SUMMARY: The American Cancer Society estimates that in 2022, about 80,470 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 20,250 individuals will die of this disease. In the US, approximately 3,300 new cases of MCL are diagnosed each year. Mantle Cell Lymphoma is an aggressive B-cell lymphoma and accounts for approximately 6% of all Non Hodgkin Lymphomas in adults, and is associated with a high relapse rate following dose-intensive therapies. Early and late relapses in patients with MCL have been attributed to persistence of residual disease.
Majority of patients with MCL are elderly and are not candidates for aggressive treatment or Autologous Stem Cell Transplantation. These patients often receive less aggressive first line therapy such as Bendamustine plus Rituximab, and this regimen has demonstrated superior Progression Free Survival compared to R-CHOP, with a better safety profile. Further, the addition of Rituximab maintenance therapy after induction therapy with Bendamustine and Rituximab has shown significantly prolonged Progression Free Survival or Overall Survival in two independent observational studies.
Bruton’s Tyrosine Kinase (BTK) is a member of the Tec family of kinases, downstream of the B-cell receptor and is predominantly expressed in B-cells. It is a mediator of B-cell receptor signaling in normal and transformed B-cells. Following binding of antigen to the B-Cell Receptor, kinases such as Syk (Spleen Tyrosine Kinase), Lyn (member of the Src family of protein tyrosine kinases) and BTK (Bruton’s Tyrosine Kinase) are activated, with subsequent propagation through PI3K/Akt, MAPK, and NF-κB pathways. This results in B-cell activation and proliferation. The 3 BTK inhibitors presently approved by the FDA for MCL include, IMBRUVICA® (Ibrutinib) approved in 2013, CALQUENCE® (Acalabrutinib) approved in 2017, and BRUKINSA® (Zanubrutinib) approved in 2019.
Single agent IMBRUVICA® is presently approved by the FDA for the treatment of MCL patients who have received at least one prior therapy. In a Phase Ib study, the addition of IMBRUVICA® to Bendamustine and Rituximab therapy was safe and effective with a Complete Response Rate of 76%, among patients with untreated, relapsed, or refractory MCL.
SHINE study is an international, randomized, double-blind, Phase III trial , in which a combination of IMBRUVICA® with Bendamustine plus Rituximab and Rituximab maintenance therapy was compared with placebo with Bendamustine plus Rrituximab and Rituximab maintenance therapy, in elderly patients with untreated Mantle Cell Lymphoma (MCL). A total of 523 previously untreated patients, 65 years of age or older, who had a centrally confirmed diagnosis of Mantle Cell Lymphoma with Cyclin D1 overexpression or translocation breakpoints at t(11;14) were randomly assigned in a 1:1 ratio to receive either to six cycles of IMBRUVICA® along with Bendamustine and Rituximab (N=261) or six cycles of placebo along with Bendamustine and Rituximab (N=262). IMBRUVICA® 560 mg or placebo was administered orally once daily. Bendamustine was administered at 90 mg/m2 IV on days 1 and 2 of each 28 day cycle along with Rituximab 375 mg/m2 IV on day 1 of each 28 day cycle. Patients in either arm who achieved a Complete or Partial Response continued to receive IMBRUVICA® or placebo daily along with Rituximab maintenance therapy at a dose of 375 mg/m2 IV every 8 weeks for up to 12 additional doses. Patients with stable disease after induction treatment could continue to receive IMBRUVICA® or placebo until disease progression or unacceptable toxicities. Both treatment groups were well balanced. The median age of the patients was 71 years and eligible patients had documented Stage II to IV disease with at least one measurable site of disease that was at least 1.5 cm in the longest diameter. Patients were excluded if stem-cell transplantation was planned or if they had known CNS involvement. The Primary endpoint was Progression Free Survival (PFS). Secondary endpoints included Objective Response Rate, Complete Response Rate, Overall Survival and Safety.
The study met its Primary endpoint and at a median follow up of 84.7 months, the median PFS was 80.6 months in the IMBRUVICA® group and 52.9 months in the placebo group (HR for disease progression or death=0.75; P=0.01). The Complete Response Rate was 65.5% in the IMBRUVICA® group and 57.6% in the placebo group (P=0.06). The Overall Survival was similar in the two treatment groups. Grade 3 or 4 adverse events during treatment were 81.5% in the IMBRUVICA® group and 77.3% in the placebo group and the most common Grade 3 and 4 adverse events were rash, pneumonia, and atrial fibrillation.
The authors concluded that treatment with IMBRUVICA® in combination with standard chemoimmunotherapy significantly prolonged Progression Free Survival, and may be a new treatment option for elderly patients with newly diagnosed Mantle Cell Lymphoma, who may not be candidates for intensive chemotherapy or Autologous Stem Cell Transplantation.
Ibrutinib plus Bendamustine and Rituximab in Untreated Mantle-Cell Lymphoma. Wang ML, Jurczak W, Jerkeman M, et al. June 3, 2022. DOI: 10.1056/NEJMoa2201817.
DOI: 10.1200/JCO.2022.40.17_suppl.LBA7502 Journal of Clinical Oncology 40, no. 17_suppl (June 10, 2022)