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20 Diseases |  |
18 Trials |
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18 Trials |  |
1690 News |  |
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- || Clinical, Journal: Drug resistance mechanisms in Japanese ALK positive NSCLC and the clinical responses based on the resistant mechanisms. (Pubmed Central) - Mar 17, 2020
L1196M + G1202R, a compound mutation, was detected in 1 specimen after lorlatinib treatment...In conclusion, resistance to ALK-TKIs based on secondary mutation in this study was similar to that in previous reports, except for crizotinib resistance. The appropriate treatment matching resistance mechanisms contributes to the efficacy of multiple ALK-TKI treatment strategies.
- Xalkori (crizotinib) / Pfizer, Zykadia (ceritinib) / Novartis
[VIRTUAL] COST-EFFECTIVENESS ANALYSIS OF CERITINIB IN PATIENTS PREVIOUSLY TREATED WITH CRIZOTINIB AND CHEMOTHERAPY IN ANAPLASTIC LYMPHOMA KINASE POSITIVE (ALK+) NON-SMALL CELL LUNG CANCER IN UNITED STATES () - Mar 8, 2020 - Abstract #ISPOR2020ISPOR_522;
Both models were most sensitive to parameters of medical cost for progression disease and cost of ceritinib. CONCLUSIONS : From both models, ceritinib is not cost effective compared to chemotherapy among patients previously treated with crizotinib and chemotherapy, from the US healthcare perspective.
- | Zykadia (ceritinib) / Novartis, AZD1208 / AstraZeneca, Alunbrig (brigatinib) / Takeda
Journal: The targetable kinase PIM1 drives ALK inhibitor resistance in high-risk neuroblastoma independent of MYCN status. (Pubmed Central) - Mar 3, 2020
Knockdown of PIM1 sensitizes cells of differing MYCN status to ALK inhibitors, and in patient-derived xenografts of high-risk NB harboring ALK mutations, the combination of the ALK inhibitor ceritinib and PIM1 inhibitor AZD1208 shows significantly enhanced anti-tumor efficacy relative to single agents. These data confirm that PIM1 overexpression decreases sensitivity to ALK inhibitors in NB, and suggests that combined front-line inhibition of ALK and PIM1 is a viable strategy for the treatment of ALK-positive NB independent of MYCN status.
- | Xalkori (crizotinib) / Pfizer, Zykadia (ceritinib) / Novartis, Alecensa (alectinib) / Roche
Retrospective data, Journal: Efficacy of Crizotinib, Ceritinib, and Alectinib in ALK-Positive Non-Small Cell Lung Cancer Treatment: A Meta-Analysis of Clinical Trials. (Pubmed Central) - Mar 1, 2020
Further head-to-head trials are needed to compare their efficacy with other types of NSCLC treatment regimens. PROSPERO registration: CRD42018085987.
- |||| Zykadia (ceritinib) / Novartis, Alunbrig (brigatinib) / Takeda, Alecensa (alectinib) / Roche
Clinical: There was no FLAURA already existing in the ALK space when alectinib came out, only ceritinib. I would more compare this to the brigatinib data NOW, no clinical need for it and now imagine if it was IV too. (Twitter) - Feb 29, 2020
- | Zykadia (ceritinib) / Novartis
Biomarker, Journal: IRS2 Amplification as a Predictive Biomarker in Response to Ceritinib in Small Cell Lung Cancer. (Pubmed Central) - Feb 27, 2020
In this study, we present that IRS2 amplification and/or expression serve as preclinical implications for a novel therapeutic target in SCLC progression. Furthermore, we suggest that insulin-like growth factor-1 (IGF-1) receptor inhibitor-based therapy could be used for treating SCLC with IRS2 amplification.
- | Xalkori (crizotinib) / Pfizer, Zykadia (ceritinib) / Novartis
Journal: Structural basis for drug resistance mechanisms against anaplastic lymphoma kinase. (Pubmed Central) - Feb 26, 2020
This study will be beneficial for designing drugs with better proficiency against ALK and the issues of drug resistance. This study can be taken as a pipeline for investigating drug-resistant mutations in other diseases as well.
