Response to Comments: MolDX: Inivata, InVisionFirst, Liquid Biopsy for Patients with Lung Cancer (BCI) Gene Expression Test (DL37921)

From Andrea Stern Ferris, President and Chief Executive Officer, LUNGevity Foundation

On behalf of LUNGevity Foundation, the nation’s preeminent lung cancer nonprofit that funds research, provides education and support, and builds communities for the 234,030 Americans diagnosed with lung cancer each year and the 541,035 Americans living with the disease, we appreciate the opportunity to submit our comments in response to the proposed Local Coverage Determination (LCD) for Inivata’s InVisionFirst liquid biopsy for patients with lung cancer (DL37870).

As a leading patient advocacy group that represents the voice and interest of the national lung cancer survivor community by accelerating research to patients that is meaningful to them, empowering patients to be active participants in their care and care decisions, and helping remove barriers to access to high quality care, LUNGevity applauds MolDX for providing a local coverage determination for the Inivata test and ensuring new testing options are available for lung cancer patients. In this era of unprecedented scientific advancements for the treatment of lung cancer, particularly in the field of biomarker testing, liquid biopsy tests, like Inivata’s, are a promising new development that identify markers predictive of response to particular treatments for patients in a convenient, low cost, and quickly-responsive manner.

Non-small cell lung cancer (NSCLC) is the more common type of lung cancer, diagnosed in about 85 percent of people with lung cancer.^1,2 The complex nature of this disease requires personalized management plans for patients.2 Since the discovery of the first epidermal growth factor receptor (EGFR) mutation in lung cancer in 2004, targeted therapies have become a major component of the treatment arsenal of NSCLC patient.^3-7 Now at least 10 driver mutations in adenocarcinoma have been identified (EGFR, ALK, ROS, RET, ERB2/HER2 mutations, ERB2/HER2 amplifications, MET amplifications, MET mutations, TRK, BRAF, KRAS).^6-9 In concert with the identification of an increasing number of targetable mutations is the development of novel, potent, and specifically targeted therapies. For example, at present, third generation EGFR10 tyrosine kinase inhibitors (TKIs) and anaplastic lymphoma kinase (ALK) TKIs¹¹ are used in clinical practice. With the increased use of targeted agents has come the problem of acquired resistance, where cancer cells inevitably develop resistance to the targeted agent. The EGFR T790M is an excellent example of a resistance mutation that develops in patients treated with first- and second-generation EGFR TKIs. This mutation can be rapidly detected using a liquid biopsy test such as the cobas EGFR Mutation Test v2.¹² Lung cancer is now leading the field of precision medicine where research is rapidly progressing to (1) develop better targeted therapies that combat mechanisms of resistance, and (2) noninvasive assays – such as liquid biopsies – that can monitor status of the resistance mutations (e.g., cobas EGFR Mutation Test v2), sequentially and in real time.¹³

The utility of liquid biopsies in the clinical management of lung cancer is unquestionable, because 1 out of 4 NCSLC patients may be ineligible for a solid tissue biopsy.¹⁴ We applaud MolDx’s decision to cover liquid biopsy-based testing for such patients. In her ASCO 2017 presentation on biomarker testing for lung cancer, LUNGevity Scientific Advisory Board (SAB) member, Dr. Alice Shaw from Massachusetts General Hospital, pointed out that liquid biopsies may help in (1) initial detection of targetable mutations in advanced-stage NSCLC at the time of diagnosis, (2) identification of acquired resistance mutations in patients who have relapsed on targeted therapies, and (3) monitoring response to targeted therapies and predicting outcome in advanced-stage NSCLC patient.¹⁵ As the science continues to evolve, the role of liquid biopsies in treatment decision-making for immunotherapies is becoming evident. In a recent report, a positive correlation between co-occuring mutations in the KRAS and LKB1/STK11 genes and lack of response to immune checkpoint blockade in advanced-stage NSCLC was demonstrated.¹⁶ Furthermore, the utility of liquid biopsies to identify predictive biomarkers for immunotherapy, such as tumor mutational burden (TMB), is becoming increasingly established.¹⁷ Therefore, the application of liquid biopsy-based multi-analyte NGS testing will become increasingly important, especially in the lung cancer space, where biomarker testing will have to keep pace with the development of newer targeted therapies and immunotherapies.

