Genomic Profiling in Previously Untreated Metastatic Non-small Cell Lung Cancer
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT02671045|
Recruitment Status : Terminated (Insufficient accrual to Horizon Bluecross Blueshield cohort)
First Posted : February 2, 2016
Last Update Posted : July 20, 2018
|First Submitted Date||January 14, 2016|
|First Posted Date||February 2, 2016|
|Last Update Posted Date||July 20, 2018|
|Study Start Date||April 2015|
|Actual Primary Completion Date||August 2017 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures
||Number of participants with all cause mortality [ Time Frame: Completion of study (estimated 5 years) ]
Comparison by cohorts
|Original Primary Outcome Measures||Same as current|
|Current Secondary Outcome Measures
|Original Secondary Outcome Measures||Same as current|
|Current Other Pre-specified Outcome Measures||Not Provided|
|Original Other Pre-specified Outcome Measures||Not Provided|
|Brief Title||Genomic Profiling in Previously Untreated Metastatic Non-small Cell Lung Cancer|
|Official Title||A Prospective Observational Study of Comprehensive Genomic Profiling in Previously Untreated Metastatic Non-small Cell Lung Cancer|
Overall survival rates for patients with metastatic NSCLC are poor utilizing conventional cytotoxic chemotherapy approaches. However, a subset of patients harbor genomic driver mutations, which when targeted with specific therapies, experience improved outcomes.
Unfortunately, identification of these mutations, although recommended in national guidelines, has been limited for a variety of factors including small biopsy samples. The broad application of a sensitive genomic profiling test, which simultaneously examines for multiple genomic alterations on limited biopsy material, could increase the identification of patients with actionable mutations and thereby improve survival in NSCLC. The FoundationOne test meets these requirements. A recent study using the FoundationOne assay identified a significant number of actionable mutations among NSCLC patients who were previously thought to be negative for mutations when tested using other approaches.
This is a non-randomized observational comparative study with various cohorts based on physician diagnostic patterns of care and biologic genomic profile status. Survival and cost information will be compared based on different use of genomic profiling.
The understanding of NSCLC is undergoing a rapid evolution from one disease treated with empirically chosen, costly cytotoxic chemotherapies, laden with adverse effects and benefits lasting only weeks or a few months, to a rapidly growing set of genomically defined diseases that can be matched to targeted therapies with markedly improved outcomes, including response rates of 70-80% and survivals often measured in years rather than months. The need for comprehensive genomic profiling tests able to accommodate the expanding list of genomic markers without necessitating new biopsies or rising cost is not just a convenience, but a medical necessity.
In October 2014, the National Comprehensive Cancer Network (NCCN) specifically recommended that patients with metastatic NSCLC undergo "broad molecular profiling" with the goal of identifying rare driver mutations for which effective drugs may already be available, or to appropriately counsel patients regarding the availability of clinical trials, including not only EGFR and ALK, but also BRAF, ERBB2 (HER2), MET, RET and ROS1. For example, while ERBB2 alterations are certainly more common in breast cancer, these same alterations have also been found in NSCLC and thus would predict response to targeted therapy with anti-HER2 agents. Specifically, each of these additional targetable alterations indicate a greatly increased likelihood of response to a respective targeted treatment, even though some of the treatments would be considered 'off-label' for lung cancer (e.g. trastuzumab or afatinib targeting patients with ERBB2 alterations; crizotinib for MET amplification and ROS1 rearrangements), or on-label drugs approved for lung cancer (e.g. crizotinib targeting patients with ALK rearrangements).
Problems in Genomic Testing: The substantial increase in the number of recommended targetable alterations in NSCLC presents multiple clinical and logistic challenges to the current model of gene-by-gene testing. These include non-validated testing, missed alterations that could have been matched to targeted therapy, insufficient tissue due to sequential or parallel testing, unacceptably long turnaround times, and physician frustration and confusion related to delays in obtaining all needed results and complex interpretation of multiple reports. Based on recent publications, it is reasonable to anticipate the list of targetable alterations that should be evaluated as 'standard of care' will only continue to expand. This reality makes the current model of individual tests in a gene-by-gene model unsustainable. For example traditional testing would require multiple modalities, including polymerase chain reaction (PCR)-based tests, capillary sequencing, fluorescence in situ hybridization (FISH)-based testing, and mass spectrometry-based sizing assays. Insufficient tissue to supply all of these tests is a particular problem. Traditional pathologic evaluation, including testing for the seven targetable alterations in the NCCN guidelines, may require more than 26 slides -- a tissue requirement that is usually beyond the amount obtained from minimally invasive biopsies. Competing demands for scarce tissue may place clinicians in an uncomfortable position of having to guess which tests to run when slides are running out, or alternatively, to consider conducting additional biopsy procedures. These challenges will only grow in complexity as biopsies become less invasive, the number of molecular markers and targeted therapeutic options increase, and evidence for newer markers becomes stronger.