- || Zykadia (ceritinib) / Novartis
Clinical, PK/PD data, Journal: ASCEND-8 pharmacokinetic, safety, and efficacy data for ceritinib 450 mg with food in patients with anaplastic lymphoma kinase-positive non-small cell lung Cancer: A clinical perspective. (Pubmed Central) - Feb 26, 2020
This review highlights and discusses published findings from the ASCEND-8 food-effect trial and includes commentary from physicians regarding their own clinical cases of patients who were enrolled in the trial and treated with either the 750-mg fasted or 450-mg fed dose of ceritinib. The review also discusses the implications of using the recently approved ceritinib 450-mg dose in the clinical setting.
- || Clinical, Journal: Comparative efficacy of brigatinib versus ceritinib and alectinib in patients with crizotinib-refractory anaplastic lymphoma kinase-positive non-small cell lung cancer. (Pubmed Central) - Feb 25, 2020
The review also discusses the implications of using the recently approved ceritinib 450-mg dose in the clinical setting. In crizotinib-refractory ALK + NSCLC patients, relative efficacy estimates suggest brigatinib may have prolonged PFS and OS vs ceritinib and prolonged PFS vs alectinib.
- |||||| Zykadia (ceritinib) / Novartis, Mekinist (trametinib) / Novartis, trametinib
Ceritinib + trametinib in ALK+ mNSCLC wirh early data. Will be interesting to see if specific molecularly (or transcriptomically?) defined subgroup may confer preferential benefit. Great work by @CarolineMccoach @collin_blakely @MattGubensMD @IASLC (Twitter) - Feb 21, 2020
- Zykadia (ceritinib) / Novartis, Mekinist (trametinib) / Novartis
Ceritinib +/- Trametinib (STARLIGHT BALLROOM) - Feb 21, 2020 - Abstract #IASLCLCTT2020IASLC_LCTT_236;
- Zykadia (ceritinib) / Novartis
Efficacy and safety of 450 mg/d or 600 mg/d ceritinib with food vs. 750 mg/d fasted in patients (pts) with ALK-positive (ALK+) non-small cell lung cancer (NSCLC): Results from ASCEND-8 Asian subgroup analysis (Hall 1) - Feb 15, 2020 - Abstract #ELCC2020ELCC_386;
- | Journal: Treatment of anaplastic lymphoma kinase-positive non-small cell lung cancer: update and perspectives. (Pubmed Central) - Feb 14, 2020
Patients with metastatic, anaplastic lymphoma kinase-rearranged nonsmall cell lung cancer should be managed by interdisciplinary expert teams. New drugs with enhanced brain activity are available, and some patients may benefit from local therapies.
- | Enrollment change, Trial completion date, Trial primary completion date: High Throughput Drug Sensitivity Assay and Genomics- Guided Treatment of Patients With Relapsed or Refractory Acute Leukemia (clinicaltrials.gov) - Feb 11, 2020
P=N/A, N=35, Recruiting, Sponsor: University of Washington
New drugs with enhanced brain activity are available, and some patients may benefit from local therapies. N=25 --> 35 | Trial completion date: Jul 2022 --> Jul 2023 | Trial primary completion date: Jul 2020 --> Jul 2021
- || Lorbrena (lorlatinib) / Pfizer
Clinical, Journal: Sarcoid-like reaction mimicking disease progression in an ALK-positive lung cancer patient receiving lorlatinib. (Pubmed Central) - Feb 7, 2020
This invasive approach, besides documenting for the first time a sarcoid-like reaction to ALK inhibitors, allowed to revert the radiological diagnosis and maintain lorlatinib, for the best patient outcome. The pragmatic relevance of these findings suggests a careful attitude towards the interpretation of radiologic patterns of disease progression in patients under TKI.
- || Xalkori (crizotinib) / Pfizer, Zykadia (ceritinib) / Novartis
Biomarker, Clinical, Journal, Real-World Evidence: Real-world anaplastic lymphoma kinase (ALK) rearrangement testing patterns, treatment sequences, and survival of ALK inhibitor-treated patients. (Pubmed Central) - Feb 7, 2020
Despite widespread crizotinib use in patients with ALK+ aNSCLC, a high proportion of patients progressed. Ongoing analyses of EHR-derived cohorts are valuable in assessing real-world testing rates and therapeutic use of ALK inhibitors.
