| Coverage Policy Manual | |
| Policy #: | 2012005 |
| Category: | Laboratory |
| Initiated: | January 2012 |
| Last Review: | October 2023 |
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| Genetic Test: Molecular Testing of Tumors for Genomic Profiling as a Therapeutic Guide | |
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| Description: |
Comprehensive genomic profiling offers the potential to evaluate a large number of genetic markers at a single time to identify cancer treatments that target specific biologic pathways. Some individual markers that have established benefit in certain types of cancers; these situations are not addressed in this policy. Rather, the focus of this review is on “expanded” panels, which are defined as molecular panels that test a wide variety of genetic markers in cancers without regard for whether specific targeted treatment has demonstrated benefit. This approach may result in a different treatment than usually selected for a patient based on the type of cancer and its stage.
Background
Tumor location, grade, stage, and the patient’s underlying physical condition have traditionally been used in clinical oncology to determine the therapeutic approach to a specific cancer, which could include surgical resection, ionizing radiation, systemic chemotherapy, or combinations thereof. Currently some 100 different types are broadly categorized according to the tissue, organ, or body compartment in which it arises. Most treatment approaches in clinical care were developed and evaluated in studies that recruited subjects and categorized results based on this traditional classification scheme.
This traditional approach to cancer treatment does not reflect the wide diversity of cancer at the molecular level. While treatment by organ type, stage, and grade may demonstrate statistically significant therapeutic efficacy overall, only a subgroup of patients may actually derive clinically significant benefit. It is unusual for a cancer treatment to be effective for all patients treated in a traditional clinical trial. Spear et al analyzed the efficacy of major drugs used to treat several important diseases (Spear, 2013). They reported heterogeneity of therapeutic responses, noting a low of 25% for cancer chemotherapeutics with response rates for most drugs falling in the range of 50% to 75%. The low rate for cancer treatments is indicative of the need for better identification of characteristics associated with treatment response and better targeting of treatment to have higher rates of therapeutic responses.
Much of the variability in clinical response may result from genetic variations. Within each broad type of cancer, there may be a large amount of variability in the genetic underpinnings of the cancer. Targeted cancer treatment refers to the identification of genetic abnormalities present in the cancer of a particular patient, and the use of drugs that target the specific genetic abnormality. The use of genetic markers allows cancers to be further classified by “pathways” defined at the molecular level. An expanding number of genetic markers have been identified. Dienstmann et al categorize these findings into 3 categories (Dienstmann, 2013). These are: (1) Genetic markers that have a direct impact on care for the specific cancer of interest, (2) Genetic markers that may be biologically important but are not currently actionable, and (3) Genetic markers of unknown importance.
A smaller number of individual genetic markers fall into the first category (i.e., have established utility for a particular cancer type). The utility of these markers has generally been demonstrated by randomized controlled trials (RCTs) that select patients with the marker, and report significant improvements in outcomes with targeted therapy compared with standard therapy. Testing for individual variants with established utility is not covered in this policy. In some cases, limited panels may be offered that are specific to 1 type of cancer, for example a panel of several markers for non-small-cell lung cancer. This policy is also not intended to address the use of these cancer-specific panels that include a few mutations. Rather, the intent is to address expanded panels that test for many potential variants that do not have established efficacy for the specific cancer in question.
When advanced cancers are tested with expanded molecular panels, most patients are found to have at least 1 potentially pathogenic variant (Drilon, 2015; Johnson, 2014; Schwaederle, 2015). The number of variants varies widely by types of cancers, different variants included in testing, and different testing methods among the available studies. In a study by Schwaederle et al, 439 patients with diverse cancers were tested with a 236-gene panel (Schwaederle, 2015). A total of 1813 molecular alterations were identified, and almost all patients (420/439 [96%]) had at least 1 molecular alteration. The median number of alterations per patient was 3, and 85% (372/439) of patients had 2 or more alterations. The most common alterations were in the TP53 (44%), KRAS (16%), and PIK3CA (12%) genes.
