Axicabtagene Ciloleucel (Yescarta)

Number: 0924

Policy

Note: REQUIRES PRECERTIFICATIONFootnotes*

Medically Necessary

• Aetna considers axicabtagene ciloleucel (Yescarta) medically necessary as single agent therapy for the treatment of adults (18 years and older) for any of the following indications:
   
  
  • Diffuse large B-cell lymphoma (DLBCL) arising from follicular lymphoma after treatment with 2 or more chemoimmunotherapy regimens which included at least one anthracycline or anthracenedione-based regimen, unless contraindicated, or
  • Diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMBL), high-grade B-cell lymphomas with translocations of MYC and BCL2 and/or BCL6 (double/triple hit lymphoma), relapsed AIDS-related DLBCL and HHV8-positive DLBCL, DLBCL not otherwise specific (NOS), or monomorphic post-transplant lymphoproliferative disorders (PTLD; B-cell type) as:
     
    • additional therapy with intention to proceed to high-dose therapy and have had partial response following second-line therapy for relapsed or refractory disease; or
    • treatment of disease in 2 or more relapses (if tisagenlecleucel or axicabtagene ciloleucel not previously given).

Experimental and Investigational

• Aetna considers repeat administration of axicabtagene ciloleucel experimental and investigational because the effectiveness of this approach has not been established.

• Aetna considers axicabtagene ciloleucel experimental and investigational for the following indications (not an all-inclusive list) because its effectiveness for these indications has not been established:

  • Acute lymphoblastic leukemia (ALL)
  • Follicular lymphoma
  • Indolent non-Hodgkin lymphoma (NHL)
  • Mantle cell lymphoma
  • Marginal zone lymphoma
  • Primary central nervous system (CNS) lymphoma

Exclusion Criteria

• History of malignancy other than non-melanoma skin cancer or carcinoma in situ (e.g., bladder, breast, cervix) or follicular lymphoma unless disease free for at least 3 years
• History of allogeneic stem cell transplantation
• Prior CAR T cell therapy or other genetically modified T cell therapy
• Presence of fungal, bacterial, viral, or other infection that is uncontrolled or requiring IV antimicrobials for management.  Simple urinary tract infection (UTI) and uncomplicated bacterial pharyngitis are permitted if responding to active treatment
• Known history of infection with HIV or hepatitis B (HBsAG positive) or hepatitis C virus (anti-HCV positive).  A history of hepatitis B or hepatitis C is permitted if the viral load is undetectable per quantitative PCR and/or nucleic acid testing
• Subjects with detectable cerebrospinal fluid (CSF) malignant cells, or brain metastases, or with a history of CNS lymphoma, CSF malignant cells or brain metastases
• History or presence of CNS disorder such as seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS involvement

Footnotes* Precertification of axicabtagene ciloleucel is required of all Aetna participating providers and members in applicable plan designs.  For precertification of axicabtagene ciloleucel, call 1-877-212-8811.

See also CPB 0799 - Tocilizumab (Actemra) and CPB 0920 - Tisagenlecleucel (Kymriah).

Background

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma (NHL) in adults.  About 72,000 new cases of NHL are diagnosed in the US yearly, and DLBCL represents about 1/3 newly diagnosed cases.  Axicabtagene ciloleucel (formerly KTE-C19), a chimeric antigen receptor (CAR) T cell therapy, has been studied for use in adult patients with large B-cell lymphoma including DLBCL, primary mediastinal large B-cell lymphoma (PMBCL), high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.

Roberts and colleagues (2018) stated that the development of clinically functional CAR T cell therapy is the culmination of multiple advances over the past 30 years.  Axicabtagene ciloleucel is an anti-CD19 CAR T cell therapy in development for patients with refractory DLBCL, including transformed follicular lymphoma (TFL) and PMBCL.  Axicabtagene ciloleucel is manufactured from patients' own peripheral blood mononuclear cells (PBMC) during which T cells are engineered to express a CAR that re-directs them to recognize CD19-expressing cells.  Studies have reported the feasibility of manufacturing axicabtagene ciloleucel in a centralized facility for use in multi-center clinical trials and have demonstrated potent anti-tumor activity in patients with refractory DLBCL.  Main acute toxicities are neurologic events as well as cytokine release syndrome (CRS), which is a systemic response to the activation and proliferation of CAR T cells causing high fever and flu-like symptoms.  The authors concluded that axicabtagene ciloleucel holds promise for the treatment of patients with CD19-positive malignancies, including refractory DLBCL.

On October 18, 2017, the U.S. Food and Drug Administration (FDA) approved axicabtagene ciloleucel (Yescarta) for the treatment of adults with relapsed or refractory (r/r)large B-cell lymphoma after 2 or more lines of systemic therapy, including DLBCL, PMBCL, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.  The safety and effectiveness of Yescarta were established in a multi-center clinical trial of 101 adults with r/r large B-cell lymphoma.  Yescarta is the 2nd gene therapy approved by the FDA and the first for certain types of non-Hodgkin lymphoma (NHL).  Moreover, Yescarta is not indicated for the treatment of patients with primary central nervous system (CNS) lymphoma.

