When Policy Topic is covered Crizotinib may be considered medically necessary in patients 18 years or older when the following criteria are met:

Transcription

1 Xalkori (crizotinib) Policy Number: Last Review: 6/2018 Origination: 7/2012 Next Review: 6/2019 Policy Blue Cross and Blue Shield of Kansas City (Blue KC) will provide coverage for crizotinib when it is determined to be medically necessary because the criteria shown below are met. When Policy Topic is covered Crizotinib may be considered medically necessary in patients 18 years or older when the following criteria are met: 1. Patients with diagnosis of metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test (documentation provided) 2. Metastatic NSCLC whose tumors are repressor of silencing (ROS-1) -positive. Other uses with supportive evidence: 1. Recurrence of non-small cell lung cancer (NSCLC) with ALK-positive tumors 2. NSCLC with MET Amplification 3. Soft tissue sarcoma - Inflammatory myofibroblastic tumor (IMT) with ALK translocation When Policy Topic is not covered Crizotinib is considered investigational when used for all other conditions, including, but not limited to: NSCLC, Metastatic Initiating Therapy with Xalkori Whose ALK Status is Negative or Unknown and who do not have the ROS1 rearrangement (or ROS1 rearrangement is unknown) or the MET amplification. Considerations Crizotinib requires prior authorization through the pharmacy services department. This Blue Cross and Blue Shield of Kansas City policy Statement was developed using available resources such as, but not limited to: Food and Drug Administration (FDA) approvals, Facts and Comparisons, National specialty guidelines, Local medical policies of other health plans, Medicare (CMS), Local providers. Description of Procedure or Service Xalkori, an oral kinase inhibitor, is indicated for treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an Food and Drug Administration (FDA)-approved test.1 Xalkori is an inhibitor of receptor tyrosine kinases including ALK, Hepatocyte Growth Factor Receptor (HGFR, c-met), ROS1 (c-ros), and Recepteur d Origine Nantais (RON). Translocations can affect the ALK gene resulting in the expression of oncogenic fusion proteins. The formation of ALK fusion proteins results in activation and dysregulation of the gene s expression and signaling which can contribute to increased cell proliferation and survival

2 in tumors expressing these proteins. Xalkori demonstrated concentration-dependent inhibition of ALK, ROS1, and c-met phosphorylation in cell-based assays using tumor cell lines and demonstrated antitumor activity in mice bearing tumor xenografts that expressed EML4- or NPM-ALK fusion proteins or c-met. The ALK gene presents in approximately 1% to 7% of patients with NSCLC, usually nonsmokers.3 Rationale Guidelines The National Comprehensive Cancer Network (NCCN) guidelines (version ) for NSCLC indicate that the ALK fusion oncogene (i.e., ALK gene rearrangement) is a new predictive biomarker that has been identified in a small subset of patients with NSCLC.3 Other gene rearrangements (i.e., gene fusions) have recently been identified (such as ROS1) that are susceptible to targeted therapy. Testing for epidermal growth factor receptor (EGFR) mutations and ALK gene rearrangements is recommended in the NCCN guidelines for select patients (such as patients with adenocarcinoma) so that patients can receive effective treatment. Other driver mutaitons and gene fusions are being identified such as ROS1. Xalkori is available to patients with this genetic alteration, although it doesn t carry the FDA indication. The NCCN guidelines recommend Xalkori for patients with ALK or ROS1 gene fusions (category 2A). Xalkori should be used in patients with ALK-positive NSCLC of nonsquamous histology as first-line therapy for advanced or metastatic disease.3 Pharmacogenomic Testing It is estimated that 2% to 7% of patients have ALK gene rearrangements, about 10,000 patients in the US.3 These patients are resistant to EGFR tyrosine kinase inhibitors (TKIs) but have similar characteristics to those with EGFR mutations (i.e., adenocarcinoma, nonsmokers or light smokers) except that they are often younger and male. In these selected populations, estimates are that about 30% of patients will have echinoderm microtubule-associated protein-like 4 (EML4)-ALK rearrangementsxalkori has been shown to yield very high response rates (> 60%) and to improve survival when used in patients with advanced NSCLC who have ALK rearrangements and have progressed on previous therapy. Patients have responded rapidly to Xalkori with improvement in symptoms (e.g., cough dyspnea, pain), although median time to progression on Xalkori is less than 1 year. ALK gene rearrangements represent the fusion between ALK and various partner genes, including echinoderm microtubule-associated protein-like 4 (EML4). For themost part, ALK translocations and EGFR mutaitons are mutually exclusive. The current standard method for detecting ALK NSCLC is fluorescence in situ hybridization (FISH), although other methods are currently being evaluated, includeing polymerase chain reaction (PCR) and IHC. The appropriate antibody and detection method for ALK protein expression can be used for rapid prescreening of ALK-rearranged lung andenocarcinomas and selection of cases that will subsequently be confirmed by FISH testing. According to the prescribing information, Xalkori was approved and should only be used in patients with metastatic NSCLC that is ALK-positive as detected by an FDA-approved test.1 The drug was approved simultaneously with and is intended to be used in conjunction with the Vysis ALK Break Apart FISH Probe Kit, also referred to as Abbott ALK test, which is a genetic test that determines if the patient has the ALK gene.1 The Abbott ALK test uses FISH technology to detect chromosomal rearrangements in tumors. The test is widely available and has a total turn-around-time (test pretreatment to results) of 48 hours. Other FISH probes are available, but these methods are not approved for use with Xalkori. Clinical Efficacy Xalkori is indicated for the treatment of patients with metastatic NSCLC that is ALK-positive as detected by an approved test.1 The NCCN guidelines for NSCLC recommend Xalkori for patients with ROS1 rearrangements (category 2A).3 Limited data are available, and the patient population is small. ROS1 gene fusions are estimated to be present in 1% to 2% of NSCLCs.5,7 There are case reports in patients who are ROS1 positive treated with Xalkori.5-7 A 31 year old, male, never-smoker without EGFR mutation or ALK rearrangement was initially treated with Tarceva (erlotinib tablets) and had no response.5 He was