Some evidence is available on the generalizability of targeted treatment based on a specific mutation among cancers that originate from different organs (Dienstmann, 2013; NCCN, 2014; O’Brien, 2014). There are several examples of variant -directed treatment that was effective in 1 type of cancer but not effective in another. For example, targeted therapy for epidermal growth factor receptor (EGFR) variants have been successful in non-small-cell lung cancer but not in trials of other cancer types. Treatment with tyrosine kinase inhibitors based on mutation variant testing has been effective for renal cell carcinoma but has not demonstrated effectiveness for other cancer types tested. "Basket" studies, in which tumors of various histologic types that share a common genetic variant are treated with a targeted agent, also have been performed. One such study was published by Hyman et al (Hyman, 2015). In this study, 122 patients with BRAF V600variants in nonmelanoma cancers were treated with vemurafenib. The authors reported that there appeared to be an antitumor activity for some but not all cancers, with the most promising results seen for non-small-cell lung cancer, Erdheim-Chester disease, and Langerhans cell histiocytosis.
Below is a list of commercially available molecular panels for solid and hematologic tumor testing:
Regulatory Status
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. Laboratories that offer laboratory-developed tests must be licensed by the Clinical Laboratory Improvement Amendments for high-complexity testing.
FoundationOne CDx (Foundation Medicine) initially received premarket approval by the U.S. Food and Drug Administration (FDA) (P170019) in 2017. It is intended as a companion diagnostic to identify patients who may benefit from treatment with the targeted therapies listed below. The approval is both tumor type and biomarker specific and does not extend to all of the components included in the FoundationOne CDx product. The test is intended to identify patients who may benefit from treatment with targeted therapies in accordance with approved therapeutic product labeling. "Additionally, F1CDx is intended to provide tumor mutation profiling to be used by qualified health care professionals in accordance with professional guidelines in oncology for patients with solid malignant neoplasms." FDA product code: PQP
In 2017, the Oncomine DX Target Test (Life Technologies Corp) received premarket approval by the FDA (P160045) to aid in selecting non-small cell lung cancer patients for treatment with approved targeted therapies. FDA product code: PQP
MSK-IMPACT (Memorial Sloan Kettering) received de novo marketing clearance in 2017 (DEN170058). "The test is intended to provide information on somatic mutations (point mutations and small insertions and deletions) and microsatellite instability for use by qualified health care professionals in accordance with professional guidelines and is not conclusive or prescriptive for labeled use of any specific therapeutic product." FDA product code: PZM
Subsequent marketing clearance through the FDA's 510(k) process (FDA product code PZM) include the following:
The intended use is by qualified health care professionals in accordance with professional guidelines for oncology, and not prescriptive for use of any specific therapeutic product.
OmniSeq Comprehensive® is approved by the New York State Clinical Laboratory Evaluation Program.
Coding
If a panel meets the requirements for one of the specific CPT codes for targeted genomic sequence analysis panel (81445-81455), the code may be reported for the test. If the panel does not meet the requirements for a CPT panel code, any specific mutation which is listed in the codes 81200-81409 would be reported using those codes and the other mutations in the panel which are not specifically listed would be reported with 1 unit of the unlisted molecular pathology code 81479.
As an example of the coding that might be used, GenPath recommends the following CPT codes in their test catalogue for OnkoMatch™ Tumor Genotyping (with the number of units indicated in parentheses): 81210 (1), 81235 (1), 81275 (1), 81323 (1). For OnkoMatch Tumor Genotyping + for Lung, they recommend the following CPT codes: 81210 (1), 81235 (1), 81275 (1), 81323 (1), 88368 (2), 88381 (1).
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Policy/ Coverage: |
Effective November 2020
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Molecular profiling of solid tumors and hematolymphoid malignancies to guide cancer therapy using the Caris Target Now® Molecular Profiling Test, the FoundationOne Test, the Guardant360 test or any other expanded cancer mutation panels does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, molecular profiling of solid tumors and hematolymphoid malignancies to guide cancer therapy using the Caris Target Now® Molecular Profiling Test, the FoundationOne® Test, the Guardant360 test or any other expanded cancer mutation panels is considered investigational. Investigational services are considered specific contract exclusions in most member benefit certificates of coverage.
Effective September 2017 to November 2020
Molecular profiling of solid tumors to guide cancer therapy using the Caris Target Now® Molecular Profiling Test, the FoundationOne Test, the Guardant360 test or any other expanded cancer mutation panels does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, molecular profiling of solid tumors to guide cancer therapy using the Caris Target Now® Molecular Profiling Test, the FoundationOne® Test, the Guardant360 test or any other expanded cancer mutation panels is considered investigational. Investigational services are considered specific contract exclusions in most member benefit certificates of coverage.