FoundationOne is a comprehensive genomic profile that applies next generation sequencing in a unique manner to identify all 4 types of genomic alterations across all genes known to be unambiguous drivers of solid tumors with high accuracy. The test simultaneously sequences the coding region of 315 cancer-related genes plus introns from 28 genes often rearranged or altered in cancer to a typical median depth of coverage of greater than 500X. Each covered read represents a unique DNA fragment to enable the highly sensitive and specific detection of genomic alterations that occur at low frequencies due to tumor heterogeneity, low tumor purity and small tissue samples. FoundationOne detects all classes of genomic alterations, including base substitutions, insertions and deletions (indels), copy number alterations (CNAs) and rearrangements using a small, routine FFPE sample (including core or fine needle biopsies).
Foundation Medicine recently collaborated with Memorial Sloan-Kettering Cancer Center (MSKCC) to evaluate the clinical utility of this approach. After appropriate institutional approvals, a group of patients with advanced NSCLC who had completed in-house clinical testing in the CLIA-accredited MSKCC lab and who tested negative for all using conventional diagnostics, and who were alive and receiving systemic cytotoxic chemotherapy were identified. Before they were tested using FoundationOne, 24 of the first 34 such patients had required additional biopsies to complete the initial requisite testing. In 9 of the 34 clinical cases, FoundationOne could not be performed due to lack of available tissue after the initial rounds of MSKCC testing. FoundationOne was successfully performed in 25 patients uncovering one or more genomic alterations linked to a targeted agent based on NCCN guidelines in 36% (9/25 cases) and a targeted agent available on an open clinical trial at MSKCC in 32% (8/25) of patients. This approach simultaneously analyzes the multiple genes and classes of genomic alteration required for clinical care and are readily adapted to efficiently incorporate a rapidly expanding landscape of targetable alterations.
Study Design: This is a non-randomized observational comparative study with various cohorts based on physician diagnostic patterns of care and biologic genomic profile status.
Treatment of Subjects
6 If an "actionable" mutation is identified that does not have an approved targeted therapy the physician will be notified of any available research trials that might be considered. However, the decision to utilize a specific agent will be at the sole discretion of the treating physician. To expand the opportunities to offer targeted therapies, participating COTA centers will be encouraged to open national trials in lung cancer. The COTA protocol team will meet with individual centers to assist in research start-up if desired. Eligibility and participation in targeted therapy trials will be per the individual protocols. Consent for study participation will be separate from this protocol.
7 At the sole discretion of the treating physician the patient may be treated with chemotherapy, radiotherapy, surgery or other means. Consent for these treatments will be obtained by the treatment team, separate from this observational study, in accordance with policies and procedures of the treating center.
8 Patients will be allocated into one of seven cohorts based on the physicians choice of genomic profiling use 9 All patients will be tracked using the COTA database using the standard collection fields for lung cancer, including but not limited to demographics, smoking history, treatments and toxicities, and survival outcomes.
10 All patients will complete ECOG performance scores at a minimum of monthly per usual protocols at each center.
11 All patients will complete the patient reported Living with Cancer (LWC) instrument at the time of diagnosis and monthly thereafter .
Response Assessments and Planned Analyses
|Study Design||Observational Model: Cohort
Time Perspective: Prospective
|Target Follow-Up Duration||Not Provided|
|Sampling Method||Probability Sample|
|Study Population||All (consecutive) adult patients with untreated metastatic non-small cell lung cancer treated at a COTA center will be considered enrolled on the trial starting with enrollment of the index subject and continuing until study enrollment is completed.|
|Condition||Carcinoma, Non-small Cell Lung|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Original Estimated Enrollment
|Actual Study Completion Date||August 2017|
|Actual Primary Completion Date||August 2017 (Final data collection date for primary outcome measure)|
|Ages||18 Years and older (Adult, Older Adult)|
|Accepts Healthy Volunteers||No|
|Contacts||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries||United States|
|Removed Location Countries|
|Other Study ID Numbers||COTA 14001|
|Has Data Monitoring Committee||No|
|U.S. FDA-regulated Product||Not Provided|
|IPD Sharing Statement||
|Responsible Party||Cota Inc.|
|Study Sponsor||Cota Inc.|
|PRS Account||Cota Inc.|
|Verification Date||July 2018|