- | Zykadia (ceritinib) / Novartis
Trial completion, Combination therapy, Metastases: Ceritinib and Combination Chemotherapy in Treating Patients With Advanced Solid Tumors or Locally Advanced or Metastatic Pancreatic Cancer (clinicaltrials.gov) - Feb 5, 2020
P1, N=38, Completed, Sponsor: Roswell Park Cancer Institute
Ongoing analyses of EHR-derived cohorts are valuable in assessing real-world testing rates and therapeutic use of ALK inhibitors. Active, not recruiting --> Completed
- || Zykadia (ceritinib) / Novartis, Kisqali (ribociclib) / Novartis, NN1213 / Novo Nordisk
Trial primary completion date: NEPENTHE: Next Generation Personalized Neuroblastoma Therapy (clinicaltrials.gov) - Jan 30, 2020
P1, N=131, Recruiting, Sponsor: Yael P Mosse
Active, not recruiting --> Completed Trial primary completion date: Jul 2020 --> Jul 2021
- | Trial termination: Capmatinib, Ceritinib, Regorafenib, or Entrectinib in Treating Patients With BRAF/NRAS Wild-Type Stage III-IV Melanoma (clinicaltrials.gov) - Jan 27, 2020
P2, N=1, Terminated, Sponsor: University of California, San Francisco
Trial primary completion date: Jul 2020 --> Jul 2021 Completed --> Terminated; Funding
- | Zykadia (ceritinib) / Novartis
Journal: Ceritinib-Induced Regression of an Insulin-Like Growth Factor-Driven Neuroepithelial Brain Tumor. (Pubmed Central) - Jan 22, 2020
Ceritinib accumulated in the tumor at a concentration of 2.72 µM. Our data suggest ceritinib as a promising drug for the treatment of IGF-driven brain tumors.
- ||| Zykadia (ceritinib) / Novartis
Trial completion date, Metastases: LDK378 Versus Chemotherapy in ALK Rearranged (ALK Positive) Patients Previously Treated With Chemotherapy (Platinum Doublet) and Crizotinib (clinicaltrials.gov) - Jan 22, 2020
P3, N=231, Active, not recruiting, Sponsor: Novartis Pharmaceuticals
Our data suggest ceritinib as a promising drug for the treatment of IGF-driven brain tumors. Trial completion date: Nov 2021 --> Jul 2022
- ||| Piqray (alpelisib) / Novartis, Zykadia (ceritinib) / Novartis, Tabrecta (capmatinib) / Novartis
Trial completion, Metastases: A Phase II, Open Label, Multiple Arm Study of AUY922, BYL719, INC280, LDK378 and MEK162 in Chinese Patients With Advanced Non-small Cell Lung Cancer (clinicaltrials.gov) - Jan 21, 2020
P2, N=66, Completed, Sponsor: Novartis Pharmaceuticals
Trial completion date: Nov 2021 --> Jul 2022 Recruiting --> Completed
- || Alunbrig (brigatinib) / Takeda
Enrollment closed, Metastases: ALTA-2: A Study of Brigatinib in Participants With Anaplastic Lymphoma Kinase-Positive (ALK+), Advanced Non-Small-Cell Lung Cancer (NSCLC) Progressed on Alectinib or Ceritinib (clinicaltrials.gov) - Jan 15, 2020
P2, N=104, Active, not recruiting, Sponsor: Ariad Pharmaceuticals
Recruiting --> Completed Recruiting --> Active, not recruiting
- |||| Xalkori (crizotinib) / Pfizer, Zykadia (ceritinib) / Novartis, Alunbrig (brigatinib) / Takeda
Activity of Brigatinib in Crizotinib and Ceritinib-Resistant ROS1 Rearranged Non–Small-Cell Lung Cancer https://t.co/i150QVfIMC @notahedge @ASCO_pubs #JCOPO #LCSM (Twitter) - Jan 11, 2020
- |||| Zykadia (ceritinib) / Novartis
Biomarker: For those who Love SCLC research - IRS2 amplification as a predictive biomarker in response to ceritinib in small cell lung cancer https://t.co/evnJmtaIFA (Twitter) - Jan 10, 2020
- |||| Zykadia (ceritinib) / Novartis
Biomarker: Novel interesting data on SCLC - IRS2 amplification as a predictive biomarker in response to ceritinib in small cell lung cancer https://t.co/evnJmtaIFA (Twitter) - Jan 10, 2020
- | Journal: Epithelial-to-mesenchymal transition is a mechanism of ALK inhibitor resistance in lung cancer independent of ALK mutation status. (Pubmed Central) - Jan 2, 2020
Pre-treatment with the histone deacetylase (HDAC) inhibitor quisinostat overcame this resistance by reverting EMT in vitro and in vivo. These findings indicate that HDAC inhibitor pre-treatment followed by a new ALK inhibitors may be useful to circumvent resistance constituted by coexistence of resistance mutations and EMT in the heterogeneous tumor.