Effective Prior to September 2017
Molecular profiling of solid tumors to guide cancer therapy using the Caris Target Now® Molecular Profiling Test, the FoundationOne Test or any other expanded cancer mutation panels does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, molecular profiling of solid tumors to guide cancer therapy using the Caris Target Now® Molecular Profiling Test, the FoundationOne® Test or any other expanded cancer mutation panels is considered investigational. Investigational services are considered specific contract exclusions in most member benefit certificates of coverage.
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| Rationale: |
The evaluation of a genetic test focuses on 3 main principles: (1) analytic validity (technical accuracy of the test in detecting a mutation that is present or in excluding a mutation that is absent); (2) clinical validity (diagnostic performance of the test [sensitivity, specificity, positive and negative predictive values] in detecting clinical disease); and (3) clinical utility (how the results of the diagnostic test will be used to change management of the patient and whether these changes in management lead to clinically important improvements in health outcomes).
Analytic Validity
There were no published studies identified that evaluated the analytic validity of these panels. The panels are performed primarily by next-generation sequencing, which has a high analytic validity. Some panels supplement the next-generation sequencing with additional testing methods, such as polymerase chain reaction (PCR), for intronic regions that are included as components of the panel. PCR is generally considered to have an analytic validity of more than 95%.
Information on analytic validity of the FoundationOne test was reported on the Foundation website (FoundationOne, 2014). This site states that the analytic sensitivity is greater than 99% for base substitutions at a mutant allele frequency of 5% or more, 98% for indels at a mutant allele frequency of 10% or more, less than 95% for copy number alterations. They also report an analytic specificity of more than 99%.
Clinical Validity
The clinical validity of the panels as a whole cannot be determined because of the many different mutations and the large number of potential cancers in which it can be used. Clinical validity would need to be reported for each specific mutation for a particular type of cancer. Because there are many hundreds of different mutations included in the panels and dozens of different cancer types, evaluation of the individual clinical validity for each pairing is beyond the scope of this review.
Clinical Utility
To demonstrate clinical utility, controlled trials are required in which a strategy of cancer mutation testing followed by targeted treatment based on mutation analysis is compared with standard treatment without mutation testing. Randomized trials will be necessary to control for selection bias in treatment decisions, because clinicians may select candidates for mutation testing based on clinical, demographic and other factors. Outcomes of these trials would be the morbidity and mortality associated with cancer and cancer treatment. Overall survival is most important; cancer-related survival and/or progression-free survival may be acceptable surrogates. Quality-of-life measurement may also be important if study design allows for treatments with different toxicities in the experimental and control groups. There are currently no published randomized controlled trials (RCTs) with this type of design.
The published evidence consists of nonrandomized studies that are intended to be pilot trials. In a study by Von Hoff et al, 86 patients with various cancers who had progression of their disease on at least 2 different prior regimens underwent molecular profiling of their cancer (Von Hoff, 2010). The molecular profile consisted of a panel of 51 gene expression assays and 11 proteins assessed by either immunohisochemical (IHC) or fluorescent in situ hybridization (FISH). The profiles were reviewed by 2 study physicians, who identified potential targeted treatments based on the results. The process described does not appear to be an integrative approach to profiling cancer, but as simply reviewing the profiles for consistency. It was not stated explicitly how a target was identified. If targets were identified, the first priority target was where both gene expression and protein measurements were concordant for the same target. Next priority targets indicated targets with IHC alone, and least priority targets were positive by gene expression alone.
Eighty-six patients underwent molecular profiling. The molecular profiling apparently yielded a target in 84 of 86 patients. Sixty-six patients underwent a treatment suggested by their molecular profiling result. Patients dropped out of the study for various reasons, the most common being worsening clinical condition. The treatments assigned to patients were all established cancer treatments, although they sometimes represented off-label use for that particular cancer.
The study did not include a control group. Investigators proposed that patients who responded to the targeted treatment would have a longer progression-free survival (PFS) than the treatment they had most recently failed. A PFS time greater than 1.3 times their previous treatment (PFS ratio ≥1.3) was considered a response, and the null hypothesis was set at 15% response. In the study 18 patients (27%) had a PFS ratio 1.3 or greater.
