A particular interesting comment is from United Healthcare, as clipped below.
Title:
Senior Medical Director, Oncology and Genetics
Organization:
UnitedHealthcare
Ms. Tamara Syrek-Jensen
Director, Coverage & Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244
Director, Coverage & Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244
December 27, 2017
RE: Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N)
Dear Ms. Syrek-Jensen:
On behalf of UnitedHealthcare, we appreciate the opportunity to comment on the Centers for Medicare & Medicaid Services’ (CMS) Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N).
Advances in molecular diagnostic testing have contributed to an improved understanding of the biology of cancer and the development of many new innovative therapies. The rapid pace of change in the methodology for performing genetic testing, including the development of Next Generation Sequencing (NGS) addressed in the Proposed Decision Memo, has led to widespread variation in the types of tests for genetic alterations that are available and bundling of tests into cancer-type agnostic panels that may include numerous tests for genetic alterations that have limited clinical utility for any one cancer type. However, due to lack of evidence supporting the tests’ clinical utility, there are limited clinical guidelines on when and how to use multi-gene panels to guide the management of a patient’s cancer treatment.
1. The Proposed Decision Memo has broad and vague criteria regarding coverage for cancer therapies and we urge CMS to revise the criteria to specify that NGS results may not be used as a basis for coverage of a drug or combinations of drugs that would not be supported by the drug(s) FDA label or statutorily approved compendia.
The proposed coverage criteria state that CMS will cover the NGS test “including the test results.” This would result in a broad expansion of coverage criteria for cancer therapies beyond their current FDA approved or compendia supported indications because it implies that any therapies with a mechanism of action that may theoretically have a biological impact on a genetic alteration identified by the test will be covered regardless of evidence of safety or efficacy in the clinical scenario in which the test is being performed. Such a broad expansion will undermine efforts to conduct the necessary clinical studies to determine the safety and efficacy of therapies targeted to genetic alterations in different cancer types, greatly increase healthcare costs, and potentially expose beneficiaries to treatments where the benefits and harms are unknown.
2. CMS should provide coverage for all of the marketed tests that meet the coverage criteria outlined in the Proposed Decision Memo not just the tests that are the proprietary tests linked with a particular type of therapy. This would not disrupt access to the most clinically appropriate and cost-effective diagnostic test to determine if a beneficiary’s tumor harbors a genetic alteration that can be targeted by a specific therapy.
By limiting its scope to the FDA-approved companion in vitro diagnostic tests, the Proposed Decision Memo may have the unintended consequence of limiting beneficiary access to more clinically appropriate and/or more cost-effective diagnostic tests. For example, BRCA1 and BRCA2 gene testing is used to target therapy for various treatments and there are many available tests but the Proposed Decision Memo would limit coverage specifically to the FoundationFocusTM diagnostic test. FoundationFocusTM is a proprietary NGS test marketed by Foundation Medicine that detects alterations in the BRCA1 and BRCA2 genes. The FoundationFocusTM was used in the trial that led to the FDA approval of RubracaTM (rucaparib) and was approved as a companion diagnostic.(1) There are currently two other PARP inhibitors on the market that are approved for the treatment of patients with ovarian cancer, LynparzaTM (olaparib) and ZejulaTM (niraparib), for which testing for BRCA1 and BRCA2 is also recommended to determine if a patient with advanced breast or ovarian cancer will benefit from treatment.(2) The Proposed Decision Memo would limit coverage for diagnostic testing for BRCA1 and 2 to only the FoundationFocusTM test if treatment to be used is RubracaTM whereas there are many other tests available and other treatments that would necessitate this type of testing.
Additionally, many laboratories have the capability of performing the diagnostic testing to determine whether a patient caries a somatic or germline mutation in BRCA1 or BRCA2, either using NGS or other methodologies for assessing genetic alterations. Will this Proposed Decision Memo supersede the LCD(3) that provides coverage criteria for all BRCA1 and BRCA2 genetic tests, not just the FoundationFocusTM? An unintended consequence of the Proposed Decision Memo will be to restrict access to the most cost-effective testing for BRCA1 and BRCA2. Coverage should be based upon evidence-based clinical criteria that can be applied irrespective of the laboratory performing the test.
3. CMS should ensure that coverage criteria for multi-gene panels are evidence-based and that there is clinical utility for all of the genes included in a proprietary panel.
In order to determine whether the expanded multi-gene panel tests meet coverage, CMS should consider whether the incremental information beyond that available in targeted testing (NGS or other methods) has clinical utility.
Expanded multi-gene NGS panels such as the F1CDx (Foundation Medicine, Inc.) include many more genes than are needed to determine the appropriateness of therapy with no clinical utility for the additional genes. As described in the Proposed Decision Memo, the F1CDx is a NGS based in vitro diagnostic device for detection of substitutions, insertion and deletion alterations (indels), and copy number alterations (CNAs) in 324 genes and select gene rearrangements, as well as genomic signatures including microsatellite instability (MSI) and tumor mutational burden (TMB), using DNA isolated from FFPE tumor tissue specimens. This test is currently not specified in any of the FDA labels of cancer therapies. The application for F1CDx approved by the FDA includes data supporting indications for five cancer types, non-small cell lung cancer, melanoma, colorectal cancer, ovarian cancer, and breast cancer.
