Cost-effectiveness analysis of first-line treatment with crizotinib in ROS1-rearranged advanced non-small cell lung cancer (NSCLC) in Canada
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Abstract:
While no direct comparative data exist for crizotinib in ROS1+ non-small cell lung cancer (NSCLC), studies have suggested clinical benefit with this targeted agent. The objective of this study was to assess the cost-effectiveness of crizotinib compared to standard platinum-doublet chemotherapy for first-line treatment of ROS1+ advanced NSCLC.A Markov model was developed with a 10-year time horizon from the perspective of the Canadian publicly-funded health care system. Health states included progression-free survival (PFS), up to two further lines of therapy post-progression, palliation and death. Given a lack of comparative data and small study samples, crizotinib or chemotherapy studies with advanced ROS1+ NSCLC patients were identified and time-to-event data from digitized Kaplan-Meier curves were collected to pool PFS data. Costs of drugs, treatment administration, monitoring, adverse events and palliative care were included in 2018 Canadian dollars, with 1.5% discounting. An incremental cost-effectiveness ratio (ICER) was estimated probabilistically using 5000 simulations.In the base-case probabilistic analysis, crizotinib produced additional 0.885 life-years and 0.772 quality-adjusted life-years (QALYs) at an incremental cost of $238,077, producing an ICER of $273,286/QALY gained. No simulations were found to be cost-effective at a willingness-to-pay threshold of $100,000/QALY gained. A scenario analysis assuming efficacy equivalent to the ALK+ NSCLC population showed a slightly more favorable cost-effectiveness profile for crizotinib.Available data appear to support superior activity of crizotinib compared to chemotherapy in ROS1+ advanced NSCLC. At the list price, crizotinib was not cost-effective at commonly accepted willingness-to-pay thresholds across a wide range of sensitivity analyses.Keywords:
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Introduction: Crizotinib (PF02341066) was first synthesized as an inhibitor of MET tyrosine kinase (TK) and was later shown to have a potent inhibitory effect on other TKs such as anaplastic lymphoma kinase (ALK) and ROS proto-oncogene 1 (ROS1), which are altered in 3 – 7% and 2% of non-small-cell lung cancers (NSCLCs), respectively. The aim of this review is to discuss the activity of crizotinib in patients with NSCLC whose tumors contain alterations in these genes.Areas covered: PubMed was searched for articles published in English between January 1, 2007, and June 1, 2015 using the terms “lung adenocarcinoma,” “NSCLC,” “crizotinib” and “ALK.” Articles relevant to the topic were also identified from our own files. This article summarizes results from various early-phase and Phase III clinical trials in NSCLC with crizotinib. The mechanisms by which NSCLCs that initially respond to crizotinib eventually acquire resistance to therapy, and the role of newer ALK inhibitors, such as ceritinib, in this setting, has also been briefly discussed.Expert opinion: While crizotinib is currently approved for use and improves outcomes in patients with metastatic ALK-rearranged NSCLC, its role in the management of NSCLCs driven by other alterations (such as MET, ROS1 and NTRK1) and early-stage disease remain to be established by ongoing studies. Furthermore, results from studies directly comparing crizotinib to newer ALK inhibitors are eagerly awaited to help identify the best first-line agent for the management of ALK-rearranged NSCLC.
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Crizotinib, an ALK/MET/ROS1 inhibitor, was approved by the U.S. Food and Drug Administration for the treatment of anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) in August 2011, merely 4 years after the first publication of ALK-rearranged NSCLC. The crizotinib approval was accompanied by the simultaneous approval of an ALK companion diagnostic fluorescent in situ hybridization assay for the detection of ALK-rearranged NSCLC. Crizotinib continued to be developed as an ALK and MET inhibitor in other tumor types driven by alteration in ALK and MET. Crizotinib has recently been shown to be an effective ROS1 inhibitor in ROS1-rearranged NSCLC, with potential future clinical applications in ROS1-rearranged tumors. Here we summarize the heterogeneity within the ALK- and ROS1-rearranged molecular subtypes of NSCLC. We review the past and future clinical development of crizotinib for ALK-rearranged NSCLC and the diagnostic assays to detect ALK-rearranged NSCLC. We highlight how the success of crizotinib has changed the paradigm of future drug development for targeted therapies by targeting a molecular-defined subtype of NSCLC despite its rarity and affected the practice of personalized medicine in oncology, emphasizing close collaboration between clinical oncologists, pathologists, and translational scientists.