Given the utility of liquid biopsy and monitoring importance, we request that you reconsider the “patient is progressing on EGFR TKIs other than osimertinib” of the coverage guidance to include patients who have been treated with front-line osimertinib. The use of osimertinib in the first-line setting (FLAURA trial) offers a far superior median progression-free survival of 18.9 months versus 10.2 months median PFS offered by first- and second-generation EGFR TKIs.¹⁸ With this progress has come the need to understand mechanisms of resistance to osimertinib in the first-line setting. In the FLAURA trial, mechanisms of resistance observed in nine patients studied includes a variety of genomic alterations (such as MET amplifications, PIK3CA mutations, or C797S mutations, for example) in the absence of an acquired T790M mutation. Despite the small sample size, this provocative data suggests that detection of resistance mutations such as PIK3CA or EGFR C797S in patients who have progressed on first-line osimertinib, using non-invasive approaches, may help determine second-line treatment options.

Currently, drugs targeting MET amplification or PIK3CA are in clinical development and there is evidence suggesting that EGFR C797S is sensitive to first-generation EGFR inhibitors such as erlotinib. ^{19- 21} Using a non-invasive test at the time of progression would not only be beneficial to the patient but also expedite the selection of second-line treatment options.

As a leading patient advocacy group that represents the voice and interest of the national lung cancer survivor community, we are excited about the role of liquid biopsies in clinical management of NSCLC. The discussion outlined above can be discussed with my staff, myself, and LUNGevity’s SAB, which is made up of some of the world’s leading experts in lung cancer biology, practice management, access to innovative medicines, and overall patient care.

I can be reached at aeferris@lungevity.org if you have any questions or would like to engage in further dialog.

LUNGevity is grateful for the opportunity to comment on this determination. Thank you for your attention to this very important matter.

Thank you for feedback and comments. As stated here, osimertinib was approved as a first-line agent for NSCLC on April 18, 2018. Approved therapies that target biomarkers that can arise in patients taking osimertinib (as a first-or-second-line agent) have been described and are identified by this test. It is reasonable to utilize this test when patients have progression on osimertinib treatment. The LCD has been modified to remove osimertinib therapy as a limitation for coverage of the test.

From Matthew D. Mega, VP, Managed Care and Reimbursement, Inivata, Inc.
On behalf of Inivata, Inc., we sincerely appreciate the opportunity to comment on the Proposed Local Coverage Determination (DL37870): Inivata, InVisionFirst, Liquid Biopsy for Patients with Lung Cancer. Through this comment we intend to provide updated information on the clinical validation and utility of InVisionFirst in addition to providing suggested modifications to the LCD language.

Summary of Updates and Suggested Modifications:

• Updated Clinical Validation Data submitted for publication:
  • Govindan et al. Prospective clinical validation of the InVisionFirst™ ctDNA assay for molecular profiling of patients with advanced NSCLC ¹ (Submitted)
  • Remon et al. Real-world utility of an amplicon-based NGS liquid biopsy for broad molecular profiling in advanced non-small cell lung cancer patients² (Accepted)
• Additional publications/presentations demonstrating clinical sensitivity, including the detection of gene fusions
  • Guibert et al. Amplicon-based next-generation sequencing of plasma cell-free DNA for detection of driver and resistance mutations in advanced non-small cell lung cancer³
  • Pritchett et al. Validation of InVisionFirst ctDNA NGS profiling via ddPCR testing in patients with Non-Small cell lung cancer (NSCLC)⁴
  • Mezquita et al. Clinical relevance OF ALK/ROS1 resistance mutations and other acquired mutations detected by liquid biopsy in advanced NSCLC patients ⁵
  • Swalduz et al. Feasibility, clinical relevance of ALK/ROS1 fusion variant detection by liquid biopsy in advanced non-small cell lung cancer⁶
• Recently presented Clinical Utility Data demonstrating the durable response to targeted therapy used in patients identified as having actionable gene alterations by InVisionFirst™ Lung
  • Remon et al. Clinical validation and utility of InVision ctDNA in advanced non-small cell lung cancer (NSCLC) patients⁷
• Updated National Comprehensive Cancer Network NSCLC guidelines (Version 1.2019)⁷ support “broad molecular profiling” and “plasma-based” biopsy when patients are medically unfit for invasive tissue testing or when tissue material is insufficient for molecular testing. This NCCN guideline is consistent with the proposed LCD (DL37870) language in addition to the International Association for the Study of Lung Cancer (IASLC) Statement Paper on Liquid Biopsy.⁹
• Suggested modifications to LCD language:
  • Expansion of the associated ICD-10 codes
  • Modification of the intended-use and coverage language
    • Lifetime limit of 2 tests (Potentially 1 at diagnosis, 1 at progression)
    • Include all patients progressing on TKIs (per IASLC Statement Paper)

Performance of InVisionFirst™ Lung is highlighted by the following factors:

• High Clinical Sensitivity: for each of the key 8 genes used for therapeutic treatment decision with an overall plasma sensitivity of 73.9% (73.9% of tissue results are identified in plasma);
• High Proportion of Informative Results: Fifty-three percent (53%) of patients will receive informative results based on utilization of 8 specific genes with high sensitivity for each individual gene;
• High Clinical Specificity: for each of the 8 panel genes that supports correct therapeutic determination (CTD) in the 53% of patients with informative results.
• Excellent positive predictive value (PPV): when alterations in the 8 important therapeutic genes are detected by InVisionFirst™ Lung liquid biopsy testing these results agree with that of tissue testing. (PPV = 97.8%).