In the study by Tsimberidou et al, patients with advanced or metastatic cancer refractory to standard therapy underwent molecular profiling (Tsimberidou, 2012). PCR-based targeted sequencing was used to assess mutations in 10 cancer genes. Loss of PTEN was determined using IHC, and anaplastic lymphoma kinase (ALK) translocation was assessed using FISH. Of 1144 patients, 460 had a molecular aberration based on this panel of tests. From this group of 460 patients, 211 were given “matched” treatment, and 141 were given nonmatched treatment. The principal analysis presented was of a subgroup of the 460 patients who had only 1 molecular aberration (n=379). Patients were enrolled in 1 of 51 phase 1 clinical trials of experimental agents.
It was not stated how patients were assigned to matched or unmatched therapy, nor how a particular therapy was considered a match or not. In the list of trials in which patients were enrolled, it appears that many of the investigational agents were inhibitors of specific kinases, and thus a patient with a particular aberration of that kinase would probably be considered a match for that agent (Tsimberidou, 2012).
Among the 175 patients who were treated with matched therapy, the overall response rate was 27%. Among the 116 patients treated with nonmatched therapy, the response rate was 5% (p<0.001 for the difference in response rates). The median time-to-failure was 5.2 months for patients on matched therapy versus 2.2 months on nonmatched therapy (p<0.001). At a median of 15 months’ follow-up, median survival was 13.4 months versus 9.0 months (p=0.017) in favor of matched therapy. Due to small numbers, individual molecular aberrations could not be analyzed, but some sensitivity analyses excluding certain aberrations were shown to demonstrate that the results were robust to exclusion of certain groups.
In the study by Dienstmann et al, patients with advanced refractory colorectal cancer had molecular profiling with matching to targeted treatment (Dienstmann, 2012). Three genes (KRAS, BRAF, PIK3CA) were analyzed for specific mutations, and PTEN and pMET gene expression levels were assessed using IHC. Sixty-eight patients were enrolled in 15 different phase 1 clinical trials, in which 82 matched targeted therapies were assigned to patients. It was not explicitly stated how a therapy was considered a match.
The outcome assessed in the study was the time-to-treatment failure (TTF), which was compared with the TTF for the patients’ treatment just before enrollment in the study. Median TTF on matched treatment was 7.9 weeks versus 16.3 weeks for prior treatment, indicating worse results on matched treatment. Only 1 patient was considered to have had a confirmed partial response to matched treatment. Stable disease longer than 16 weeks was observed in 10 patients.
A major concern with clinical utility is the identification of genetic variants that are not clinically important. It is expected that variants of uncertain significance will be very frequent with use of panels that include several hundred markers. The FoundationOne website reports that in their database of over 2200 test results, the average number of variants identified per sample is 3.06 (range, 0-23). There is potential for harm with this high number of variants identified. Patients may be given treatments that have substantial toxicity and no benefit if treatment decisions are made based on variants with uncertain clinical significance.
Section Summary
These 3 trials of molecular marker profiling in cancer patients are early studies in the evaluation of molecular profiling to choose treatment and do not provide strong evidence of the approach. The studies by Von Hoff et al and Dienstmann et al lacked control groups. It is uncertain whether a comparison to patients’ just previously failed treatment is a valid measure of patient response or benefit. The biologic state of patients’ cancer is probably different after treatment failure. The patients’ state of health is probably worse. In the study by Tsimberidou et al, the patients in the matched and nonmatched treatment groups were not randomly allocated, and there may be confounding in either patient characteristics or treatment responsible for the difference. In the studies of Tsimberidou et al and Dienstmann et al, the targeted treatments assigned were generally agents in phase I clinical trials, thus possibly of uncertain benefit to any kind of patient. It cannot be determined if the testing strategy apart from the treatment assigned had any influence on patient outcome. A further concern is the presence of many variants of uncertain significance, which may lead to harm due to adverse events that result from unnecessary treatment.
Summary
Genetic panels that test for a large number of cancer-associated mutations are commercially available. These expanded panels are intended for use in patients with cancer for whom a specific targeted therapy based on mutation analysis is not available. The analytic validity of these panels is likely to be high when next generation sequencing is used. The clinical validity of the individual mutations for particular types of cancer is not easily obtained from the available published literature. To demonstrate clinical utility, RCTs are needed that compare the strategy of targeted treatment based on panel results with standard care. No such trials have currently been published. The available literature on clinical utility consists of a small number of uncontrolled studies, and nonrandomized controlled trials that use imperfect comparators. This evidence is not sufficient to make any conclusions on clinical utility. In addition, there is potential for harm if ineffective therapy is given based on test results, because there may be adverse effects of therapy in absence of a benefit. As a result, the use of expanded mutation panel testing for targeted treatment in cancer is considered investigational.