3 found to be ROS1 positive and started on Xalkori 250 mg twice daily (BID) [approved dose]. In less than 1 week, he noted a significant improvement in symptoms, and by 2 weeks, his hypoxia had resolved. Restaging at 8 weeks demonstrated near complete resolution of his multifocal lung tumor. The patient continued on Xalkori and at the time of the report (6 months after starting therapy) the patient had no evidence of recurrence. Another patient, a 55 year old women with stage IV relapsed lung adenocarcinoma (no EGFR mutations or ALK rearrangement) was found to have a ROS1 translocation positive tumor and subsequently was treated with Xalkori.6 She experienced clinical improvement corresponding to a complete metabolic response in fluorodeoxyglucose positron emisson tomography (18F-FDG-PET) and a good and confirmed patients response in computed temography (CT). Another patient testing positive for ROS1 rearrangement demonstrated tumor shrinkage with Xalkori treatment.7 This patient was a 65 year-old male, never-smoker with adenocarcinoma that was found to be wild-type for EGFR and KRAS and negative for rearrangement of ALK. He was treated with Xalkori 250 mg BID in 28 day cycles. After two cycles of continous Xalkori therapy there was a 57% tumor shrinkage (using Response Evaluation Criteria In Solid Tumors [RECIST 1.1]) with an associated decrease in standardized uptake value (SUV) from 10.8 to 3.7. This was confirmed on subsequent imaging and consistent with a partial response to Xalkori. A Phase I study enrolled 50 patients with advanced NSCLC who tested positive for ROS1 rearrangement.11 Patients were treated wth the standard Xalkori dose of 250 mg BID. Xalkori showed marked antitumor activity with objective response rate of 72% (95% CI: 58, 84) with three complete responses and 33 partial responses. The median duration of response was 17.6 months and the median progression-free survival was 19.2 months The NCCN guidelines for NSCLC recommend Xalkori for patients with MET amplification (category 2A).3 There are limited data available with Xalkori use in patients with NSCLC and MET amplification.8,10 The NCCN guidelines for soft tissue sarcoma (version ) recommend Xalkori as single-agent therapy for the treatment of IMT with ALK translocation (category 2A recommendation).4 Rearrangements involving the ALK locus on chromosome 2p33 have been documented in approximately 50% of inflammatory myofibroblastic tumors (IMTs).2 IMTs occur primarily during the first two decades of life and typically arise in the lung, retroperitoneum, or abdominal region. Local recurrence may occur after initial surgery, with a low risk of distant metastases. Sustained partial response to Xalkori in a patient with ALK-translocated IMT, and no observed activity in a patient without ALK translocation have been reported. The patient with a translocation in ALK received doxorubicin and ifosfamide for 3 months followed by maintenance therapy with Gleevec (imatinib tablets/capsules) for 3 months at which time a follow-up CT revealed asymptomatic, multifocal, recurrent peritoneal nodules. The patient began Xalkori (200 mg BID) 1 month later and on two subsequent CT scans (2 and 3 months after starting therapy, respectively) reductions of 40% and 53%, respectively in the sum of unidimensional measurements of target lesions, were classified as partial response, according to RECIST. The maximal response was achieved 7 months after Xalkori was started, at that time despite the continued partial response of multiple mesenteric and peritoneal lesions, growth of three lesions (hepatic, peripancreatic, and perirectal masses) were noted. Further growth was noted and the patient subsequently had the growing lesions resected. Following recovery, Xalkori was restarted (250 mg BID). As of September 2012, the patient remained in complete radiographic remission. In another case report, a 45-year old Hispanic female was eventually diagnosed to have IMT with systemic involvement and ALK gene rearrangement.9 The patient presented with synchronous tumors in the liver and lumbar spine. The patient was treated with Xalkori and had a successful resolution of her lesions and symptoms. After a 27-month follow-up, the patient remained in complete clinical and radiologic remission. Xalkori is not indicated for use in patients with ALK-negative NSCLC.1 The NCCN guidelines for NSCLC indicate that testing for ALK gene rearrangements is recommended for select patients (e.g., those with adenocarcinoma) so that patients with these genetic abnormalities can receive effective

