment among Chinese patients with advanced-stage NSCLC.MethodsWe retrospectively analyzed patients with EML4-ALK positive advanced NSCLC who were treated with crizotinib from May 2012 to Aug 2013. Baseline clinical parameters, treatment protocol, response to therapy and survival were noted. The primary goal was to evaluate the efficacy of crizotinib in patients who were previously treated patients or who had poor ECOG performance status (PS).ResultsForty patients were evaluable for safety and efficacy. Median age was 43 years, 100% had adenocarcinoma and stage IV disease, and 42.5% were female. Six patients received frontline treatment with crizotinib, 17 patients had 1 prior treatment, and 17 patients had more than 2 lines of prior treatment. Patients received a median of 5 cycles of treatment (range 1–15 cycles). After the first cycle, 92.5% (37/40) patients archived partial remission (PR). At the end of the follow-up period, the overall PR rate was 70% (28/40), and progression of disease (PD) occurred in 30% of patients (12/40). The median PFS was 28 weeks (95% CI 15.4 to 40.5 weeks), and median OS was 40 weeks (95% CI 38.6 to 49.3 weeks). The most frequent treatment-related AEs were vomiting (47.5%), vision disorder (27.5%) and increased ALT/AST (42%); most toxicities were Grade 1/2. Observed treatment-related Grade 3/4 AEs included increased ALT/AST (10%) and vomiting (5%). The EML4-ALK fusion rate and number of prior chemotherapy cycles did not appear to significantly affect the efficacy of crizotinib. However, PS 0–2 patients had improved PFS (50 weeks vs. 24 weeks, p = 0.015).ConclusionsCrizotinib was safe, well-tolerated, and effective in Chinese patients with pre-treated ALK-rearranged NSCLC. QOL was improved and PS appears to have an effect on the efficacy of crizotinib, but prior treatment and ALK fusion rate do not.