Ongoing Trials
There are ongoing randomized controlled trials underway and/or in the planning stages that will address the strategy of targeted therapy based on testing for a wide range of cancer-related mutations. A few examples are provided here.
Le Tourneau et al published a description of their trial of molecular marker profiling in 2012. The SHIVA trial (Le Tourneau, 2012) is a rigorously designed trial, and it highlights important issues in the evaluation of efficacy of this approach. In this study, patients with a variety of advanced cancers will be enrolled. It is proposed that no more than 20% of patients with the same tumor type will be included. Nineteen molecular markers will be measured using genotyping, gene expression, or IHC. Based on the pattern of abnormalities found, 9 different regimens of established cancer treatments will be assigned to the experimental treatment arm. For example, patients with HER-2 positive cancer will be given lapatinib and trastuzumab. Patients with androgen receptor-positive cancer will be given abiraterone. The patients will be randomized to targeted treatment versus conventional therapy based on treating physicians’ choice.
The National Cancer Institute is sponsoring a study called the M-PACT trial (NCI, 2014). This trial will screen patients with advanced refractory solid tumors that are resistant to standard therapy for 391 mutations in 20 genes. A total of 180 patients will be selected who have mutations for which a trial of treatment with an available targeted medication is feasible. If mutations of interest are detected, using a panel of mutations and a sequencing protocol approved by FDA, those patients will be enrolled in the trial and randomly assigned to 1 of 2 treatment arms to receive 1 of the 4 treatment regimens that are part of this study. This trial is in the early stages of implementation.
Practice Guidelines and Position Statements
NCCN guidelines do not contain recommendations for the general strategy of testing a tumor for a wide range of mutations. The guidelines do contain recommendations for specific genetic testing for individual cancers, based on situations where there is a known mutation-drug combination that has demonstrated benefits for that specific tumor type. Some examples of their recommendations for common solid tumors are listed next:
· Breast cancer.(NCCN, 2014) HER2 testing, when specific criteria are met.
· Colon cancer.(NCCN, 2014)
· KRAS/NRAS testing for patients with metastatic colon cancer.
· Consider V600E BRAF testing for patients with metastatic colon cancer
· Non-small-cell lung cancer.(NCCN, 2014)
· EGFR [epidermal growth factor receptor] and ALK [anaplastic lymphoma kinase] testing for patients with metastatic adenocarcinoma
· Consider EGFR and ALK testing especially in never smokers, mixed histology, or small biopsy specimen
· Melanoma.(NCCN, 2014) V600 BRAF testing for patients with metastatic disease
2015 Update
A literature search conducted through February 2015 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
Practice Guidelines and Position Statements
The National Comprehensive Cancer Network guidelines do not contain recommendations for the general strategy of testing a tumor for a wide range of mutations. The guidelines do contain recommendations for specific genetic testing for individual cancers, based on situations where there is a known mutation-drug combination that has demonstrated benefits for that specific tumor type. Some examples of their recommendations for common solid tumors are listed next:
2016 Update
A literature search conducted through November 2016 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
Numerous nonrandomized studies have been published that use some type of control.
Some of these studies have a prospective, interventional design. In 2016, Wheler and colleagues reported a prospective comparative trial of patients who had failed standard treatment and had been referred to their tertiary center for admission into phase 1 trials (Wheler, 2016). Comprehensive molecular profiling (Foundation One tumor panel) was performed on 339 patients, of whom 122 went on to a phase 1 therapy that was matched to their genetic profile, and based on physician evaluation of additional information, 66 patients went on to a phase 1 trial that was not matched to their genetic profile. Table 2 summarizes study results; there was a significant benefit on time to treatment failure and a trend for an increased percentage of patients with stable disease and median OS in patients matched to their genetic profile. When exploratory analysis divided patients into groups that had high matching results or low matching results (number of molecular matches per patient divided by the number of molecular alterations per patient), the percentage of patients with stable disease and the median time to failure were significantly better in the high match group. Median OS was not significantly different between the groups. Notably, this is a group of patients who had failed multiple prior therapies (median of 4) and had a number (median 5, range, 1-14) of gene alterations in the tumors. For comparison, response rates in phase I trials with treatment resistant tumors is typically around 5% to10%.