4 treatment (e.g., Xalkori).3 Patients may have the ROS1 rearrangement but be ALK negative, use in such patients (with ROS1 rearrangement) is supported in NCCN guidelines (see Other Uses with Supportive Evidence). For patients whose ALK status is negative or unkown, and who do not have an ROS1 rearrangement use of Xalkori is not indicated. Dosing Considerations [1] Crizotinib is available as both 200-mg and 250-mg capsules. The usual dose of crizotinib is 250 mg orally twice a day. This is the dose studied in the crizotinib clinical trials and the maximum dose listed in the FDA labeling for the product. The dose of crizotinib may be reduced to 200 mg orally twice a day, or 250 mg orally once daily based on individual safety or tolerability. There is the potential for significant drug-drug interactions when crizotinib is administered with medications that are strong inhibitors (e.g. clarithromycin, itraconazole) or inducers (e.g. carbamazepine, rifampin) of the CYP3A4 metabolic pathway. In addition, crizotinib may affect the metabolism of other medications that are metabolized via this pathway. References: 1. Xalkori capsules [package insert]. New York, NY: Pfizer Inc; May Butrynski JE, D'Adamo DR, Hornick JL, et al. Crizotinib in ALK-rearranged inflammatory myofibroblastic tumor. N Engl J Med. 2010;363(18): The NCCN Non-Small Cell Lung Cancer Clinical Practice Guidelines in Oncology (Version ) National Comprehensive Cancer Network, Inc. Available at: Accessed November 19, The NCCN Soft Tissue Sarcoma Clinical Practice Guidelines in Oncology (Version ) National Comprehensive Cancer Network, Inc. Available at: Accessed November 19, Bergethon K, Shaw AT, Ignatius SH, et al. ROS1 rearrangements define a uniqe molecular class of lung cancers. J Clin Oncol. 2012;30(8): Bos M, Gardizi M, Schildhaus HU, et al. Complete metabolic response in a patient with repeatedly relapsed non-small cell lung cancer harboring ROS1 gener rearrangement after treatment with crizotinib. Lung Cancer. 2013;81: Davies KD, Le AT, Theodoro MF, et al. Identifying and targeting ROS1 gene fusions in non-small cell lung cancer. Clin Cancer Res. 2012;18(17): Ou S-HI, Kwak EL, Siwak-Tapp C, et al. Activity of crizotinib (PF ), a dual mesenchymalepithelial transition (MET) and anaplastic lymphoma kinase (ALK) inhibitor, in a non-small cell lung cancer patient with de novo MET amplification. J Thorac Oncol. 2011;6: Jacob SV, Reith JD, Kojima AY, et al. An unusual case of systemic inflammatory myofibroblastic tumor with successful treatment with ALK-inhibitor. Case Rep Pathol. 2014;2014: Schwab R, Petak I, Kollar M, et al. Major partial response to crizotinib, a dual MET/ALK inhibitor, in a squamous cell lung carcinoma (SCC) patient with de novo c-met amplification in the absence of ALK rearrangement. Lung Cancer. 2014;83: Shaw AT, Ou SHI, Bang YJ, et al. Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med. 2014, September 27 [Epub ahead of print]. Billing Coding/Physician Documentation Information Xalkori is a pharmacy benefit Additional Policy Key Words Policy Number: Policy Implementation/Update Information

5 7/2012 New Policy Titled Xalkori 7/2013 Reviewed-no policy changes made 7/2014 Reviewed-no policy changes made 7/2015 Reviewed policy changed indication to match prescribing information and added new criteria for approval in NSCLC with MET amplification based on NCCN guidelines 7/2016 Reviewed- no policy changes made 7/2017 Reviewed- no policy changes made 6/2018 Reviewed- no policy changes made State and Federal mandates and health plan contract language, including specific provisions/exclusions, take precedence over Medical Policy and must be considered first in determining eligibility for coverage. The medical policies contained herein are for informational purposes. The medical policies do not constitute medical advice or medical care. Treating health care providers are independent contractors and are neither employees nor agents Blue KC and are solely responsible for diagnosis, treatment and medical advice. No part of this publication may be reproduced, stored in a retrieval system or transmitted, in any form or by any means, electronic, photocopying, or otherwise, without permission from Blue KC.