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Abstract ALK rearrangements and ROS1 rearrangements are important therapeutic targets in non-small cell lung cancer (NSCLC). ALK-positive NSCLC is currently treated with the first-generation ALK inhibitor crizotinib followed by more potent, second-generation ALK inhibitors, such as ceritinib, alectinib, or brigatinib, and ROS1-positve NSCLC is currently treated with crizotinib. Even though these drugs produce responses in most patients, drug resistance eventually develops. Notable mechanisms of resistance are kinase domain solvent front mutations, such as ALK G1202R and ROS1 G2032R. Genomic analysis of relapsed cases show ALK G1202R in 21%, 29%, or 43% of ceritinib-, alectinib-, or brigarinib-resistant cases, and ROS1 G2032R in 41% of crizotinib-resistant cases. The novel ALK/ROS1 inhibitor TPX-0005 was designed to overcome clinical resistance mutations, especially solvent front mutations, and is currently being evaluated in a phase 1/2 study. Engineered preclinical models have demonstrated the potency of TPX-0005 against ALK G1202R and ROS1 G2032R. For example, Ba/F3 cells expressing EML4-ALK G1202R or CD74-ROS1 G2032R resistant to second-generation ALK inhibitors or crizotinib, respectively, but were sensitive to TPX-0005. Here we investigate the potency of TPX-0005 to overcome solvent front mutations in resistant patient-derived models. We generated cell lines and patient-derived xenograft mouse models from ALK G1202R and ROS1 G2032R tumors at the time of relapse on second-generation ALK inhibitors or crizotinib, respectively. As expected, these models were resistant to second-generation ALK inhibitors or crizotinib. In contrast, TPX-0005 suppressed ALK or ROS1 phosphorylation, and led to decreased cell viability and tumor regression in vivo. These data demonstrate that TPX-0005 overcomes solvent front mutations in clinically relevant models and provides rationale for the clinical development of TPX-0005 for patients harboring ALK G1202R or ROS1 G2032R resistance mutations. Citation Format: Satoshi Yoda, Leila Dardaei, Kylie Prutisto-Chang, Jean Cui, Alice T. Shaw, Aaron N. Hata. Potency of a new ALK/ROS1 inhibitor TPX-0005 to ALK G1202R mutation and ROS1 G2032R mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4795.
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Crizotinib is a tyrosine kinase inhibitor (TKI) indicated in first-line treatment of rearranged c-ros oncogene 1 (ROS1) and anaplastic lymphoma kinase (ALK) metastatic non-small-cell lung cancer (NSCLC). However, the common response reported after treatment is partial and few complete responses have been reported in PROFILE studies with computed tomography (CT) evaluation. To date, only one case report of complete metabolic response on 2-deoxy-2-[ 18 F] fluoro-D-glucose positron emission tomography-computed tomography ( 18 F-FDG-PET/CT) was published, reporting on a patient with ROS1 rearranged NSCLC. We highlighted the 18 F-FDG-PET/CT useful approach for therapeutic assessment of TKI in metastatic mutated NSCLC reporting two complete metabolic responses in patients treated with crizotinib for a rearranged ROS1 and a metastatic ALK NSCLC.