Another meta-analysis by this group compared outcomes from 44 FDA-regulated drug trials that utilized a personalized treatment approach to 68 trials that used a non-personalized approach to cancer treatment (Jardim, 2015). Response rate was significantly higher in the personalized treatment trials (48%)
2018 Update
A literature search was conducted through September 2018. There was no new information identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
College of American Pathologists et al
The College of American Pathologists and 2 other associations updated their joint guidelines on molecular testing of patients with non-small-cell lung cancer (CAP, 2018). The groups gave a strong recommendation for EGFR, ALK, and ROS1 testing. Based on expert consensus opinion KRAS was recommended as a single gene test if EGFR, ALK, and ROS1 were negative. Tests that were not recommended for single gene testing outside of a clinical trial were BRAF, RET, ERBB2 (HER2), and MET, although these genes should be tested if included in a panel.
American Society of Clinical Oncology
The American Society of Clinical Oncology affirmed the majority of these guidelines. The Society guidelines also recommended BRAF testing on all patients with advanced lung adenocarcinoma (ASCO, 2018).
2019 Update
A literature search was conducted through September 2019. There was no new information identified that would prompt a change in the coverage statement.
2020 Update
Annual policy review completed with a literature search using the MEDLINE database through September 2020. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Systematic reviews compare the outcomes of patients who were enrolled in trials with personalized therapy with those of patients enrolled in non-personalized therapy trials. Schwaederle et al assessed outcomes in single-agent phase 2 trials, while Jardim et al evaluated trials for 58 newly approved cancer agents (Schwaederle, 2015; Jardim, 2015). Treatment directed by a personalized strategy was associated with an increased response rate, PFS, and OS compared to treatment that was not personalized. While these studies support a strategy of targeted therapy within a specific tumor type, they do not provide evidence that broad genomic profiling is more effective than tumor-specific variant assessment.
Nonrandomized studies have been published that use some type of control. These studies are summarized in a review by Zimmer et al (Zimmer, 2019). Some of these studies had a prospective, interventional design (Wheler, 2016). Another type of study compares patients matched to targeted treatment with patients not matched. In this type of study, all patients undergo comprehensive genetic testing, but only a subset is matched to targeted therapy. Patients who are not matched continue to receive standard care. These studies have reported that outcomes are superior in patients receiving matched treatment. However, there are potential issues with this design that could compromise the validity of comparing these two populations. They include the following: (1) differences in clinical and demographic factors, (2) differences in the severity of disease or prognosis of disease (ie, patients with more undifferentiated anaplastic cancers might be less likely to express genetic markers), and (3) differences in the treatments received. It is possible that one of the "targeted" drugs could be more effective than standard treatment whether or not patients were matched.
One of the largest studies of molecular targeting in phase 1 trials was the Initiative for Molecular Profiling and Advanced Cancer Therapy (IMPACT) study, reported by Tsimberidou from the MD Anderson Cancer Center (Tsimberidou, 2017). Patients with advanced cancer who underwent comprehensive genomic profiling were treated with matched targeted therapy when available. Out of 1,436 patients who underwent genomic profiling, 1,170 (82.1%) had one or more mutations, of which 637 were actionable. The most frequent alterations were estrogen receptor overexpression, and variants in TP53, KRAS, PTEN, PIK3CA, and BRAF. The group that had matched therapy had a higher response rate (11% vs 5%), longer progression-free survival (3.4 vs 2.9 mo), and longer overall survival (8.4 vs 7.3 mo).
The Centers for Medicare and Medicaid Services (CMS) will cover diagnostic testing with next-generation sequencing for beneficiaries with recurrent, relapsed, refractory, metastatic cancer, or advanced stages III or IV cancer if the beneficiary has not been previously tested using the same next generation sequencing test, unless a new primary cancer diagnosis is made by the treating physician, and if the patient has decided to seek further cancer treatment (CAG-00450N) (CMS, 2019). The test must have a Food and Drug Administration approved or cleared indication as an in vitro diagnostic, with results and treatment options provided to the treating physician for patient management.