- ||| Zykadia (ceritinib) / Novartis
Trial termination, Metastases: Ceritinib Rare Indications Study in ALK+ Tumors (clinicaltrials.gov) - Dec 26, 2019
P2, N=22, Terminated, Sponsor: Novartis Pharmaceuticals
These findings indicate that HDAC inhibitor pre-treatment followed by a new ALK inhibitors may be useful to circumvent resistance constituted by coexistence of resistance mutations and EMT in the heterogeneous tumor. Completed --> Terminated
- | Zykadia (ceritinib) / Novartis
Journal, Myeloid-derived suppressor cells: Protective effect of LDK378 during sepsis: a novel mechanism of action targeting myeloid-derived suppressor cells. (Pubmed Central) - Dec 25, 2019
Completed --> Terminated No abstract available
- | Xalkori (crizotinib) / Pfizer, Zykadia (ceritinib) / Novartis, Alecensa (alectinib) / Roche
Retrospective data, Journal: Meta-analysis comparing incidence of grade 3-4 neutropenia with ALK inhibitors and chemotherapy in patients with non-small-cell lung cancer. (Pubmed Central) - Dec 23, 2019
Probabilities of developing grade 3-4 neutropenia were 6.56 and 14.19%, respectively; no significant difference was found. In patients with non-small-cell lung cancer, incidence of grade 3-4 neutropenia with ALK-targeted therapy is not significantly different compared with chemotherapy.
- || Review, Journal: New generation anaplastic lymphoma kinase inhibitors. (Pubmed Central) - Dec 22, 2019
Some of them were approved after the failure of crizotinib (ceritinib, alectinib, brigatinib and lorlatinib) and in first line setting (ceritinib, alectinib and brigatinib) while others are still under evaluation for TKI-naive patients such as lorlatinib, ensartinib and entrectinib. In this review we will discuss the most recent results of new TKIs in order to describe a fast growing therapeutic landscape in this setting.
- || Review, Journal: Brain metastases in oncogene-driven non-small cell lung cancer. (Pubmed Central) - Dec 22, 2019
In this review, we discuss the various aspects of brain metastases occurring in NSCLC patients with driver gene mutations. We also propose a treatment algorithm for these patients.
- ||| Xalkori (crizotinib) / Pfizer, Zykadia (ceritinib) / Novartis
Clinical, Journal, Adverse events: ALK inhibition in two emblematic cases of pediatric inflammatory myofibroblastic tumor: Efficacy and side effects. (Pubmed Central) - Dec 21, 2019
P1
However, data on the second-generation ALK inhibitors are limited. We report two emblematic cases of IMT in pediatric patients, treated with the second-generation ALK inhibitor ceritinib in the context of a clinical trial (NCT01742286).
- || Clinical, Journal: IGF1R Is a Potential New Therapeutic Target for HGNET-BCOR Brain Tumor Patients. (Pubmed Central) - Dec 20, 2019
Ceritinib was able to abrogate the proliferation of PhKh1 cells and blocked the phosphorylation of IGF1R and AKT. (4) IGF1R is as an attractive target for the development of new therapy protocols for HGNET-BCOR patients, which may include ceritinib and vinblastine.
- | Zykadia (ceritinib) / Novartis, Focus V (anlotinib) / Advenchen, Sino Biopharmaceutical, Imbruvica (ibrutinib) / AbbVie, J&J
PK/PD data, Preclinical, Journal: A selective and robust UPLC-MS/MS method for the simultaneous quantitative determination of anlotinib, ceritinib and ibrutinib in rat plasma and its application to a pharmacokinetic study. (Pubmed Central) - Dec 19, 2019
ANL, CER and IBR were sufficiently stable under most investigated conditions. The optimized method was successfully applied for a pharmacokinetic study after single oral gavage administration of mixture (ANL, CER and IBR) at dose of 6 mg kg-1, 25 mg kg-1 and 10 mg kg-1.
