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28393111000001103

New Medicines

ImbruvicaChronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma - first-line in young fit patients in combination with rituxumab

Information

Imbruvica
Licence extension / variation
Janssen-Cilag
Pharmacyclics & Janssen

Development and Regulatory status

Launched
Launched
Launched
August 2020
Yes
Aug 20Approved in EU [10].
Jul 20First-line use of ibrutinib in combination with rituximab for CLL is for recommended for EU approval by CHMP - the amended CLL indication is as a single agent or in combination with rituximab or obinutuzumab ... for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL) [9].
Apr 20FDA approve ibrutinib in combination with rituximab for CLL or SLL in pts new to therapy.[8]
Jan 20Filed in EU [7].
Nov 19AbbVie has submitted a supplemental New Drug Application to the U.S. FDA for ibrutinib in combination with rituximab for the first-line treatment of younger patients (70 years old or younger) with chronic lymphocytic leukemia or small lymphocytic lymphoma [6].
Dec 17Will be filed in EU via centralised procedure [1].
Dec 17Has orphan drug status in EU & US [3].

Category

A selective Bruton's tyrosine kinase (Btk) inhibitor
CLL is the most common leukaemia in the Western world with an incidence of 4.2 per 100,000 a year. The incidence increases to more than 30 per 100,000 a year at an age of >80 years. The median age at diagnosis is 72 years. About 10% of CLL patients are reported to be younger than 55 years.
Chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma - first-line in young fit patients in combination with rituxumab
Oral

Further information

Yes

Trial or other data

Aug 19Results of PIII NCT02048813 (n=529) are published; the authors report at median follow-up of 33.6 months, ibrutinib–rituximab resulted in superior progression-free survival vs. standard chemoimmunotherapy (89.4 vs. 72.9% at 3 years; HR 0.35; 95% CI, 0.22 to 0.56; p<0.001) among patients age ≤70 years with previously untreated CLL [5].
Dec 18Latest results from the PIII National Cancer Institute-sponsored PIII Study (E1912; NCT02048813) presented at the annual American Society of Hematology meeting. At a median follow-up of 33.4 months, ibrutinib plus rituximab showed significantly prolonged PFS vs FCR in previously untreated patients aged 70 years or younger with CLL/SLL (HR: 0.35; 95% CI: 0.22-0.56; p<0.0001). The study also demonstrated an improved OS for the ibrutinib plus rituximab treatment arm vs FCR (HR: 0.17; 95% CI: 0.05-0.54; p=0.0003). In a subgroup analysis for PFS, ibrutinib plus rituximab showed prolonged PFS independent of age, sex, performance status (0-2), disease stage, or the presence/absence of deletion 11q23 [4].
Feb 14PIII study in approximately 519 patients starts in the US (NCT02048813). It will assess ibrutinib and rituximab to see how well they work compared to fludarabine phosphate, cyclophosphamide, and rituximab in treating patients with untreated chronic lymphocytic leukemia or small lymphocytic lymphoma. Collection of primary outcome data (PFS and quality of life) is due to complete Mar 20 [2].

Evidence based evaluations

ImbruvicaChronic lymphocytic leukaemia (CLL) or small lymphocytic leukaemia (SLL) - first-line in combination with venetoclax

Information

Imbruvica
Licence extension / variation
Janssen-Cilag
Pharmacyclics & Janssen

Development and Regulatory status

Phase III Clinical Trials
Recommended for approval (Positive opinion)
Phase III Clinical Trials
Yes
Jun 22CHMP recommends a change to the indications for Imbruvica to permit use in combination with venetoclax. The proposed revised indication is “Imbruvica as a single agent or in combination with rituximab or obinutuzumab or venetoclax is indicated for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL)” [8].
Nov 21Filed in EU based on data from GLOW [7].
Nov 21This product is no longer an orphan medicine in the EU. Imbruvica was withdrawn from the Community register of orphan medicinal products in October 2021 upon request of the marketing-authorisation holder [6].
Jan 21EU & US filings planned for 2021 [4].
Jun 19Has orphan drug status for CLL in US & EU [2].

