Radioimmunotherapy for Non-Hodgkin's Lymphoma

The Lymphoma Research Foundation, a private research foundation that represents lymphoma patients, researchers, and caregivers, would like to express its appreciation to the Centers for Medicare & Medicaid Services (CMS) for publication of a proposed decision memo for radioimmunotherapy for non-Hodgkin’s lymphoma. The standards for Medicare coverage of radioimmunotherapies have been unclear since the agency announced a review of Zevalin almost three years ago. Substantial delays in the completion of coverage analyses have the potential to create confusion among Medicare patients and their physicians regarding Medicare payment for new therapies, and we encourage the agency to avoid delays of this sort in the future.

Although formal action to clarify the standards for coverage of radioimmunotherapy is a step forward, we are concerned that the off-label coverage policy in the draft memo may limit patient access to radioimmunotherapy and is at odds with the statutory requirements for off- label coverage of cancer drugs. The draft memo describes radioimmunotherapy as a diagnostic x- ray test and radioactive isotope therapy, benefit categories for Medicare coverage according to Food and Drug Administration labeling. In addition, according to the draft memo, contractors will retain the authority to provide coverage for off-label uses when such uses are supported by evidence in peer-reviewed medical literature.

The proposed coverage standard is at least potentially inconsistent with the requirements of the Medicare statute that off-label uses of cancer drugs be covered if they are recognized in certain medical compendia or in peer-reviewed literature. 42 U.S.C. §1395(t)(2). The classification of the radioimmunotherapies as diagnostic x-ray and radioactive isotope therapy should not be the means for exempting these therapies from the off-label provisions governing cancer drugs. The products involved in the entire therapy should be governed by the off- label coverage provisions of the Medicare statute.

We look forward to working with CMS on this and future coverage decisions to ensure that patient access to important cancer therapies is ensured.

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GlaxoSmithKline (GSK) wants to express our appreciation for the opportunity to comment on the recent proposed National Coverage Decision (NCD) regarding radioimmunotherapy treatment for non-Hodgkin’s lymphoma (NHL). That decision dealt with coverage of potential off label used for such products.

As you know, GSK manufactures one of the two existing radioimmunotherapy treatments for NHL, namely BEXXAR® (Tositumomab and Iodine I 131 Tositumomab). This modality of treatment is still relatively new. While the BEXXAR therapeutic regimen is complex to manufacture, distribute and administer, it has already shown promising results in the treatment of NHL.

Given the available data and the limited use of radioimmunotherapies to date, we believe that the proposal by CMS to continue to allow local carriers to make individual determinations regarding potential off label uses of these therapies is entirely appropriate. We will continue to work with local carriers to inform them about relevant data as they become available.

In addition, while GSK did submit the most current data during the NCD process, research concerning the BEXXAR therapeutic regimen has continued and we wanted to let you know of some additional, recently published studies evaluating the BEXXAR therapeutic regimen in previously untreated low grade/follicular NHL patients that were not included in the Internal Technology Assessment. The references for the studies as well as a short summary of the data are provided below:

1. Kaminski MS, Tuck M, Estes J, et al. 131I- Tositumomab therapy as initial treatment for follicular lymphoma. N Engl J Med 2005; 352: 441- 449.

Background: A single-arm, open-label, single center study was conducted to determine the efficacy of the BEXXAR therapeutic regimen in 76 pts with previously untreated follicular NHL.
Efficacy Results: Ninety five percent (72/76) of patients had an overall response, and 75% (57/76) had a complete response (CR), with 20% (15/76) experiencing a partial response (PR). The actuarial 5-year progression-free survival (PFS) for all patients was 59%, with a median PFS of 6.1 years. Of 57 patients who had a complete response, 40 remained in remission for 4.3 to 7.7 years.
Safety Results: Grade 3/4 neutropenia and thrombocytopenia occurred in 34% and 17% of patients, respectively. With a median follow-up of 5.1 years, no cases of myelodysplastic syndrome (MDS) or secondary acute leukemia were reported.

2. Press OW, Unger JM, Braziel RM, et al. A phase II trial of CHOP chemotherapy followed by tositumomab/iodine I 131 tositumomab for previously untreated follicular non-Hodgkin lymphoma: Southwest Oncology Group Protocol S9911. Blood 2003; 102: 1606-1612.

Background: An phase II single-arm, open-label, multi-center study was conducted by the Southwest Oncology Group (SWOG) to determine the efficacy of the BEXXAR therapeutic regimen following CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy in 90 pts with previously untreated follicular NHL.
Efficacy Results: The overall response rate after CHOP chemotherapy was 88% (39% CR and 49% PR). Among 47 assessable patients with a PR or unconfirmed complete response (CRu) after CHOP, the addition of BEXXAR therapeutic regimen improved the best overall response in 27 patients (57%), either from a PR to a CRu (49%), or from a CRu to a CR (9%). With a median follow-up of 2.3 years, the 2-year PFS was estimated to be 81%, with a 2-year overall survival of 97%.
Safety Results: Hematologic adverse events were the most common toxicities after CHOP or BEXXAR. After the BEXXAR therapeutic regimen, Grade 3 or 4 non-hematologic adverse events of any kind were reported in 16% and 2 % of patients, respectively.

3. Leonard JP, Coleman M, Kostakoglu A, et al. Durable remissions from fludarabine followed by the iodine I-131 tositumomab Bexxar therapeutic regimen for patients with previously untreated follicular non-Hodgkin's lymphoma (NHL). Proc Am Soc Clin Oncol 2004; 23:560. Abstract 6518 & Poster.

