Data presented at the 18th Annual Congress of the European Hematology Association (EHA) being held in Stockholm, Sweden, June 13 – 16, 2013, of two separate Phase II studies suggest that ibrutinib (PCI-32765), an investigational oral Bruton’s tyrosine kinase (BTK) inhibitor, shows efficacy when used as a monotherapy in patients with relapsed/refractory mantle cell lymphoma (MCL) or diffuse large B-cell lymphoma (DLBCL).[1]
Both MCL and DLBCL are part of a family of blood cancers which originate from malignant B-cells. Unlike healthy B-cells, malignant B-cells ignore signals to die and continue to develop and reproduce in the lymph.[2][3][4] When a malignancy is described as ‘relapsed’, it means that it has returned after an initial partial or total remission.[5] ‘Refractory’ refers to cancer that has become resistant to current treatment.[6]
Patients with B-cell malignancies, including diffuse large B-cell lymphoma and relapsed/refractory mantle cell lymphoma, are in real need of new treatment options
Ibrutinib is an investigational, oral Bruton’s tyrosine kinase (BTK) inhibitor and is jointly developed by Janssen Research & Development, LLC and Pharmacyclics, Inc. The effectiveness and safety of ibrutinib alone or in combination with other treatments is being studied in several B-cell malignancies. BTK is a mediator of the B-cell-receptor signaling pathway implicated in the pathogenesis of B-cell cancers.
“Our comprehensive clinical development program is studying ibrutinib across a variety of B-cell malignancies; these patients, including those with DLBCL and MCL, are in real need of new treatment options,” said Peter F. Lebowitz, M.D., Ph.D., Global Oncology Therapeutic Area Head, Janssen R&D. “It’s particularly exciting to observe the differences in response rates now as compared to earlier data from this study that were presented several months ago.”
Ibrutinib in Relapsed/Refractory MCL
In the treatment of patients with relapsed/refractory MCL ibrutinib monotherapy showed an overall response rate (ORR) of 68%, including a complete response (CR) of 21% and a partial response (PR) of 47%. The estimated median duration of response (DOR) in all responding patients was 17.5 months. Median progression-free survival (PFS) was 13.9 months. In this trial, median overall survival (OS) has not yet been reached, but is estimated to be 58% at 18 months.
Treatment-emergent adverse events (AEs) were seen in greater than 20% of patients and included diarrhea (50%), fatigue (41%), nausea (31%), peripheral edema (28%), dyspnea (27%), constipation (25%), upper respiratory tract infection (23%), vomiting (23%) and decreased appetite (21%) and were consistent with previously reported data. Only 7% of patients discontinued due to an adverse events related to the treatment.
“The results of this single-agent study are encouraging. It is exciting to see how active ibrutinib is in the treatment of relapsed and refractory mantle cell lymphoma, particularly as the responses appear to last.,” noted Professor Simon Rule, Consultant Hematologist in the Department of Hematology at the Derriford Hospital in Plymouth, United Kingdom. “What is equally important is that no new safety signals were observed during this study.”
Study design of the MCL trial
The MCL study was a Phase II multicenter, open-label, study including 111 patients with relapsed/refractory MCL at 18 sites internationally. Patients had received a median of three prior therapies and were enrolled into two cohorts based on prior bortezomib exposure ? either bortezomib-naive (n=63) or bortezomib-exposed (n=48), with both groups receiving 560 mg of ibrutinib orally, once a day. The primary endpoint of the study was ORR. Secondary endpoints included DOR, PFS, OS and frequency and severity of adverse events.
Relapsed/Refractory DLBCL
In the second Phase II study involving patients with relapsed/refractory DLBCL (n=70), investigators tested the hypothesis that ibrutinib would be more active in the Activated B-cell-like (ABC) subtype compared to the Germinal Center B-cell-like (GCB) subtype, given that the ABC subtype is dependent on the B-cell antigen receptor (BCR) pathway. Ibrutinib targets the BCR pathway by inhibiting BTK, a critical mediator in malignant B-cell growth and proliferation.
The results of the study show that patients with the ABC subtype showed a significantly greater response to ibrutinib monotherapy compared to those with the GCB subtype (ORR = 41% vs 5%, p=0.007, Fisher’s exact test). Median OS was 9.76 months for the ABC subtype, compared to 3.35 months for the GCB subtype (p=0.05). Within the ABC subtype group, only patients who had a CD79B mutation responded to treatment. Patients with only an MYD88 mutation did not respond to treatment, suggesting a MYD88-dependent but BCR-independent pathogenesis for some DLBCL tumors.
Safety data from 70 patients identified no new safety signals. Grade 3 or higher AEs were seen in greater than 3% of patients and included fatigue (9%), hyponatremia (9%), pneumonia (7%), dehydration (4%), and pleural effusion (4%).
“These results indicate the important function BTK plays in the survival of ABC type DLBCL,” explained presenting investigator Sven de Vos, M.D., Ph.D. (photo), Associate Professor in the Department of Medicine at the UCLA Medical Center, Los Angeles, who reported the results at the EHA Congress today. “Seeing clinically meaningful responses among the ABC subtype was encouraging, as patients at this stage are challenging to treat. Additional trials among this patient group are ongoing.”
The DLBCL study was a Phase II multicenter, open-label, study that included 70 patients with relapsed/refractory DLBCL with a median of three prior therapies. All patients underwent gene expression profiling to determine their DLBCL subtype, 29 patients were identified with the ABC subtype, and 20 with the GCB subtype. Patients received ibrutinib 560 mg orally, once a day, until disease progression or unacceptable toxicity. The primary objective of the study was to assess ORR categorized by subtype, with secondary objectives being to assess the safety and tolerability of ibrutinib in people with DLBCL.
Regulatory status
To date, ibrutinib has been granted three Breakthrough Therapy Designations by the U.S. Food & Drug Administration (FDA) as a monotherapy for the treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) with deletion of the short arm of chromosome 17 (del17p); patients with relapsed/refractory MCL who have received prior therapy, and in patients with Waldenstrom’s macroglobulinemia (WM). The implications of Breakthrough Therapy Designation cannot be determined at this time.
References:
[1]Wang ML, Rule S, Martin P, Goy A, Auer R, Kahl BS, Jurczak W, Advani RH, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2013 Jun 19. [Epub ahead of print]DOI: 10.1056/NEJMoa1306220.[PubMed Abstract][Full Text Article]
[2]Murphy K, Travers P, Walport M. Janeway’s Immunobiology. 7th ed. Garland Science; 2008:257-320.
[3] Shaffer AL, Rosenwald A, Staudt LM. Lymphoid malignancies: the dark side of B-cell differentiation. Nat Rev Immunol. 2002. Dec; 2(12):920
-32.[PubMed Abstract]
[4] LeBien TW, Tedder, TF. B lymphocytes: how they develop and function. Blood. 2008 Sep 1;112(5):1570-80. doi: 10.1182/blood-2008-02-078071. [PubMed Abstract]
[5] PubMed Health. Relapse Definition. Last accessed on June16, 2013. [Definition]
[6] PubMed Health. Refractory Cancer Definition. Last accessed on June 16, 2013. [Definition]
Photo:Sven de Vos, M.D., Ph.D., Associate Professor in the Department of Medicine at the UCLA Medical Center, Los Angeles. Photo Courtesy:UCLA’s Jonsson Comprehensive Cancer Center.
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