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Abstract Oncogenic fusions of anaplastic lymphoma kinase (ALK) define a subset of human lung adenocarcinoma. The 1st generation ALK inhibitor crizotinib demonstrated impressive clinical benefit in ALK-fusion positive lung cancers and was approved by the FDA for the treatment of ALK-fusion positive NSCLC in 2011. However, as seen with most kinase inhibitors, patients treated with crizotinib eventually develop resistance to therapy. Acquired ALK kinase domain mutations and disease progression in the central nervous system (CNS) are reported as main contributors to patient relapse after ALK inhibitor therapy. Preclinically, crizotinib lacks significant brain penetration and does not potently inhibit activity of ALK kinase domain mutants, so a drug discovery program was initiated aimed to develop a second generation ALK inhibitor that is more potent than existing ALK inhibitors, capable of inhibiting the resistant ALK mutants and penetrating the blood-brain-barrier. These objectives present a considerable challenge in kinase inhibitor chemical space. Here we report that PF-06463922, a novel small molecule ATP-competitive inhibitor of ALK/ROS1, showed exquisite potencies against non-mutant ALK (Ki <0.2 nM; cell IC50 ∼2 nM) and ROS1 kinase (Ki <0.005 nM; cell IC50 ∼0.2 nM), and demonstrated low nanomolar inhibitory activity against a panel of ALK kinase domain mutants representing all of the patient crizotinib resistant mutations reported to date. The more commonly reported L1196M gatekeeper mutant shows significant sensitivity to PF-06463922 (Ki 0.7 nM; cell IC50 16 nM). PF-06463922 is also very selective, and showed >100 fold kinase selectivity against 95% of the kinases tested in a 207 recombinant kinase panel. Specific design considerations were developed leading to novel ATP-competitive kinase inhibitors with desired low efflux in cell lines over-expressing p-glycoprotein and breast cancer resistance protein, providing excellent blood-brain-barrier and cell penetration properties. Efforts to optimize ligand efficiency and lipophilic efficiency leveraging structure based drug design techniques led to ligands with overlapping broad spectrum potency and low efflux. Single and repeat dose preclinical rat in vivo studies of PF-06463922 demonstrated excellent oral bioavailability and CNS availability with free brain exposure approximately 30% of free plasma levels. In addition, CNS-directed safety studies showed no adverse events at predicted efficacious concentrations. It is anticipated that PF-06463922 with its potent activities on non-mutant ALK, ALK kinase domain mutations and CNS metastases would provide great promise for patients with ALK and ROS1 positive cancers. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):PR10. Citation Format: Ted W. Johnson, Simon Bailey, Benjamin J. Burke, Michael R. Collins, J. Jean Cui, Judy Deal, Ya-Li Deng, Martin P. Edwards, Mingying He, Jacqui Hoffman, Robert L. Hoffman, Qinhua Huang, Robert S. Kania, Phuong Le, Michele McTigue, Cynthia L. Palmer, Paul F. Richardson, Neal W. Sach, Graham L. Smith, Lars Engstrom, Wenyue Hu, Hieu Lam, Justine L. Lam, Tod Smeal, Helen Y. Zou. Is CNS availability for oncology a no-brainer? Discovery of PF-06463922, a novel small molecule inhibitor of ALK/ROS1 with preclinical brain availability and broad spectrum potency against ALK-resistant mutations. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr PR10.
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Introduction: Anaplastic lymphoma kinase (ALK) and ROS1 rearrangements define important molecular subgroups of advanced non-small cell lung cancer (NSCLC). The identification of these genetic driver alterations created new potential for highly active therapeutic interventions. After discovery of ALK rearrangements in NSCLC, it was recognized that these confer sensitivity to ALK inhibition.Areas covered: Crizotinib, the first-in-class ALK/ROS1/MET inhibitor, was initially approved as second-line treatment of ALK-positive advanced NSCLC but after this, it was firmly established as the standard first-line therapy for advanced ALK-positive NSCLC. After initial response to crizotinib, tumors inevitably relapse. Next-generation ALK inhibitors, more potent and brain-penetrable than crizotinib, may be effective in re-inducing remissions when cancers are still addicted to ALK. Ceritinib and alectinib are approved for metastatic ALK positive NSCLC patients, while brigatinib received granted accelerated approval by the United States Food and Drug Administration. Regarding ROS1 rearrangement, to date crizotinib is the only ALK-tyrosine kinase inhibitor receiving indication as treatment of ROS1 positive advanced NSCLC.Expert commentary: Although novel ALK-inhibitors are under clinical investigation compared to crizotinib as front-line treatment for ALK-positive NSCLC, nowadays the current standard first-line therapy for these patients is crizotinib. Further research will clarify the best management of ALK-positive NSCLC, above all who progress on first-line crizotinib.
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