- ||||| Next-Generation Sequencing: Lung Adenoca with EML4- ALK rearrangement with progression on Ceritinib.NGS on repeat Biopsy s/o G1202R mutation . Apart from Lorlatinib,does Entrectinib also work on this mutation? @LeciaSequist @geoff_oxnard @JustinGainor @Jbauml @HornLeora @christine_lovly @n8pennell (Twitter) - Dec 10, 2019
- | Alunbrig (brigatinib) / Takeda
Journal: An evaluation of brigatinib as a promising treatment option for non-small cell lung cancer. (Pubmed Central) - Nov 27, 2019
Besides this TKI, the second-line ALK inhibitors alectinib and ceritinib, as well as the third-line lorlatinib are approved for the treatment of ALK-positive NSCLC patients. The main challenge is to find sequences and combinations of ALK inhibitors which provide the best benefit for the patients.
- | Review, Journal: Targeted therapies for ROS1-rearranged non-small cell lung cancer. (Pubmed Central) - Nov 27, 2019
Additionally, appreciation of novel resistance mechanisms to crizotinib has led to the development of newer tyrosine kinase inhibitors (TKIs). In this review, we highlight known and emerging TKIs for the management of ROS1+ NSCLC.
- | Zykadia (ceritinib) / Novartis
Preclinical, Journal: WWOX Possesses N-Terminal Cell Surface-Exposed Epitopes WWOX and WWOX for Signaling Cancer Growth Suppression and Prevention In Vivo. (Pubmed Central) - Nov 24, 2019
Time-lapse microscopy revealed that WWOX7-21 peptide potently enhanced the explosion and death of 4T1 breast cancer stem cell spheres by ceritinib...Together, the N-terminal epitopes WWOX7-21 and WWOX7-11 are potent in blocking cancer growth in vivo. WWOX7-21 and WWOX7-11 peptides and pS14-WWOX antibody are of therapeutic values in suppressing and preventing cancer growth in vivo.
- | Xalkori (crizotinib) / Pfizer, Zykadia (ceritinib) / Novartis, Alecensa (alectinib) / Roche
Journal: Novel derivatives of anaplastic lymphoma kinase inhibitors: Synthesis, radiolabeling, and preliminary biological studies of fluoroethyl analogues of crizotinib, alectinib, and ceritinib. (Pubmed Central) - Nov 23, 2019
A cytotoxicity screen in ALK-expressing H2228 lung cancer cells showed that the analogues had up to nanomolar potency and the addition of the fluorinated moiety had minimal impact overall on the potency of the original drugs. Positron emission tomography in healthy mice showed that the analogues had enhanced BBB penetration, suggesting that they have therapeutic potential against central nervous system metastases.
- | Xalkori (crizotinib) / Pfizer, Zykadia (ceritinib) / Novartis, Alecensa (alectinib) / Roche
Journal, HEOR: Cost-Effectiveness Analysis Of Ceritinib And Alectinib Versus Crizotinib In The Treatment Of Anaplastic Lymphoma Kinase-Positive Advanced Non-Small Cell Lung Cancer. (Pubmed Central) - Nov 23, 2019
As a first-line treatment regimen, ceritinib and alectinib can extend the survival time of patients compared with crizotinib, but the medical cost also increases accordingly. According to the World Health Organization's three-percent GDP measurement, first-line treatment with Crizotinib is the most cost-effective.
- |||| Xalkori (crizotinib) / Pfizer, Zykadia (ceritinib) / Novartis, Alunbrig (brigatinib) / Takeda
Activity of Brigatinib in Crizotinib and Ceritinib-Resistant ROS1 Rearranged Non–Small-Cell Lung Cancer https://t.co/iec9txwmdR @notahedge @JCO_ASCO #JCOPO (Twitter) - Nov 20, 2019
- | Zykadia (ceritinib) / Novartis
Journal: HFIP Promoted Low Temperature SNAr of ChloroHeteroarenes Using Thiols and Amines. (Pubmed Central) - Nov 20, 2019
A highly efficient and an unprecedented HFIP promoted low temperature aromatic nucleophilic substitutions of chlorohete-roarenes has been performed using thiols and (secondary) amines under base-free and metal-free conditions. The developed protocol also provides excellent regio-control for the selective functionalisation of dichloroheteroarenes, while the utility of the protocol was demonstrated by the modification of a commercially available drug Ceritinib.
