Acalabrutinib Receives US FDA Accelerated Approval

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2017 remains a banner year for B cell lymphomas and chronic lymphocytic leukemia (CLL) is a B cell lymphoma.

The good news continued today with the approval of acalabrutinib, now known by the brand name CALQUENCE, for Mantle Cell Lymphoma (MCL).

Acalabrutinib (formerly ACP-196) is similar to ibrutinib in that it blocks  BTK, a pathway critical for B cell survival.

While ibrutinib has proven to be very effective in CLL, the most common reason patients discontinue therapy is intolerance. Acalabrutinib may have a different side effect profile and so the hope is that patients who can’t tolerate ibrutinib, but for whom it is working, might be able to better tolerate acalabrutinib and get similar benefits. That question is being studied right now.

Having acalabrutinib as another option will be a great thing for CLL patients, and this approval for MCL, a harder to treat lymphoma than CLL, is great news for our fellow patients with MCL and hopeful news for us with CLL.

Below is the press release the CLL Society received from AstraZeneca.

Dear CLL Society,

We are pleased to share that the US Food and Drug Administration (FDA) has granted acceleratedapproval for CALQUENCE^® (acalabrutinib). A Bruton tyrosine kinase (BTK) inhibitor, CALQUENCE is indicated for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.¹ This indication is approved under the FDA’s accelerated approval pathway, based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.¹

CALQUENCE will be available to patients immediately. This is the first FDA approval for AstraZeneca in hematology.

As you know, MCL is an aggressive B-cell non-Hodgkin lymphoma (NHL) with poor prognosis.^2,3,4,5While MCL patients initially respond to treatment, there is a high relapse rate and there is no standard therapy for relapsed or refractory disease.³

The approval of CALQUENCE is based on results as assessed by Independent Review Committee (IRC) from the Phase II open-label, single-arm ACE-LY-004 clinical trial, which evaluated CALQUENCE in patients with relapsed or refractory MCL and showed:

• 80% (95% CI: 72, 87) of patients taking CALQUENCE achieved an overall response rate, 40% (95% CI: 31, 49) achieved a complete response, and 40% (95% CI: 32, 50) achieved a partial response, per 2014 Lugano classification.¹
• The most common adverse reactions (> 20%) of any grade were anemia,* thrombocytopenia,* headache (39%), neutropenia,* diarrhea (31%), fatigue (28%), myalgia (21%), and bruising (21%).¹

• • *Treatment-emergent decreases (all grades) of hemoglobin (46%), platelets (44%), and neutrophils (36%) were based on laboratory measurements and adverse reactions.¹

• Dosage reductions or discontinuation due to any adverse reaction were reported in 1.6% and 6.5% of patients, respectively.¹

See below for additional Important Safety Information about CALQUENCE.

The accelerated approval program was established to allow for earlier approval of drugs that treat serious conditions and that fill an unmet medical need based on a surrogate endpoint.⁶

Questions or requests for more information may arise as news of this approval begins to travel among patients, healthcare professionals, and the general public. View the full press release here issued by AstraZeneca announcing the FDA approval for your reference.

Please see full Prescribing Information here.

IMPORTANT SAFETY INFORMATION

Hemorrhage

Serious hemorrhagic events, including fatal events, have occurred in the combined safety database of 612 patients with hematologic malignancies treated with CALQUENCE monotherapy. Grade 3 or higher bleeding events, including gastrointestinal, intracranial, and epistaxis, have been reported in 2% of patients. Overall, bleeding events, including bruising and petechiae of any grade, occurred in approximately 50% of patients with hematological malignancies.

The mechanism for the bleeding events is not well understood.

CALQUENCE may further increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies, and patients should be monitored for signs of bleeding.

Consider the benefit-risk of withholding CALQUENCE for 3 to 7 days pre- and post-surgery, depending upon the type of surgery and the risk of bleeding.

Infection

Serious infections (bacterial, viral, or fungal), including fatal events and opportunistic infections, have occurred in the combined safety database of 612 patients with hematologic malignancies treated with CALQUENCE monotherapy. Grade 3 or higher infections occurred in 18% of these patients. The most frequently reported Grade 3 or 4 infection was pneumonia. Infections due to hepatitis B virus (HBV) reactivation and progressive multifocal leukoencephalopathy (PML) have occurred.

Monitor patients for signs and symptoms of infection and treat as medically appropriate. Consider prophylaxis in patients who are at increased risk for opportunistic infections.

Cytopenias

In the combined safety database of 612 patients with hematologic malignancies, patients treated with CALQUENCE monotherapy experienced Grade 3 or 4 cytopenias, including neutropenia (23%), anemia (11%), and thrombocytopenia (8%), based on laboratory measurements. Monitor complete blood counts monthly during treatment.

Second Primary Malignancies

Second primary malignancies, including non-skin carcinomas, have occurred in 11% of patients with hematologic malignancies treated with CALQUENCE monotherapy in the combined safety database of 612 patients. The most frequent second primary malignancy was skin cancer, reported in 7% of patients. Advise protection from sun exposure.

Atrial Fibrillation and Flutter

In the combined safety database of 612 patients with hematologic malignancies treated with CALQUENCE monotherapy, atrial fibrillation and atrial flutter of any grade occurred in 3% of patients, and Grade 3 in 1% of patients. Monitor for atrial fibrillation and atrial flutter and manage as appropriate.

ADVERSE REACTIONS

The most common adverse reactions (≥20%) of any grade were anemia,* thrombocytopenia,* headache (39%), neutropenia,* diarrhea (31%), fatigue (28%), myalgia (21%), and bruising (21%).

*Treatment-emergent decreases (all grades) of hemoglobin (46%), platelets (44%), and neutrophils (36%) were based on laboratory measurements and adverse reactions.

The most common Grade ≥ 3 non-hematological adverse reaction (reported in at least 2% of patients) was diarrhea (3.2%).

Dosage reductions or discontinuations due to any adverse reaction were reported in 1.6% and 6.5% of patients, respectively.

Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 4.8% of patients.

DRUG INTERACTIONS

Strong CYP3A Inhibitors: Avoid co-administration with a strong CYP3A inhibitor. If a strong CYP3A inhibitor will be used short-term, interrupt CALQUENCE.

Moderate CYP3A Inhibitors: When CALQUENCE is co-administered with a moderate CYP3A inhibitor, reduce the CALQUENCE dose to 100 mg once daily.

Strong CYP3A Inducers: Avoid co-administration with a strong CYP3A inducer. If a strong CYP3A inducer cannot be avoided, increase the CALQUENCE dose to 200 mg twice daily.

Gastric Acid Reducing Agents: If treatment with a gastric acid reducing agent is required, consider using an H2-receptor antagonist or an antacid. Take CALQUENCE 2 hours before taking an H2-receptor antagonist. Separate dosing with an antacid by at least 2 hours.

Avoid co-administration with proton pump inhibitors. Due to the long-lasting effect of proton pump inhibitors, separation of doses may not eliminate the interaction with CALQUENCE.

SPECIFIC POPULATIONS

There is insufficient clinical data on CALQUENCE use in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. Advise women of the potential risk to a fetus.

It is not known if CALQUENCE is present in human milk. Advise lactating women not to breastfeed while taking CALQUENCE and for at least 2 weeks after the final dose.

References

1. CALQUENCE® (acalabrutinib) Prescribing Information.
2. Leukemia & Lymphoma Society. Mantle Cell Lymphoma Facts. Available online. Accessed June 2017.
3. Cheah CY, Seymour JF, Wang M. Mantle Cell Lymphoma. J Clin Oncol. 34, no. 11 (April 2016) 1256-1269.
4. Hoster E, Klapper W et al. Confirmation of the Mantle-Cell Lymphoma International Prognostic Index in Randomized Trials of the European Mantle-Cell Lymphoma Network. Journal of Clinical Oncology 2014;32:1338-1346.
5. Dreyling M, Ferrero S. The role of targeted treatment in mantle cell lymphoma: is transplant dead or alive? Haematologica 2016 Volume 101(2):104-114.
6. US Food and Drug Administration. Guidance for Industry Labeling for Human Prescription Drug and Biological Products Approved Under the Accelerated Approval Regulatory Pathway Available online. Accessed August 2017.