Neelapu and co-workers (2017) stated that in a phase-I clinical trial, axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 CAR T-cell therapy, showed efficacy in patients with refractory large B-cell lymphoma after the failure of conventional therapy.  In this multi-center, phase-II clinical trial, these researchers enrolled 111 patients with DLBCL, primary mediastinal B-cell lymphoma, or transformed follicular lymphoma who had refractory disease despite undergoing recommended prior therapy.  Patients received a target dose of 2×10⁶ anti-CD19 CAR T cells/kg body weight after receiving a conditioning regimen of low-dose cyclophosphamide and fludarabine.  The primary end-point was the rate of objective response (calculated as the combined rates of CR and PR); secondary end-points included overall survival, safety, and biomarker assessments.  Among the 111 patients who were enrolled, axi-cel was successfully manufactured for 110 (99 %) and administered to 101 (91 %).  The objective response rate (ORR) was 82 %, and the CR rate was 54 %.  With a median follow-up of 15.4 months, 42 % of the patients continued to have a response, with 40 % continuing to have a CR.  The overall rate of survival at 18 months was 52 %.  The most common adverse events (AEs) of grade-3 or higher during treatment were neutropenia (in 78 % of the patients), anemia (in 43 %), and thrombocytopenia (in 38 %).  Grade-3 or higher CRS and neurologic events occurred in 13 % and 28 % of the patients, respectively; 3 of the patients died during treatment.  Higher CAR T-cell levels in blood were associated with response.  The authors concluded that in this multi-center study, patients with refractory large B-cell lymphoma who received CAR T-cell therapy with axi-cel had high levels of durable response, with a safety profile that included myelosuppression, the CRS, and neurologic events.

Sharma and colleagues (2018) noted that B-cell NHL are the most common hematological malignancies, which despite improvements in chemo-immunotherapy, carry a uniformly poor prognosis in the relapsed/refractory setting.  CD19 is an antigen expressed on the surface of most malignancies arising from the B cells, and adoptive transfer of anti-CD19 chimeric antigen receptor (CAR)-expressing T cells has been shown to be effective in treating these B-cell malignancies.  Axicabtagene ciloleucel (KTE-C19) is an autologous anti-CD19 CAR T-cell therapy that has shown high ORRs and a manageable safety profile in patients with relapsed or refractory B-cell malignancies who lack effective and curative therapeutic options.  Axi-cel is currently approved by the FDA for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after 2 or more lines of systemic therapy including DLBCL, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma and DLBCL arising from follicular lymphoma, and is also being evaluated in other B-cell malignancies in ongoing clinical trials. 

Jain and associates (2018) stated that adoptive T-cell immunotherapy is a rapidly growing field and is shifting the paradigm of clinical cancer treatment.  Axicabtagene ciloleucel was initially developed at the National Cancer Institute (NCI) and has recently been commercially approved by the FDA for relapsed or refractory aggressive NHL including DLBCL and its variants.  The ZUMA-1 phase-I and phase-II clinical trials formed the basis of the FDA approval of this product, and these investigators discussed the particulars of the clinical trials and the pharmacology of axi-cel.

The National Comprehensive Cancer Netowrk (NCCN) Drugs & Biologics Compendium (2018) included the following category 2A recommendations:

Treatment of histologic transformation to diffuse large B-cell lymphoma (DLBCL) in patients who have received

• minimal or no chemotherapy prior to histologic transformation to DLBCL and have partial response, no response, relapsed, or progressive disease following chemoimmunotherapy for transformed disease (only after treatment with ≥2 chemoimmunotherapy regimens which included at least one anthracycline or anthracenedione-based regimen, unless contraindicated)
• multiple lines of chemoimmunotherapy (not including axicabtagene ciloleucel or tisagenlecleucel) for indolent or transformed disease (only after treatment with ≥2 chemoimmunotherapy regimens which included at least one anthracycline or anthracenedione-based regimen, unless contraindicated)

Used for diffuse large B-cell lymphoma, primary mediastinal large B-cell lymphoma, or high-grade B-cell lymphomas with translocations of MYC and BCL2 and/or BCL6 (double/triple hit lymphoma) as

• additional therapy for patients with intention to proceed to high-dose therapy who have partial response following second-line therapy for relapsed or refractory disease
• treatment of disease in second relapse or greater (if axicabtagene ciloleucel or tisagenlecleucel not previously given)

Treatment for monomorphic PTLD (B-cell type) as

• additional therapy for patients with intention to proceed to high-dose therapy who have partial response following second-line chemoimmunotherapy for relapsed or refractory disease
• treatment of disease in second relapse or greater (if not previously given).

