Crizotinib in  ROS1 -rearranged advanced non-small-cell lung cancer (NSCLC): updated results, including overall survival, from PROFILE 1001

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Abstract

Background

In 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 methods

ROS1 status was determined by FISH or reverse transcriptase–polymerase chain reaction. All patients received crizotinib at a starting dose of 250 mg twice daily.

Results

Fifty-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.

Conclusions

These 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 Number

ClinicalTrials.gov identifier NCT00585195

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Most cited references 12

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Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer.

Klarisa Rikova, Ailan Guo, Qingfu Zeng … (2008)

Despite the success of tyrosine kinase-based cancer therapeutics, for most solid tumors the tyrosine kinases that drive disease remain unknown, limiting our ability to identify drug targets and predict response. Here we present the first large-scale survey of tyrosine kinase activity in lung cancer. Using a phosphoproteomic approach, we characterize tyrosine kinase signaling across 41 non-small cell lung cancer (NSCLC) cell lines and over 150 NSCLC tumors. Profiles of phosphotyrosine signaling are generated and analyzed to identify known oncogenic kinases such as EGFR and c-Met as well as novel ALK and ROS fusion proteins. Other activated tyrosine kinases such as PDGFRalpha and DDR1 not previously implicated in the genesis of NSCLC are also identified. By focusing on activated cell circuitry, the approach outlined here provides insight into cancer biology not available at the chromosomal and transcriptional levels and can be applied broadly across all human cancers.

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ROS1 rearrangements define a unique molecular class of lung cancers.

Kristin Bergethon, Alice Shaw, Sai-Hong Ignatius Ou … (2012)

Chromosomal rearrangements involving the ROS1 receptor tyrosine kinase gene have recently been described in a subset of non-small-cell lung cancers (NSCLCs). Because little is known about these tumors, we examined the clinical characteristics and treatment outcomes of patients with NSCLC with ROS1 rearrangement. Using a ROS1 fluorescent in situ hybridization (FISH) assay, we screened 1,073 patients with NSCLC and correlated ROS1 rearrangement status with clinical characteristics, overall survival, and when available, ALK rearrangement status. In vitro studies assessed the responsiveness of cells with ROS1 rearrangement to the tyrosine kinase inhibitor crizotinib. The clinical response of one patient with ROS1-rearranged NSCLC to crizotinib was investigated as part of an expanded phase I cohort. Of 1,073 tumors screened, 18 (1.7%) were ROS1 rearranged by FISH, and 31 (2.9%) were ALK rearranged. Compared with the ROS1-negative group, patients with ROS1 rearrangements were significantly younger and more likely to be never-smokers (each P < .001). All of the ROS1-positive tumors were adenocarcinomas, with a tendency toward higher grade. ROS1-positive and -negative groups showed no difference in overall survival. The HCC78 ROS1-rearranged NSCLC cell line and 293 cells transfected with CD74-ROS1 showed evidence of sensitivity to crizotinib. The patient treated with crizotinib showed tumor shrinkage, with a near complete response. ROS1 rearrangement defines a molecular subset of NSCLC with distinct clinical characteristics that are similar to those observed in patients with ALK-rearranged NSCLC. Crizotinib shows in vitro activity and early evidence of clinical activity in ROS1-rearranged NSCLC.

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Identifying and targeting ROS1 gene fusions in non-small cell lung cancer.

Kurtis Davies, Anh Le, Mariana Theodoro … (2012)

Oncogenic gene fusions involving the 3' region of ROS1 kinase have been identified in various human cancers. In this study, we sought to characterize ROS1 fusion genes in non-small cell lung cancer (NSCLC) and establish the fusion proteins as drug targets. An NSCLC tissue microarray (TMA) panel containing 447 samples was screened for ROS1 rearrangement by FISH. This assay was also used to screen patients with NSCLC. In positive samples, the identity of the fusion partner was determined through inverse PCR and reverse transcriptase PCR. In addition, the clinical efficacy of ROS1 inhibition was assessed by treating a ROS1-positive patient with crizotinib. The HCC78 cell line, which expresses the SLC34A2-ROS1 fusion, was treated with kinase inhibitors that have activity against ROS1. The effects of ROS1 inhibition on proliferation, cell-cycle progression, and cell signaling pathways were analyzed by MTS assay, flow cytometry, and Western blotting. In the TMA panel, 5 of 428 (1.2%) evaluable samples were found to be positive for ROS1 rearrangement. In addition, 1 of 48 patients tested positive for rearrangement, and this patient showed tumor shrinkage upon treatment with crizotinib. The patient and one TMA sample displayed expression of the recently identified SDC4-ROS1 fusion, whereas two TMA samples expressed the CD74-ROS1 fusion and two others expressed the SLC34A2-ROS1 fusion. In HCC78 cells, treatment with ROS1 inhibitors was antiproliferative and downregulated signaling pathways that are critical for growth and survival. ROS1 inhibition may be an effective treatment strategy for the subset of patients with NSCLC whose tumors express ROS1 fusion genes. ©2012 AACR.

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Author and article information

Journal

Journal ID (nlm-ta): Ann Oncol

Journal ID (iso-abbrev): Ann. Oncol

Journal ID (publisher-id): annonc

Title: Annals of Oncology

Publisher: Oxford University Press

ISSN (Print): 0923-7534

ISSN (Electronic): 1569-8041

Publication date (Print): July 2019

Publication date (Electronic): 13 April 2019

Publication date PMC-release: 13 April 2019

Volume: 30

Issue: 7 , Targeting the PI3-kinase pathway in triple-negative breast cancer

Pages: 1121-1126

Affiliations

[1 ]Department of Medicine, Massachusetts General Hospital Cancer Center, Boston

[2 ]Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA

[3 ]Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea

[4 ]Division of Medical Oncology, University of Colorado Cancer Center, Aurora, USA

[5 ]Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia

[6 ]Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA

[7 ]Pfizer Oncology, Milan, Italy

[8 ]Pfizer Oncology, La Jolla

[9 ]Chao Family Comprehensive Cancer Center, University of California, Irvine, USA

Author notes

Correspondence to: Prof. Alice T. Shaw, Department of Medicine, Massachusetts General Hospital Cancer Center, 55 Fruit St, Boston, MA 02114, USA. Tel: +1 617-643-0563; E-mail: ashaw1@ 123456mgh.harvard.edu

Article

Publisher ID: mdz131

DOI: 10.1093/annonc/mdz131

PMC ID: 6637370

PubMed ID: 30980071

SO-VID: a2a0f01f-49ae-49cc-8b81-3f883a0eb693

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

History

Page count

Pages: 6

Funding

Funded by: PROFILE 1001 study

Award ID: NCT00585195

Funded by: Pfizer Inc. 10.13039/100004319

Funded by: Springer Healthcare

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Crizotinib in ROS1-rearranged advanced non-small-cell lung cancer (NSCLC): updated results, including overall survival, from PROFILE 1001

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Abstract

Background

Patients and methods

Results

Conclusions

Trial Registration Number

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Karger: Oncology

Most cited references 12

Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer.

ROS1 rearrangements define a unique molecular class of lung cancers.

Identifying and targeting ROS1 gene fusions in non-small cell lung cancer.

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