Category

A selective Brutons tyrosine kinase (Btk) inhibitor
CLL is the most common leukaemia in the Western world with an incidence of 4.2 per 100,000 a year. The incidence increases to more than 30 per 100,000 a year at an age of >80 years. The median age at diagnosis is 72 years. About 10% of CLL patients are reported to be younger than 55 years.
Chronic lymphocytic leukaemia (CLL) or small lymphocytic leukaemia (SLL) - first-line in combination with venetoclax
Oral

Further information

Yes

Trial or other data

Jun 21Abbvie announce PIII GLOW study (n=211) met its primary endpoint of superior PFS, demonstrating a reduction in risk of disease progression or death of ~78% (HR 0.216, 95% CI[0.131-0.357]; p<0.0001) [5].
Aug 20PIII GLOW study is no longer recruiting [3].
Oct 19PIII (NCT03462719) study = GLOW study [2].
May 19PIII trial (NCT03462719) is recruiting [1].
Apr 18PIII trial to evaluate the combination of ibrutinib plus venetoclax versus chlorambucil plus obinutuzumab for the first-line treatment of subjects with CLL) or SLL (NCT03462719). The trial is enrolling 200 patients in the US, Belgium, Spain, Canada, Czech Republic, Denmark, France, Israel, the Netherlands, Poland, Russia, Sweden, Turkey and the UK. Primary outcome is PFS; collection of these data is due to complete Feb 21 [1].

ImbruvicaMantle cell lymphoma (MCL), newly diagnosed in adults aged >64 years

Information

Imbruvica
Licence extension / variation
Janssen-Cilag
Pharmacyclics & Janssen

Development and Regulatory status

Phase III Clinical Trials
Pre-registration (Filed)
Phase III Clinical Trials
Apr 22Pre-registration in the EU. Company has applied for an extension of indication to include treatment with Imbruvica in combination with bendamustine and rituximab of adult patients with previously untreated MCL who are unsuitable for autologous stem cell transplantation, based on final results from the PIII SHINE study [11].
Oct 15Remains in PIII development in US & EU [4].
Mar 15EU filing will be via the centralised procedure [3].
May 13PIII study starts [1].

Category

First-in-class selective Bruton's tyrosine kinase (Btk) inhibitor
MCL is a rare and aggressive type of non-Hodgkin’s lymphoma (NHL), comprising 5-10% of newly diagnosed cases of NHL. Approximately 600-1,200 new cases are diagnosed each year in the UK.
Mantle cell lymphoma (MCL), newly diagnosed in adults aged >64 years
Oral

Further information

Yes

Trial or other data

Jun 22Data from PIII SHINE study to be presented at ASCO. Adding ibrutinib to bendamustine and rituxmab reduced risk of disease progression or death by 25%. The study enrolled patients over age 65. These older patients cannot receive intensive chemotherapy or stem cell transplantation because of toxicities. After a median follow-up of seven years (84.7 months) patients who got the ibrutinib combination went 80.6 months without disease progression vs. 52.9 months for the bendamustine-rituximab group. Patients in both groups also received rituximab maintenance treatment after six cycles of bendamustine and rituximab. Although a long time since the trial started, the regimen used in the control arm is considered highly relevant and still in use today [10].
Jun 21PIII SHINE study (NCT01776840) completes collection of primary outcome data [9].
Dec 20PIII (NCT01776840) study is now due to finish collecting primary outcome data in Jun 21 [8].
Dec 19PIII (NCT01776840) study is due to finish collecting primary outcome data in May 20 [7].
Nov 18PIII (NCT01776840) study is now due to complete collection of primary outcome data in Nov 19 [6].
Dec 16PIII (NCT01776840) study on course to complete collection of primary outcome data in Mar 18 [5].
Mar 15PIII NCT01776840 study is ongoing but no longer recruiting pts. Timelines unchanged [2].
Aug 13NCT01776840 is a randomized, double-blind, placebo-controlled PIII study of ibrutinib in combination with bendamustine and rituximab in 520 subjects (>64 years) with newly diagnosed mantle cell lymphoma. Patients will be stratified by simplified MCL International Prognostic Index (MIPI) score (low [0-3], intermediate [4-5] and high risk [6-11]). All participants will receive open-label bendamustine and rituximab background therapy for a maximum of 6 cycles; participants with a complete or partial response will continue to receive rituximab maintenance every second cycle for a maximum of 12 additional doses. In addition all participants will receive blinded study drug (ibrutinib or placebo) daily until disease progression, unacceptable toxicity, or study end. The primary outcome is progression free survival. The study started May 13 and is due to complete Oct 19 (primary outcome data collection Mar 18). Three clinical cutoffs are planned; the first 2 when ~ 134 and 265 PFS events have been observed (interim and final analysis, respectively. The last cutoff will be when 60% of randomized participants have died or the Sponsor terminates the study, whichever comes first [1].