- ||| Zykadia (ceritinib) / Novartis
Trial completion date: ASCEND-4: LDK378 Versus Chemotherapy in Previously Untreated Patients With ALK Rearranged Non-small Cell Lung Cancer (clinicaltrials.gov) - Nov 20, 2019
P3, N=375, Active, not recruiting, Sponsor: Novartis Pharmaceuticals
The developed protocol also provides excellent regio-control for the selective functionalisation of dichloroheteroarenes, while the utility of the protocol was demonstrated by the modification of a commercially available drug Ceritinib. Trial completion date: Apr 2022 --> Feb 2023
- || Alunbrig (brigatinib) / Takeda
Trial completion date, Trial primary completion date, Metastases: ALTA-2: A Study of Brigatinib in Participants With Anaplastic Lymphoma Kinase-Positive (ALK+), Advanced Non-Small-Cell Lung Cancer (NSCLC) Progressed on Alectinib or Ceritinib (clinicaltrials.gov) - Nov 19, 2019
P2, N=103, Recruiting, Sponsor: Ariad Pharmaceuticals
Trial completion date: Apr 2022 --> Feb 2023 Trial completion date: Apr 2022 --> Jul 2021 | Trial primary completion date: Dec 2019 --> Jun 2020
- |||||| Zykadia (ceritinib) / Novartis, Alunbrig (brigatinib) / Takeda, Alecensa (alectinib) / Roche
Clinical data: #DCLUNG19 Resistance in #ALK dictated by initial therapy. Clinical findings replicate preclinical models: I1171N seen post alectinib but not brigatinib or ceritinib. G1202R an issue for all. Clinical data coming in now. #OncoAlert #LCSM #LCAM (Twitter) - Nov 16, 2019
- || Zykadia (ceritinib) / Novartis
Trial completion date, Trial primary completion date: Study of Safety and Efficacy of Ceritinib in Combination With Nivolumab in Patients With ALK-positive Non-small Cell Lung Cancer (clinicaltrials.gov) - Nov 15, 2019
P1, N=57, Active, not recruiting, Sponsor: Novartis Pharmaceuticals
Trial completion date: Apr 2022 --> Jul 2021 | Trial primary completion date: Dec 2019 --> Jun 2020 Trial completion date: Jun 2020 --> Jun 2021 | Trial primary completion date: Jun 2020 --> Jun 2021
- || Zykadia (ceritinib) / Novartis, Mekinist (trametinib) / Novartis, BeiGene
Trial completion date, Trial primary completion date, Metastases: Ceritinib + Trametinib in Patients With Advanced ALK-Positive Non-Small Cell Lung Cancer (NSCLC) (clinicaltrials.gov) - Nov 15, 2019
P1/2, N=69, Recruiting, Sponsor: University of California, San Francisco
Trial completion date: Jun 2020 --> Jun 2021 | Trial primary completion date: Jun 2020 --> Jun 2021 Trial completion date: Mar 2021 --> Jun 2021 | Trial primary completion date: Mar 2020 --> Jun 2020
- ||| Zykadia (ceritinib) / Novartis, Mekinist (trametinib) / Novartis, BeiGene
Trial suspension: Study of Trametinib + Ceritinib in Patients With Unresectable Melanoma (clinicaltrials.gov) - Nov 13, 2019
P2, N=27, Suspended, Sponsor: H. Lee Moffitt Cancer Center and Research Institute
Trial completion date: Mar 2021 --> Jun 2021 | Trial primary completion date: Mar 2020 --> Jun 2020 Recruiting --> Suspended
- | Xalkori (crizotinib) / Pfizer, Zykadia (ceritinib) / Novartis, Alecensa (alectinib) / Roche
Retrospective data, Journal: The efficacy and safety of ALK inhibitors in the treatment of ALK-positive non-small cell lung cancer: A network meta-analysis. (Pubmed Central) - Nov 11, 2019
Patients treated with alectinib or ceritinib tended to have higher ORR and DCR than patients with similar baselines treated with crizotinib or chemotherapy. No significant differences in discontinuation rate were found for alectinib, ceritinib, crizotinib, and chemotherapy.