Dataset Information

Crizotinib inhibition of ROS1-positive tumours in advanced non-small-cell lung cancer: a Canadian perspective.

ABSTRACT: The ros1 kinase is an oncogenic driver in non-small-cell lung cancer (nsclc). Fusion events involving the ROS1 gene are found in 1%-2% of nsclc patients and lead to deregulation of a tyrosine kinase-mediated multi-use intracellular signalling pathway, which then promotes the growth, proliferation, and progression of tumour cells. ROS1 fusion is a distinct molecular subtype of nsclc, found independently of other recognized driver mutations, and it is predominantly identified in younger patients (<50 years of age), women, never-smokers, and patients with adenocarcinoma histology. Targeted inhibition of the aberrant ros1 kinase with crizotinib is associated with increased progression-free survival (pfs) and improved quality-of-life measures. As the sole approved treatment for ROS1-rearranged nsclc, crizotinib has been demonstrated, through a variety of clinical trials and retrospective analyses, to be a safe, effective, well-tolerated, and appropriate treatment for patients having the ROS1 rearrangement. Canadian physicians endorse current guidelines which recommend that all patients with nonsquamous advanced nsclc, regardless of clinical characteristics, be tested for ROS1 rearrangement. Future integration of multigene testing panels into the standard of care could allow for efficient and cost-effective comprehensive testing of all patients with advanced nsclc. If a ROS1 rearrangement is found, treatment with crizotinib, preferably in the first-line setting, constitutes the standard of care, with other treatment options being investigated, as appropriate, should resistance to crizotinib develop.

SUBMITTER: Bebb DG

PROVIDER: S-EPMC6726257 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Crizotinib inhibition of ROS1-positive tumours in advanced non-small-cell lung cancer: a Canadian perspective.

Bebb D G DG Agulnik J J Albadine R R Banerji S S Bigras G G Butts C C Couture C C Cutz J C JC Desmeules P P Ionescu D N DN Leighl N B NB Melosky B B Morzycki W W Rashid-Kolvear F F Lab Clin C Sekhon H S HS Smith A C AC Stockley T L TL Torlakovic E E Xu Z Z Tsao M S MS

Current oncology (Toronto, Ont.) 20190801 4

The ros1 kinase is an oncogenic driver in non-small-cell lung cancer (nsclc). Fusion events involving the ROS1 gene are found in 1%-2% of nsclc patients and lead to deregulation of a tyrosine kinase-mediated multi-use intracellular signalling pathway, which then promotes the growth, proliferation, and progression of tumour cells. ROS1 fusion is a distinct molecular subtype of nsclc, found independently of other recognized driver mutations, and it is predominantly identified in youn ...[more]

PMID: 31548824

Similar Datasets

Project description:BackgroundCrizotinib was the first oral targeted therapy approved by the US Food and Drug Administration (FDA), on 11 March 2016, for c-ros oncogene 1 (ROS1)-positive advanced non-small-cell lung cancer (NSCLC). Data to support long-term clinical benefit in a real-world setting are limited.ObjectiveThis study aimed to assess real-world clinical outcomes among patients with ROS1-positive advanced NSCLC treated with crizotinib in the US community oncology setting.Patients and methodsWe conducted a retrospective cohort study using iKnowMed electronic health record data to identify adult patients with ROS1-positive advanced NSCLC who initiated crizotinib between 17 January 2013 (time of the addition of crizotinib for ROS1-positive NSCLC to National Comprehensive Cancer Network (NCCN) treatment guidelines) and 1 June 2019 with a potential follow-up period through 1 December 2019. Patient characteristics were assessed descriptively. Kaplan-Meier analyses were used to evaluate time to treatment discontinuation (TTD), time to next treatment (TTNT), and overall survival (OS). A Cox proportional hazards model was conducted to determine factors associated with OS.ResultsThe study cohort included 38 ROS1-positive patients treated with crizotinib. The median age was 68 years (interquartile range 60.0-73.0) and 65.8% were female. Over 50% were current/former smokers, and 18.4% had an Eastern Cooperative Oncology Group (ECOG) performance status of 2. Overall, 21 (55.3%) patients remained on crizotinib, 10 (26.3%) had evidence of subsequent treatment, and 16 (42.1%) died. The median TTD, TTNT, and OS were 25.2 months [95% confidence interval (CI): 5.2-not reached (NR)], 25.0 months (95% CI 5.2-61.0), and 36.2 months (95% CI 15.9-NR), respectively. In a multivariate Cox regression model, ECOG performance status of 2 was associated with a 4.9-fold higher risk of death (hazard ratio = 4.9; 95% CI 1.1-21.4) compared to ECOG performance status of 0 or 1.ConclusionsThis ROS1-positive NSCLC real-world population was older and had a higher proportion of smokers and of patients with poorer ECOG performance status than those investigated in clinical trials. Nevertheless, our findings support the clinical benefit of crizotinib in this patient population with ROS1-positive advanced NSCLC.