Supporting Data

Recently Presented Clinical Validation Data Submitted for Publication

The InVisionFirst™ Lung test was investigated prospectively in advanced untreated patients with non- squamous NSCLC blood samples. Clinical validation data consists of combined analysis of three studies. Two prospective multicenter studies (NCT02906852 and NCT03116633) demonstrated the concordance of the InVision assay with tissue-based comprehensive genomic profile (CGP) in 254 patients with untreated advanced (stage IIIB/IV) non-squamous NSCLC. A third study consisted of a small group of banked matched tissue and plasma samples (n=10) from an equivalent patient population that were procured from a commercial bio-repository and used to supplement the prospective collections. Across the 264 patients, only 165 patients (62.5%) had tissue available for point mutation/indel testing. For 159 patients (60.2%), tissue was tested for ROS1 and/or ALK fusions. 119 patients (45% of patients) underwent CGP with tissue.

Clinical correct therapeutic determination (CTD) performance based on InVision profiling results yielded actionable genes in 18.2% of patients and rule out findings in 35.6%, an informative result in 53.8% of patients (95%; CI 41%-56.2%) (Table 1). Of the plasma positive gene results, when either a molecular change in the 6 actionable driver genes (rule-in) or a non-targetable gene (rule-out) was detected, the CTD was 100%. This clinical CTD evidence is consistent across the entire intended use population (n=264), both those with and without tissue for profiling.

Table 1: Summary of actionable and rule-out status using InVision

Recently Presented Clinical Utility Data

Clinical utility has been demonstrated with prospective outcome collection from within the clinical validation study and within additional prospective studies at the Institute Gustave Roussy (Paris, France) and Centre Leon Berard (Lyon, France), across 3 groups of patients with genomic alterations detected by InVisionFirst, had received appropriate targeted therapy and had sufficient clinical follow-up to assess the 3-month disease control rate, namely:

1. Patients not exposed to any prior therapy and receiving targeted therapy as their initial therapy
2. Patients with no prior targeted therapy but having received previous chemotherapy, and
3. Patients with prior anti-EGFR targeted therapy and now progressing with the specific osimertinib sensitive mutation T790M detected by the assay.
4. Patients with prior anti-ALK targeted therapy and now progressing with recurrence or ALK resistance mutations detected by the assay

As detailed recently by the FDA, time on treatment was used as the endpoint for clinical impact of targeted therapy. When targeted therapies are used in patients without a specific target, average time on treatment is well under 2 months, compared to 3-month disease control of over 80% in those who have the target genomic alteration. Regardless of which group mentioned above was assessed, disease control at 3 months was approximately 80% or more, consistent with reported literature (Table 2). This is strong evidence that therapeutic determination based on InVisionFirst™ Lung results is equivalent to outcomes reported in clinical trials, and most importantly unlikely to be causing patient harm.

The utility of the assay has also been demonstrated in the untreated advanced NSCLC setting in patients receiving afatinib.

Table 2: Actionable Genomic Alterations Detected by InVision:
Patients Treated with Appropriate Targeted Therapy and Remaining on Therapy at 3 Months

Professional Society Clinical Practice Guidelines

National Comprehensive Cancer Network (NCCN) clinical practice guidelines (v1.2019) for non-small cell adenocarcinoma recommend a broad molecular profile panel. NCCN recommends molecular testing in never- smokers regardless of histology or mixed histology, and in small biopsies with the goal of identifying rare driver mutations for which effective drugs may be available. Tissue profiling is recommended to include EGFR and ERBB2 point mutations and indels; BRAF mutations; ALK, ROS1, and RET rearrangements; and MET amplification and deletion/skipping of exon. The guidelines indicate that if tissue biopsy is not feasible, plasma biopsy should be considered. If plasma biopsy is negative, then repeat tissue biopsy is recommended, if feasible.37

Proposed LCD Modifications

• Expansion of the associated ICD-10 codes
• Modification of the intended-use and coverage language
  • Lifetime limit of 2 tests (1 at diagnosis, 1 at progression)
  • All the TKIs upon progression (per IASLC Statement Paper)

Expansion of the associated ICD-10 codes

It is critical to incorporate comprehensive coding for malignant neoplasms of the bronchus and lung, which includes ICD-10 codes C34.90-C34.92 (the most widely used diagnostic codes for stage III/IV NSCLC) since the location of the tumor in the lung (at original diagnosis) is no longer relevant to systemic treatments such as
genomically targeted therapy.