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through September 2021. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
NCI-MATCH is a master basket trial protocol in which tumors of various types are sequenced and patients assigned to targeted treatment based on the molecular alteration (Murciano-Goroff, 2021). A total of 6391 patients were enrolled across 1117 clinical sites between 2015 and 2017 and underwent tumor sequencing. Patients had received a median of 3 lines of prior therapy. Common tumors comprised 37.5% of the total; the remainder had less common tumor histologies. Sequencing included 143 genes, of which approximately 40% of alterations were considered actionable, and 18% of patients were assigned to 30 treatment subprotocols. The majority of alterations identified in the 143 gene panel were either not actionable or led to experimental treatments in clinical trials. Response to treatments in the subprotocols are being reported and will provide preliminary evidence on tumor agnostic treatments (Kalinsky, 2021; Salama, 2020). Co-alterations discovered in NCI-MATCH have also led to a new biomarker-selected combination therapy trial by the National Cancer Institute, NCI-COMBOMATCH. Controlled basket trials that compare tumor-agnostic treatment based on a molecular marker with standard treatments are ongoing.
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through September 2022. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
In 2022, the American Society of Clinical Oncology (ASCO) published a provisional clinical opinion based on informal consensus in the absence of a formal systematic review on the appropriate use of tumor genomic testing in patients with metastatic or advanced solid tumors (Chakravarty, 2022). The opinion notes the following:
PCO 1.1. Genomic testing should be performed for patients with metastatic or advanced solid tumors with adequate performance status in the following 2 clinical scenarios:
PCO 1.2.1. For patients with metastatic or advanced solid tumors, genomic testing using multigene genomic sequencing is preferred whenever patients are eligible for a genomic biomarker–linked therapy that a regulatory agency has approved (strength of recommendation: moderate).
PCO 1.2.2. Multigene panel–based genomic testing should be used whenever more than one genomic biomarker is linked to a regulatory agency–approved therapy (strength of recommendation: strong).
PCO 2.1. Mismatch repair deficiency status (dMMR) should be evaluated on patients with metastatic or advanced solid tumors who are candidates for immunotherapy. There are multiple approaches, including using large multigene panel-based testing to assess microsatellite instability (MSI). Consider the prevalence of dMMR and/or MSI-H status in individual tumor types when making this decision (strength of recommendation: strong).
PCO 2.2. When tumor mutational burden (TMB) may influence the decision to use immunotherapy, testing should be performed with either large multigene panels with validated TMB testing or whole-exome analysis (strength of recommendation: strong).
PCO 4.1. Genomic testing should be considered to determine candidacy for tumor-agnostic therapies in patients with metastatic or advanced solid tumors without approved genomic biomarker–linked therapies (strength of recommendation: moderate).
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through September 2023. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
TAPUR is an ongoing phase II, prospective, non-randomized, open-label basket study that evaluates the antitumor activity of targeted agents in individuals who have advanced cancers and have genomic alterations that are targets for these drugs and was initiated in March of 2016 (NCT02693535) (ASCO, 2023). The American Society of Clinical Oncology (ASCO) designed and led the trial and matched patients' tumor genomic alternations to FDA-approved, commercially available, targeted anticancer agents. The primary endpoint of the study is the rate of disease control, defined as a complete response or partial response at 8 weeks or later or stable disease at 16 weeks after study treatment; secondary endpoints included PFS, OS, and safety. Enrollment was initially limited to 10 individuals per cohort and participants were followed for 16 weeks or more. Enrollment is stopped if 2 or fewer participants have a successful outcome, but if ≥ 2 participants have a successful outcome, the cohort is expanded to enroll an additional 18 participants. As of August 2023, 21 cohorts have had positive findings, and there are currently 14 treatments being investigated in expanded cohorts for multiple indications after showing initial treatment success.
The Drug Rediscovery Protocol (DRUP) is a prospective, non-randomized clinical trial that aims to describe the safety and efficacy of commercially available anticancer agents that are targeted to actionable genomic or protein expression variants (NCT02925234) (Hoes, 2022). Patients are enrolled in separate cohorts based on tumor histology and were matched to off-label targeted molecular therapies or immunotherapies. The study's primary endpoint is a complete response, partial response, or stable disease at ≥ 16 weeks. A total of 1145 participants with cancer were screened, and 500 initiated therapies with one of 25 drugs and had evaluable outcomes. Approximately a third of participants (33%), including those with rare cancers (n=164), experienced a clinical benefit. These patients with rare cancers were more likely to have inactivating CDKN2A or activating BRAF mutations(P≤.001) when compared to individuals with non-rare cancers and were found to have higher rates of clinical benefit when treated with small-molecular inhibitors that target BRAF when compared versus the non-rare cancer subgroup.
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| References: |
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