Evidence based evaluations

Relapsed or refractory follicular lymphoma (FL)

Information

Licence extension / variation
Janssen-Cilag
Pharmacyclics & Janssen

Development and Regulatory status

Phase III Clinical Trials
Phase III Clinical Trials
Phase III Clinical Trials
Yes

Category

First-in-class selective Bruton's tyrosine kinase (Btk)
The two most common types of NHL are DLBCL and follicular lymphomas. Annual incidence of DLBCL is 5-6/100,000 (increasing from 0.3/100,000 in those aged 35-39 years to 26.6/100,000 in those aged 80-84 years). Annual incidence of follicular lymphomas has increased from 2-3/100,000 during the 1950s to 5-7/100,000 recently [2].
Relapsed or refractory follicular lymphoma (FL)
Oral

Further information

Yes

Relapsed or refractory marginal zone lymphoma

Information

Licence extension / variation
Janssen-Cilag
Pharmacyclics & Janssen

Development and Regulatory status

Phase III Clinical Trials
Phase III Clinical Trials
Launched
Yes
Jan 17Approved in US for treatment of patients requiring systematic therapy who have received at least one prior anti-CD20 therapy [6].
Sep 16Filed in US for treatment of patients with MZL who require systemic therapy. The filing is based on data from the PCYC-1121 trial (NCT01980628) [5].
Aug 15Orphan designation (EU/3/15/1541) granted by the European Commission to Janssen-Cilag for ibrutinib for treatment of marginal zone lymphoma [4].

Category

First-in-class selective Bruton's tyrosine kinase (Btk)
Non-Hodgkin lymphoma is the sixth most common cancer in the UK; in 2011, approximately 12,800 new cases of non-Hodgkin’s lymphoma were diagnosed accounting for 4% of all new cases in the UK. It is estimated that MZL together with follicular lymphoma account for one-fifth of all non-Hodgkin cases [1].
Relapsed or refractory marginal zone lymphoma
Oral

Further information

Yes

Trial or other data

Dec 21PIII SELENE trial (NCT01974440) is comparing ibrutinib with placebo, in combination with either bendamustine and rituximab (BR), or rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in 400 subjects with previously treated follicular lymphoma or marginal zone lymphoma. Primary outcome is progression-free survival ; collection of these data are due to complete Feb 22 [8].
Nov 18PII (NCT01980628) study final analysis results posted (n=63). Mean ORR 46% (33.5 to 59.3). Analysis was conducted with the cutoff date of 02 Nov 2017, with a median follow-up time of 33.1 months. Median duration of response (DOR) was not reached - NA (16.7 to NA) [7].
Oct 17PII (NCT01980628) study completes [7].
Dec 13PII (NCT01980628) study begins. This open-label, non-randomised, monotherapy study will evaluate safety and efficacy of ibrutinib in 60 pts with relapsed/refractory Marginal Zone Lymphoma (MZL) recruited from sites in the US, Belgium, France, Germany & UK. Collection of primary outcome data (overall response rate) should complete Dec 17 [3].
Nov 13PII (NCT01980628) study is ongoing but no longer recruiting pts. Collection of primary outcome data should compete in Feb 2016 [3].

Evidence based evaluations

ImbruvicaChronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma - first-line in Binet Stage A patients with risk of early disease progression

Information

Imbruvica
Licence extension / variation
Janssen-Cilag
Pharmacyclics & Janssen

Development and Regulatory status

None
Phase III Clinical Trials
None
Yes

Category

A selective Bruton's tyrosine kinase (Btk) inhibitor
CLL is the most common leukaemia in the Western world with an incidence of 4.2 per 100,000 a year. The incidence increases to more than 30 per 100,000 a year at an age of >80 years. The median age at diagnosis is 72 years. About 10% of CLL patients are reported to be younger than 55 years.
Chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma - first-line in Binet Stage A patients with risk of early disease progression
Oral

ImbruvicaRelapsed mantle cell lymphoma (MCL) - second-line or greater in combination with venetoclax

Information

Imbruvica
Licence extension / variation
Janssen-Cilag
Pharmacyclics & Janssen

Development and Regulatory status

Phase III Clinical Trials
Phase III Clinical Trials
Phase III Clinical Trials

Category

First-in-class selective Brutons tyrosine kinase (Btk) inhibitor
The two most common types of NHL are DLBCL and follicular lymphomas. Overall annual incidence of DLBCL in Europe is 3.8/100,000. Annual incidence of follicular lymphomas has increased from 2-3/100,000 during the 1950s to 5-7/100,000 recently. Mantle cell lymphoma accounts for about 3-10% of all cases of NHL. Mantle cell lymphoma is more common in the over-50s and is three times more common in men than in women [1].
Relapsed mantle cell lymphoma (MCL) - second-line or greater in combination with venetoclax
Oral