Additionally, codes C34.00, C34.10, C34.30, and C34.80 should be covered since the unspecified location in the lung does not change the need to diagnose and treat the disease. The table below summarizes suggested revisions.

Modifications of the Intended Use and Coverage Language

Lifetime limit of two tests, 1 at diagnosis, 1 at progression

Based on the current LCD Coverage Criteria for use in patients “At Diagnosis” or “At Progression” we recommend expansion of the “Lifetime Testing Limit” from 1 test per patient” to “2 tests per patient”. This modification will allow for CMS members profiled in the 1^st line setting, found to have an actionable alteration and treated with a TKI to also be eligible for testing again on relapse under the proposed language. Therefore, a lifetime limit of 2 is required to allow such testing.

Expansion of indicated patient group in the relapsed disease setting

We believe that the indications in the LCD should be expanded to allow diagnostic testing of all patients who are progressing on any targeted-therapy tyrosine kinase inhibitor (TKI), (including osimertinib).
While the clinical importance of the EGFR T790 resistance mutation is well documented in patients progressing on 1^st generation EGFR TKI’s, there is now accumulating evidence regarding the potential for resistance mutations in other patients to have clinical relevance.

Several specific ‘driver’ mutations and gene fusions of NSCLC have been identified and specific targeted therapies developed.

In the case of EGFR –mutant NSCLC, the first-generation inhibitors gefitinib (Iressa®) and erlotinib (Tarceva®) produced significant improvements in outcome relative to doublet chemotherapy in the first-line setting (Mok et al¹⁰, Rosell et al¹¹). On progression, a secondary ‘resistance’ mutation in Exon 20 (T790M) was identified, and subsequently a T790M inhibitor osimertinib (Tagrisso®) was developed which demonstrated significant improvement in outcome relative to chemotherapy, when used following progression on erlotinib or gefitinib (Mok et al)¹². Identification of the emergence of a resistance mutation in patients receiving first-line EGFR-targeted therapy is clearly of critical importance in determining the most appropriate second-line therapy. InvisionFirst® testing of ctDNA allows such a determination, and would be of immense clinical value in enabling selection of specific targeted therapy based on the presence of a T790M mutation

Similarly, patients with fusions of the EML/Alk genes or re-arrangements of the ROS-1 gene gain significant therapeutic benefit from the targeted-agent crizotinib, when used in the first-line setting. On progression, subsequent mutations in Alk are amenable to treatment with the specific inhibitors ceritinib (Shaw et al)¹³ and alectinib (Shaw et al).¹⁴

Both agents have been shown to have significant therapeutic benefit relative to chemotherapy. Detection of Alk resistance mutations with InvisionFirst® testing is invaluable in selecting the most appropriate therapy for such patients.

In summary, we believe this modified language allowing use of InVisionFirst for patients progressing on “any TKI” is appropriate to ensure CMS members have access to actionable targeted therapies identifiable by the assay.

Proposed Language:

Coverage Indications, Limitations, and/or Medical Necessity

This policy provides coverage for InvisionFirst™- Lung (Inivata, Research Triangle Park, NC) (hereafter InVision) a plasma-based, somatic comprehensive genomic profiling test (CGP) for patients with advanced (Stage IIIB/IV) non-small cell lung cancer (NSCLC):

• At diagnosis –
  • When results for EGFR single nucleotide variants (SNVs) and insertions and deletions (indels); rearrangements in ALK and ROS1; and SNVs for BRAF are not available AND when tissue-based CGP is infeasible [i.e., quantity not sufficient (QNS) for tissue-based CGP or invasive biopsy is medically contraindicated],
    

    And/or

• At progression-
  • For patients progressing on or after chemotherapy or immunotherapy who have never been tested for EGFR SNVs and indels; rearrangements in ALK and ROS1; and SNVs for BRAFs, and for whom tissue-based CGP is infeasible (i.e., QNS for tissue-based CGP from original biopsy);
  • For patients progressing on tyrosine kinase inhibitors (TKIs)

Thank you for your feedback and comments. We will address the two requests for change to the language of the draft document separately:

1. ICD-10 code revisions: We agree to all the codes described under ICD-10 C34.00-C34.92 as all pertain to malignant neoplasms of the lung in different lobes and regions of the lung and can be sites of Lung NSCLC.
2. Coverage limitation to once per lifetime: This coverage policy is allowable under section D of the National Coverage Determination (NCD90.2) for Next-Generation Sequencing. This section limits NGS testing for patient with advanced cancer to one such test per primary diagnosis. This LCD policy cannot supersede nor contradict the NCD; as such this limitation must be retained. However, the text has been modified to be more consistent with the NCD language.