Background: A single-arm, open-label, single center study was conducted to determine the efficacy of the BEXXAR therapeutic regimen following 3 cycles of fludarabine chemotherapy in 35 pts with previously untreated low-grade NHL.
Efficacy Results: After completion of fludarabine therapy, 89% of patients had an overall response (9% CR, 80% PR). Following the BEXXAR therapeutic regimen, a response was observed in 35 of 35 (100%) evaluable patients, 30 CR (86%) and 5 PR (14%). With a median follow-up of 4.4 years, median PFS had not been reached, and 72% of patients who achieved a CR, remained in CR.
Safety Results: Absolute neutrophil count < 500 cells/mm3 was reported in 9% (3 of 35) and 34% (12 of 35) of the patients after fludarabine and BEXXAR, respectively. Platelet count < 10,000/mm3 was reported in 3% (1 of 35) of the patients after BEXXAR.

4. Link B, Kaminski M, Coleman M, Leonard JP. Phase II study of CVP followed by tositumomab and iodine I 131 tositumomab (Bexxar therapeutic regimen) in patients with untreated follicular non-Hodgkin's lymphoma. Proc Am Soc Clin Oncol 2004; 23:560. Abstract 6520 & Poster.

Background: A phase II single-arm, open-label, multi-center study was conducted to determine the efficacy of the BEXXAR therapeutic regimen following CVP (cyclophosphamide, vincristine, and prednisone) chemotherapy in 30 pts with previously untreated follicular NHL.
Efficacy Results: The overall response rate after CVP chemotherapy was 100% (50% CR and 50% PR). The addition of BEXXAR therapeutic regimen improved the response of 13 of 15 patients (87%) from a PR to a CR resulting in a CR in 28 of 30 patients (93%). With a median follow-up of 3.1 years from initiation of therapy, median PFS had not been reached.
Safety Results: Hematologic adverse events were the most common toxicities after CVP or BEXXAR. Grade 3 or 4 neutropenia was reported in 57% and 60% of the patients after CVP and BEXXAR, respectively. Grade 3 or 4 non-hematologic adverse events of any kind were reported in 63% and 13% of patients, respectively.

We would be glad to forward copies of the references if they would be useful to you. In addition, we would be pleased to continue to provide periodic updates on ongoing research activities.

Again, thank you for your work on this proposed NCD. Please let us know if we can be of further assistance.

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The Biotechnology Industry Organization (BIO) appreciates this opportunity to comment on the Centers for Medicare and Medicaid Services’ (CMS) draft coverage decision memorandum for Radioimmunotherapy for Non-Hodgkin’s Lymphoma (CAG-00163N). BIO is the largest trade organization to serve and represent the biotechnology industry in the United States and around the globe. BIO represents more than 1,000 biotechnology companies, academic institutions, state biotechnology centers, and related organizations in the United States. BIO members are involved in the research and development of health-care, agricultural, industrial and environmental biotechnology products.

Representing an industry that is devoted to discovering new treatments and ensuring patient access to them, BIO applauds CMS for deciding not to change current coverage policy on the off-label use of ZEVALIN® or BEXXAR® for the treatment of non-Hodgkin’s lymphoma. By allowing contractors to continue to cover these therapies under Medicare’s existing policies for off-label uses of anti-cancer drugs and biologicals, CMS ensures that contractors will have the flexibility to make timely, evidence-based coverage decisions. This national coverage decision (NCD) will help to ensure that Medicare beneficiaries fighting non-Hodgkin’s lymphoma will be able to choose the most appropriate treatment, as recommended by their physicians.

CMS notes that contractors “would continue to provide coverage for medically accepted uses of off-label indications when such uses are supported by evidence appearing in CMS-approved peer-reviewed medical literature.” CMS also says, the decision “makes no change in coverage for any off-label uses of the agents in clinical trials.” Although we appreciate these instructions to protect access to ZEVALIN® and BEXXAR®, we request that CMS clarify that contractors also must cover off-label indications supported by the compendia. The Medicare statute requires contractors to cover “drugs and biologicals used in an anticancer chemotherapeutic regimen for a medically accepted indication,” defined as a use supported by citations in certain compendia or by peer- reviewed medical literature. Medicare’s longstanding manual instructions also permit contractors to cover off-label uses that are “medically accepted generally as safe and effective for the particular use.” In the proposed decision memorandum, CMS states that contractors will cover uses supported by peer- reviewed literature, but does not include the requirement to cover uses supported by the compendia or the option to cover other medically accepted uses. Unless CMS includes this additional language in the final decision, the decision will have the unintended consequence of restricting the local coverage discretion CMS stated it would preserve.

We also encourage CMS to use the creation of this decision as a learning experience for future NCDs. As we explained in our comments on the draft guidance document regarding the factors CMS considers when opening an NCD, CMS should provide stakeholders notice and opportunity for consultation before the agency initially generates an internal request for an NCD. Early communication with stakeholders would help CMS learn more about the item or service. To help CMS use its resources more efficiently, we recommend that CMS (1) inform the public of topics being considered for internally-generated requests at the earliest possible stage and (2) involve stakeholders in the decision to open an NCD.

BIO appreciates the opportunity to comment on this proposed decision memorandum. We thank the agency for its decision to protect beneficiary access to these therapies, and we recommend that CMS further ensure that patients will have a choice of appropriate therapies by stating expressly that off-label uses supported by compendia citations must be covered, and other medically accepted uses may be covered as well. We also recommend that CMS consult with stakeholders before opening another internally generated NCD, such as this.

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