AIDS-Related B-Cell Lymphomas

National Comprehensive Cancer Network’s Drugs & Biologics Compendium (2018) list AIDS-related B-cell lymphomas as a recommended indication of axicabtagene ciloleucel:

Therapy for relapsed AIDS-related diffuse large B-cell lymphoma and HHV8-positive diffuse large B-cell lymphoma, not otherwise specific (NOS) as (Recommendation: 2A)

• Additional therapy for patients with intention to proceed to high-dose therapy who have partial response, no response, or progressive disease following second-line therapy for relapsed or refractory disease
• Treatment of disease in second relapse or greater (if not previously given).

The Prescribing Information of Yescarta described a single-arm, open-label, multi-center trial that examined the effectiveness of a single infusion of Yescarta in adults with relapsed or r/r aggressive B-cell NHL.  Eligible patients had refractory disease to the most recent therapy or relapse within 1 year after autologous hematopoietic stem cell transplantation (HSCT).  The study excluded patients with prior allogeneic HSCT, any history of CNS lymphoma, Eastern cooperative oncology group (ECOG) performance status of 2 or greater, absolute lymphocyte count of less than 100/μL, creatinine clearance less than 60 ml/min, hepatic transaminases more than 2.5 times the upper limit of normal, cardiac ejection fraction of less than 50 %, or active serious infection.  Following lympho-depleting chemotherapy, Yescarta was administered as a single intravenous infusion at a target dose of 2 × 10⁶ CAR-positive viable T cells/kg (maximum permitted dose: 2 × 10⁸ cells).  The lympho-depleting regimen consisted of intravenous (iv) cyclophosphamide 500 mg/m2 and iv fludarabine 30 mg/m2, both given on the 5th, 4th, and 3rd day prior to initiation of Yescarta.  Bridging chemotherapy between leukapheresis and lympho-depleting chemotherapy was not permitted.  All patients were hospitalized for Yescarta infusion and for a minimum of 7 days afterward.  Of 111 patients who underwent leukapheresis, 101 received Yescarta.  Of the patients treated, the median age was 58 years (range of 23 to 76), 67 % were men, and 89 % were white.  Most (76 %) had DLBCL, 16 % had TFL, and 8 % had PMBCL.  The median number of prior therapies was 3 (range of 1 to 10), 77 % of the patients had refractory disease to a 2nd or greater line of therapy, and 21 % had relapsed within 1 year of autologous HSCT; 1 out of 111 patients did not receive the product due to manufacturing failure; 9 other patients were not treated, primarily due to progressive disease or serious adverse reactions following leukapheresis.  The median time from leukapheresis to product delivery was 17 days (range of 14 to 51 days), and the median time from leukapheresis to infusion was 24 days (range of 16 to 73 days).  The median dose was 2.0 × 10⁶ CAR-positive viable T cells/kg (range of 1.1 to 2.2 × 106 cells/kg).  Effectiveness was established on the basis of complete remission (CR) rate and duration of response (DOR), as determined by an independent review committee.  The median time to response was 0.9 months (range of 0.8 to 6.2 months).  Response durations were longer in patients who achieved CR, as compared to patients with a best response of partial remission (PR).  Of the 52 patients (51.5 %) who achieved CR, 14 initially had stable disease (7 patients) or PR (7 patients), with a median time to improvement of 2.1 months (range of 1.6 to 5.3 months).  Treatment with Yescarta can result in severe side effects, which usually appear within the first 1 to 2 weeks, but some side effects may occur later.  The most common non-laboratory adverse reactions (incidence greater than or equal to 20 %) are: CRS, fever, hypotension, encephalopathy, tachycardia, fatigue, headache, decreased appetite, chills, diarrhea, febrile neutropenia, infections-pathogen unspecified, nausea, hypoxia, tremor, cough, vomiting, dizziness, constipation, and cardiac arrhythmias.  The Prescribing Information of Yescarta carries a boxed warning for CRS and neurologic toxicities, which can be fatal or life-threatening. 

Axicabtagene ciloleucel is also being investigated for the treatment of acute lymphoblastic leukemia (ALL), follicular lymphoma, indolent NHL, mantle cell lymphoma, and marginal zone lymphoma (NLM, 2017).

Appendix

Dosing Information

• Yescarta is available as a cell suspension for infusion
• Yescarta comprises a suspension of 2 × 10⁶ CAR-positive viable T cells/kg of body weight, with a maximum of 2 × 10⁸ CAR-positive viable T cells in approximately 68 ml
• Pre-medicate with acetaminophen and an H1-antihistamine
• Confirm availability of tocilizumab prior to infusion
• Dosing is based on the number of CAR-positive viable T cells
• The target Yescarta dose is 2 × 10⁶ CAR-positive viable T cells/kg body weight, with a maximum of 2 × 10⁸ CAR-positive viable T cells

Source: Highlights of Prescribing Information. Axicabtagene ciloleucel (Yescarta). Kite Pharma, Inc.

The above policy is based on the following references: