Imbruvica (ibrutinib) - 5 indications

Scroll down for information on each indication:

• the treatment of mantle cell lymphoma; approved November of 2013
• the treatment of chronic lymphocytic leukemia and small lymphocytic lymphoma, including patients who carry a deletion in chromosome 17 (17p deletion); approved February and July of 2014
• the treatment of Waldenström’s macroglobulinemia; approved January 2015
• the treatment of marginal zone lymphoma; approved January 2017
• the treatment of chronic graft-versus-host disease; approved August 2017

General Information

Imbruvica (ibrutinib) is an orally available, selective inhibitor of Bruton's tyrosine kinase (Btk), a gene that is disrupted in the human disease X-linked agammaglobulenemia (XLA). BTK is a signaling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways.

Imbruvica is specifically approved for the following indications:

• the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy
• the treatment of adult patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), including patients who carry a deletion in chromosome 17 (17p deletion)
• the treatment of adult patients with Waldenström’s macroglobulinemia
• the treatment of adult patients with marginal zone lymphoma (MZL) who require systemic therapy and have received at least one prior anti-CD20-based therapy
• the treatment of patients one year of age and older with chronic graft-versus-host disease (cGVHD) after failure of one or more lines of systemic therapy

Imbruvica is supplied as capsules, tablets and a liquid suspension for oral administration. Administer Imbruvica at approximately the same time each day with a glass of water. Swallow tablets or capsule whole. Do not open, break, or chew the capsules. Do not cut, crush, or chew the tablets. If a dose of Imbruvica is not taken at the scheduled time, it can be taken as soon as possible on the same day with a return to the normal schedule the following day. Do not take extra doses of Imbruvica to make up for the missed dose. 

Scroll down to see the recommended dosing/administration for each indication.

Mechanism of Action

Imbruvica (ibrutinib) is an orally available, selective inhibitor of Bruton's tyrosine kinase (Btk). Ibrutinib forms a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK enzymatic activity. BTK is a signaling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways. BTK’s role in signaling through the B-cell surface receptors results in activation of pathways necessary for B-cell trafficking, chemotaxis, and adhesion.

Side Effects

Adverse effects associated with the use of Imbruvica in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) may include, but are not limited to, the following:

• thrombocytopenia
• diarrhea
• fatigue
• musculoskeletal pain
• neutropenia
• rash
• anemia
• bruising

Adverse effects associated with the use of Imbruvica in patients with cGVHD may include, but are not limited to, the following:

• fatigue
• bruising
• diarrhea
• thrombocytopenia
• muscle spasms
• stomatitis
• nausea
• hemorrhage
• anemia
• pneumonia

Indication 1 - mantle cell lymphoma

approved November of 2013

Dosing/Administration

The recommended dosage is 560 mg orally once daily until disease progression or unacceptable toxicity.

Clinical Trial Results

The FDA approval of Imbruvica for MCL was based on an open-label, multi-center, single-arm trial of 111 previously treated subjects. The median age was 68 years. The subjects received Imbruvica orally at 560 mg once daily until disease progression or unacceptable toxicity. Tumor response was assessed according to the revised International Working Group (IWG) for non-Hodgkin’s lymphoma (NHL) criteria. The primary endpoint in this study was investigator-assessed overall response rate (ORR). The ORR was 69% and the median time to response was 1.9 months.

Indication 2 - chronic lymphocytic leukemia and small lymphocytic lymphoma, including patients who carry a deletion in chromosome 17 (17p deletion)

approved February and July of 2014

Dosing/Administration

The recommended dosage is 420 mg orally once daily until disease progression or unacceptable toxicity. Imbruvica can be administered as a single agent, in combination with rituximab or obinutuzumab, or in combination with bendamustine and rituximab.

Clinical Trial Results

The FDA approval of Imbruvica for chronic lymphocytic leukemia was based on an open-label, multi-center trial of 48 previously treated patients. Imbruvica was administered orally at 420 mg once daily until disease progression or unacceptable toxicity. The overall response rate (ORR) and duration of response (DOR) were assessed using a modified version of the International Workshop on CLL Criteria by an Independent Review Committee. The ORR was 58.3%, all partial responses. None of the patients achieved a complete response. The DOR ranged from 5.6 to 24.2+ months. The median DOR was not reached.

The FDA approved of Imbruvica for CLL with 17p deletion was based on a clinical study of 391 previously treated patients, 127 of whom had CLL with 17p deletion. The patients were randomly assigned to receive Imbruvica or Arzerra until disease progression or side effects became intolerable. The trial was stopped early for efficacy after a pre-planned interim analysis showed Imbruvica-treated patients experienced a 78% reduction in risk of disease progression or death (progression-free survival). Results also showed a 57% reduction in risk of death (overall survival) in patients treated with Imbruvica. Of the 127 patients who had CLL with 17p deletion, those treated with Imbruvica experienced a 75% reduction in risk of disease progression or death.

The FDA approval of Imbruvica as a first-line treatment for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) was based on data from the randomized, multi-center, open-label Phase 3 RESONATE-2 (PCYC-1115) trial, which evaluated the use of Imbruvica versus chlorambucil in 269 treatment-naïve patients with CLL or SLL aged 65 years or older. Imbruvica significantly prolonged progression-free survival (PFS; primary endpoint) as determined by an Independent Review Committee (IRC), reducing the risk of progression or death by 84% versus chlorambucil; median PFS: not reached for Imbruvica vs. 18.9 months for chlorambucil). Imbruvica was also associated with a significantly higher IRC-assessed overall response rate (ORR: a composite of complete and partial responses; 82.4% vs. 35.3%) versus chlorambucil. Five patients (3.7 percent) in the Imbruvica arm achieved a complete response, compared to two patients (1.5 percent) in the chlorambucil arm.

The FDA Approval of Imbruvica in combination with rituximab for the treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who are new to therapy was based on the E1912 Study. The study evaluated 529 previously untreated CLL patients ages 70 years or younger (median age of 58) who were randomly assigned to receive Imbruvica plus rituximab (n=354) or the chemoimmunotherapy FCR (n=175). The patients treated with Imbruvica plus rituximab lived longer without disease progression, with a progression-free survival (PFS) rate of 88 percent at 37 months, compared to patients treated with fludarabine, cyclophosphamide and rituximab (FCR), with a PFS rate of 75 percent.

Indication 3 - Waldenström’s macroglobulinemia

approved January 2015

Dosing/Administration

The recommended dosage is 420 mg orally once daily until disease progression or unacceptable toxicity. Imbruvica can be administered as a single agent or in combination with rituximab.

Clinical Trial Results

Single Agent: The FDA approval for Waldenström’s macroglobulinemia was based on a clinical study of 63 previously treated subjects. All study subjects received a daily 420 milligram orally administered dose of the medication until disease progression or side effects became intolerable. Results showed 62% of subjects had their cancer shrink after treatment (overall response rate). At the time of the study, the duration of response ranged from 2.8 months to approximately 18.8 months.

The FDA approval of Imbruvica in combination with rituximab was based on results from the randomized, double-blind, placebo-controlled iNNOVATE study (PCYC-1127). The iNNOVATE study evaluated Imbruvica in combination with rituximab versus placebo plus rituximab in 150 patients with either relapsed/refractory (r/r) disease or previously untreated WM. At a median follow up of 26.5 months, a significant improvement in the Independent Review Committee (IRC)-assessed primary endpoint of progression-free survival (PFS) was seen with Imbruvica plus rituximab when compared with placebo plus rituximab (30-month PFS rates were 82% vs. 28%, respectively). Patients in the Imbruvica plus rituximab treatment arm experienced an 80% reduction in relative risk of disease progression or death compared with patients treated with placebo plus rituximab.

Indication 4 - marginal zone lymphoma

approved January 2017

Dosing/Administration

The recommended dose is 560 mg orally once daily until disease progression or unacceptable toxicity.

Clinical Trial Results

The FDA approval of Imbruvica for MZL was based on a phase 2, open-label, multi-center, single-arm study, which evaluated the safety and efficacy of Imbruvica in MZL patients who require systemic therapy and have received at least one prior anti-CD20-based therapy. The efficacy analysis included 63 patients. The ORR was achieved in nearly half (46%) of the patients as assessed by an Independent Review Committee (IRC) using criteria adopted from the International Working Group criteria for malignant lymphoma. The median time to response was 4.5 months. In the trial, 3.2% of patients had a complete response (CR) and 42.9% of patients had a partial response (PR). The median duration of responses was not reached (NR) (range 16.7 months to NR).

Indication 5 - chronic graft-versus-host disease

approved August 2017

Dosing/Administration

The recommended dosage is 420 mg orally once daily until cGVHD progression, recurrence of an underlying malignancy, or unacceptable toxicity. When a patient no longer requires therapy for the treatment of cGVHD, Imbruvica should be discontinued considering the medical assessment of the individual patient.

Patients 1 to less than 12 years of age: 240 mg/m2 taken orally once daily (up to a dose of 420 mg)

Clinical Trial Results

The FDA approval of Imbruvica for cGVHD was based on a single-arm trial of 42 patients with cGVHD whose symptoms persisted despite standard treatment with corticosteroids. Most patients’ symptoms included mouth ulcers and skin rashes, and more than 50 percent of patients had two or more organs affected by cGVHD. In the trial, 67 percent of patients experienced improvements in their cGVHD symptoms. The improvement of symptoms lasted for up to five months or longer in 48% of the subjects.