- For non-small cell lung cancer, Foundation One provided data supporting the utility of only 5 alterations in the 324 genes in the panel (EGFR exon 19 deletions, EGFR exon 21 L858R, EGFR exon 20 T790M alterations, ALK rearrangements, BRAF V600E) to determine the appropriateness of Gilotrif® (afatinib), Iressa® (gefitinib), Tarceva® (erlotinib), Tagrisso® (osimertinib), Alecensa® (alectinib), Xalkori® (crizotinib), Zykadia® (ceritinib) Tafinlar® (dabrafenib) in combination Mekinist® (trametinib).
- For melanoma, there are therapies targeting 2 alterations in 1 of the 324 genes in the Foundation One panel (BRAF V600E and V600K: Tafinlar® (dabrafenib), Zelboraf® (vemurafenib), or Mekinist® (trametinib) or Cotellic® (cobimetinib) in combination with Zelboraf® (vemurafenib).
- For colorectal cancer, there are indications for testing for 2 of the 324 genes (KRAS and NRAS) in the F1CDx to determine the efficacy of Erbitux® (cetuximab) or Vectibix®(panitumumab).
- Similarly for ovarian cancer, there are indications for testing just 2 of the 324 genes included in the F1CDx (BRCA1 and BRCA2) to determine efficacy of the FDA approved therapy Rubraca® (rucaparib).
- Finally for breast cancer, Foundation One provided data on the amplification of ERBB2 (HER2) which correlates with the expression of HER2 antigen, the target for Herceptin® (trastuzumab), Kadcyla® (adotrastuzumab-emtansine), or Perjeta® (pertuzumab); however this would be of limited clinical utility since breast cancer specimens are routinely evaluated for HER2 expression by immunocytochemistry or in situ hybridization.(4)
Given the limited number of genetic alterations needed to determine appropriateness of therapy for these cancers, most of the genes included in the F1CDx lack clinical utility.
Summary
The Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer provides broad coverage for select proprietary genetic tests with limited evidence of clinical utility and may also result in restricting access to the most cost-effective testing by promoting the selected proprietary tests. This establishes a dangerous precedent of creating coverage criteria that prioritize the manufacturer of a test or therapy instead of a careful and deliberate consideration of the test itself, along with the scientific evidence, balancing the benefits and harms to a clearly defined population of beneficiaries. The final National Coverage Determination should allow Medicare Advantage Plans such as UnitedHealthcare to continue making evidence based determinations so that beneficiaries have access to the appropriate care.
Thank you for the opportunity to provide comments on this Proposed Decision Memo. If you have any questions or would like to discuss this issue further, please contact me at (763) 283-2401.
Sincerely,
Jennifer Malin, M.D.
Senior Medical Director, Oncology and Genetics
Senior Medical Director, Oncology and Genetics
Cc: Sam Ho, M.D.
UnitedHealthcare Chief Medical Officer
UnitedHealthcare Chief Medical Officer
(1) Rucaparib Approved for Ovarian Cancer. Cancer Discov. 2017 Feb;7(2):120-121
(2) PARP inhibitors: Clinical utility and possibilities of overcoming resistance. Benjamin G. Bitler, Zachary L. Watson, Lindsay J. Wheeler, and Kian Behbakht. Gynecologic Oncology 2017; 147:695-704.
(3) MolDX: BRCA1 and BRCA2 Genetic Testing (L36082)
(4) Recommendations for Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Update. Antonio C. Wolff, M. Elizabeth H. Hammond, David G. Hicks, Mitch Dowsett, Lisa M. McShane, Kimberly H. Allison, Donald C. Allred, John M.S. Bartlett, Michael Bilous, Patrick Fitzgibbons, Wedad Hanna, Robert B. Jenkins, Pamela B. Mangu, Soonmyung Paik, Edith A. Perez, Michael F. Press, Patricia A. Spears, Gail H. Vance, Giuseppe Viale, and Daniel F. Hayes. Journal of Clinical Oncology 2013; 31:3997-4013.
(2) PARP inhibitors: Clinical utility and possibilities of overcoming resistance. Benjamin G. Bitler, Zachary L. Watson, Lindsay J. Wheeler, and Kian Behbakht. Gynecologic Oncology 2017; 147:695-704.
(3) MolDX: BRCA1 and BRCA2 Genetic Testing (L36082)
(4) Recommendations for Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Update. Antonio C. Wolff, M. Elizabeth H. Hammond, David G. Hicks, Mitch Dowsett, Lisa M. McShane, Kimberly H. Allison, Donald C. Allred, John M.S. Bartlett, Michael Bilous, Patrick Fitzgibbons, Wedad Hanna, Robert B. Jenkins, Pamela B. Mangu, Soonmyung Paik, Edith A. Perez, Michael F. Press, Patricia A. Spears, Gail H. Vance, Giuseppe Viale, and Daniel F. Hayes. Journal of Clinical Oncology 2013; 31:3997-4013.
