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EMA Green Light for Avapritinib for GIST, Acalabrutinib for CLL

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The European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP) has given a thumbs up to two new oncology drugs.

The Committee has recommended granting conditional marketing authorization for avapritinib (Ayvakit, Blueprint Medicines) for use in adults with unresectable or metastatic gastrointestinal stromal tumors (GIST) harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation, including PDGFRA D842V mutations. About 6%-10% of GIST tumors harbor this mutation, and avapritinib is a selective and potent inhibitor of KIT and PDGFRA mutant kinases.

The EMA committee also adopted a positive opinion for acalabrutinib (Calquence, AstraZeneca) for the treatment of chronic lymphocytic leukemia (CLL) as monotherapy in patients who are treatment naive or have received at least one prior therapy.

First Targeted Therapy for Mutation

Avapritinib was approved by the US Food and Drug Administration (FDA) earlier this year for the same indication. The FDA approval was based on findings from the phase 1 NAVIGATOR clinical trial that included 43 patients with GIST harboring a PDGFRA exon 18 mutation, including 38 patients with the most common mutation, PDGFRA D842V.

For patients harboring a PDGFRA exon 18 mutation, the overall response rate (ORR) was 84%, with 7% having a complete response and 77% having a partial response. Patients with the PDGFRA D842V mutation achieved an ORR of 89%, with 8% having a complete response and 82% having a partial response.

“GIST harboring a PDGFRA exon 18 mutation do not respond to standard therapies…today’s approval provides patients with the first drug specifically approved for GIST harboring this mutation,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence, in a statement at the time of approval.

The most common side effects (≥ 20% of patients) observed in those taking avapritinib include nausea, fatigue, anemia, periorbital edema, face edema, hyperbilirubinemia, diarrhea, vomiting, peripheral edema, increased lacrimation, decreased appetite, and memory impairment. There may also be a risk of intracranial hemorrhage, in which case the dose should be reduced or the drug should be discontinued.

In the EU, conditional marketing authorization is granted to a medicinal product that fulfills an unmet medical need when the benefit to public health of immediate availability outweighs the risk inherent in the fact that additional data are still required, the CHMP notes on its website.

Avapritinib had received an orphan medicine designation during development, which the EMA will now review to determine if the designation can be maintained.

New Treatment for CLL

Acalabrutinib is already approved in the United States, Canada, and Australia for the treatment of CLL and small lymphocytic lymphoma. The product was approved at the same time by all three regulatory authorities last year.

In the United States, acalabrutinib had previously been approved for use in mantle cell lymphoma.

The drug’s benefit in the treatment of CLL was shown in the ASCEND trial, in which it was compared with physician’s choice of idelalisib or bendamustine with rituximab. The trial, which involved 310 patients with relapsed/refractory CLL, showed acalabrutinib as monotherapy had significantly improved tolerability as well as progression-free survival versus standard treatment regimens.

“The ASCEND study demonstrated that acalabrutinib can provide a more effective and tolerable treatment option for patients with relapsed/refractory CLL compared to the standard combination therapies, including chemo-free approaches such as idelalisib plus rituximab,” first author Paolo Ghia, MD, a professor of medical oncology at the Vita-Salute San Raffaele University, Milan, Italy,

The most commonly reported adverse events seen with acalabrutinib were respiratory tract infections, headache, bruising, contusion, diarrhea, nausea, rash, musculoskeletal pain, fatigue, decreased hemoglobin, and decreased platelets.

Detailed recommendations for the use of both drugs will be provided in the summary of product characteristics, which will be published in the European public assessment report and made available in all official EU languages after the products receive marketing authorization by the European Commission.