Project description:Patients with non-small cell lung cancer (NSCLC) harboring ROS proto-oncogene 1, receptor tyrosine kinase gene (ROS1) chromosomal rearrangements benefit from treatment with the ROS1 inhibitor crizotinib. Limited data exist on the spectrum of resistance mechanisms in ROS1-positive NSCLC. To delineate mechanisms of acquired resistance, we analyzed biopsy samples of tumor lesions that progressed while patients were receiving crizotinib.An activating mutation in the KIT proto-oncogene receptor tyrosine kinase (KIT) (p.D816G) was identified by SNaPshot sequencing in a tumor sample from a patient with ROS1-positive NSCLC identified by fluorescence in situ hybridization whose disease progressed after initial response to crizotinib. In vitro studies included evaluation of KIT mRNA expression by quantitative reverse-transcriptase polymerase chain reactions, transduction of Ba/F3 cells and NSCLC cell lines with KIT-expressing lentiviral plasmids, immunoblotting, and cellular proliferation assays.KIT(D816G) is an activating mutation that induces autophosphorylation and cell proliferation. Expression of the mutant KIT(D816G) receptor in ROS1-positive NSCLC cell lines led to constitutively activated KIT as measured by phosphorylation of the KIT receptor. Expression of the KIT(D816G) rendered the HCC78 and CUTO2 cell lines resistant to crizotinib, and only dual inhibition of ROS1 and KIT with crizotinib and ponatinib could resensitize the cells to inhibition of proliferation. The oncogenic switch observed in ROS1-positive cell lines was not immediate and required pharmacologic inactivation of ROS1.Activation of KIT by a gain-of-function somatic mutation is a novel mechanism of resistance to crizotinib in ROS1-rearranged NSCLC. This bypass signaling pathway serves as a ROS1-independent mechanism of resistance, similarly to previously identified epidermal growth factor receptor or Kirsten rat sarcoma viral oncogene homolog/neuroblastoma RAS viral oncogene homolog signaling pathways, and can potentially be targeted by KIT inhibitors.

Project description:ObjectivesFood and Drug Administration (FDA) approved crizotinib for advanced ROS1-rearranged (ROS1+) non-small-cell lung cancer (NSCLC) patients due to a single-arm study PROFILE 1001. However, there is no direct comparison between crizotinib and platinum-pemetrexed chemotherapy.Materials and methodsClinical data of advanced ROS1+NSCLC patients treated with first-line crizotinib or platinum-pemetrexed chemotherapy between August 2010 and December 2017 were analyzed.ResultsSeventy-seven patients were eligible, including 30 (39.0%) in the crizotinib group and 47 (61.0%) in the platinum-pemetrexed chemotherapy group. The median follow-up was 28.1 months (95% confidence interval [CI]: 19.2-39.0). The objective response rate (ORR) of crizotinib (86.7%, 95% CI: 73.3-96.7) was higher than that of platinum-pemetrexed chemotherapy (44.7%, 95% CI: 29.8-57.4, P < .001). The disease control rate (DCR) was 96.7% (95% CI: 90.0-100) in the crizotinib group and 85.1% (95% CI: 74.5-95.7) in the chemotherapy group (P = .140). Significantly longer progression-free survival (PFS) was observed in the patients treated with crizotinib (18.4 months, 95% CI: 6.4-30.3) versus platinum-pemetrexed chemotherapy (8.6 months, 95% CI: 6.9-10.3, P < .001). Overall survival (OS) was also compared between the two groups and no significant difference was seen (Not reach vs 28.4 months [95% CI: 20.7-36.0], P = .176). Notably, a total of 37 patients have treatment crossover after the failure of first-line treatment. Among those patients, difference in OS was not statistically significant between seven patients who have given first-line crizotinib (38.6 months, 95% CI: 0-81.0) and 30 patients who have given platinum-pemetrexed chemotherapy initially (32.8 months, 95% CI: 11.9-53.8, P = .805).ConclusionsOur results suggested that first-line crizotinib had higher ORR and longer PFS than platinum-pemetrexed chemotherapy in patients with advanced ROS1+NSCLC, but the differences were not observed for OS.

Project description:BackgroundIn the ongoing phase I PROFILE 1001 study, crizotinib showed antitumor activity in patients with ROS1-rearranged advanced non-small-cell lung cancer (NSCLC). Here, we present updated antitumor activity, overall survival (OS) and safety data (additional 46.2 months follow-up) for patients with ROS1-rearranged advanced NSCLC from PROFILE 1001.Patients and methodsROS1 status was determined by FISH or reverse transcriptase-polymerase chain reaction. All patients received crizotinib at a starting dose of 250 mg twice daily.ResultsFifty-three patients received crizotinib, with a median duration of treatment of 22.4 months. At data cut-off, treatment was ongoing in 12 patients (23%). The objective response rate (ORR) was 72% [95% confidence interval (CI), 58% to 83%], including six confirmed complete responses and 32 confirmed partial responses; 10 patients had stable disease. Responses were durable (median duration of response 24.7 months; 95% CI, 15.2-45.3). ORRs were consistent across different patient subgroups. Median progression-free survival was 19.3 months (95% CI, 15.2-39.1). A total of 26 deaths (49%) occurred (median follow-up period of 62.6 months), and of the remaining 27 patients (51%), 14 (26%) were in follow-up at data cut-off. Median OS was 51.4 months (95% CI, 29.3 to not reached) and survival probabilities at 12, 24, 36, and 48 months were 79%, 67%, 53%, and 51%, respectively. No correlation was observed between OS and specific ROS1 fusion partner. Treatment-related adverse events (TRAEs) were mainly grade 1 or 2, per CTCAE v3.0. There were no grade ≥4 TRAEs and no TRAEs associated with permanent discontinuation. No new safety signals were reported with long-term crizotinib treatment.ConclusionsThese findings serve as a new benchmark for OS in ROS1-rearranged advanced NSCLC, and continue to show the clinically meaningful benefit and safety of crizotinib in this molecular subgroup.Trial registration numberClinicalTrials.gov identifier NCT00585195.

Dataset Information

Crizotinib inhibition of ROS1-positive tumours in advanced non-small-cell lung cancer: a Canadian perspective.

Publications

Crizotinib inhibition of <i>ROS1-</i>positive tumours in advanced non-small-cell lung cancer: a Canadian perspective.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets