December 19, 2019 - FDA News & Updates

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Brukinsa Receives Accelerated FDA Approval for Mantle-Cell Lymphoma

On November 14, 2019, the FDA granted accelerated approval to zanubrutinib capsules (Brukinsa; BeiGene), a Bruton’s tyrosine kinase (BTK) inhibitor, for the treatment of adults with mantle-cell lymphoma who have received at least 1 previous therapy. This is the second BTK inhibitor to be approved by the FDA.

“Mantle cell lymphoma usually responds well to initial treatment, but eventually returns or stops responding, and the cancer cells continue to grow. This is a life-threatening condition,” said Richard Pazdur, MD, Director of the FDA’s Oncology Center of Excellence. “Clinical trials showed that 84% of patients saw tumor shrinkage with this therapy. For patients whose disease relapses or becomes refractory, secondary therapies may be successful in providing another remission, and today’s approval will provide patients with another treatment option.”

The FDA designated zanubrutinib as a breakthrough therapy and an orphan drug. Mantle-cell lymphoma represents 3% to 10% cases of all non-Hodgkin lymphoma in the United States.

This approval was based on a phase 2 open-label, multicenter, single-arm clinical trial of 86 patients with mantle-cell lymphoma who had received at least 1 previous therapy. The overall response rate (ORR) was 84% (95% confidence interval [CI], 74-91), with a complete response rate of 59% (95% CI, 48-70) and a median duration of response of 19.5 months (95% CI, 16.6-not estimable). This approval was also based on an earlier phase 1/2 open-label, dose-escalation, multicenter, single-arm clinical trial of 32 patients with mantle-cell lymphoma who had received at least 1 previous therapy. The ORR was 84% (95% CI, 67-95), with a complete response rate of 22% (95% CI, 9-40) and a median duration of response of 18.5 months (95% CI, 12.6-not estimable).

The most common (≥20%) side effects with zanubrutinib were reduced neutrophils, decreased platelets, upper-respiratory tract infection, decreased white blood cells, decreased hemoglobin level, rash, bruising, diarrhea, and cough. The most common serious adverse reactions were pneumonia (11%) and hemorrhage (5%).

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Ziextenzo Third Biosimilar to Neulasta Approved for Febrile Neutropenia

On November 5, 2019, the FDA approved pegfilgrastim-bmez (Ziextenzo; Sandoz) as a third biosimilar to Neulasta (pegfilgrastim), a granulocyte colony-stimulating factor. The previous 2 biosimilars to Neulasta were approved in 2018.

Pegfilgrastim-bmez is approved for the same indications as its reference drug—to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies who receive myelosuppressive drugs (which are associated with an increased risk for febrile neutropenia). Pegfilgrastim-bmez is not approved for the mobilization of peripheral blood progenitor cells for hematopoietic stem-cell transplant.

The FDA approval of pegfilgrastim-bmez was based on data showing that it is highly similar to its reference drug, and that there are no clinically meaningful differences between these 2 drugs.

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Tecentriq Approved with Chemotherapy for First-Line Treatment of Metastatic NSCLC without EGFR or ALK Mutations

On December 3, 2019, the FDA approved atezolizumab (Tecentriq; ­Genentech), in combination with paclitaxel protein-bound (Abraxane) and carboplatin chemotherapy, for the first-line treatment of adults with metastatic nonsquamous non–small-cell lung cancer (NSCLC) that does not harbor EGFR or ALK genomic mutations.

The approval was based on the IMpower130 study, a multicenter, randomized, open-label clinical trial of patients with stage IV nonsquamous NSCLC who did not receive any chemotherapy for metastatic disease; the patients could have received a previous EGFR or ALK inhibitor, if appropriate. A total of 724 patients were randomized to atezolizumab, paclitaxel protein-bound, and carboplatin, followed by monotherapy with atezolizumab or to paclitaxel protein-bound and carboplatin, followed by maintenance therapy with pemetrexed.

In the primary analysis of 681 patients without EGFR or ALK mutations, the estimated median progression-free survival was 7.2 months (95% confidence interval [CI], 6.7-8.3) with atezolizumab versus 6.5 months (95% CI, 5.6-7.4) in the control arm (hazard ratio, 0.75; 95% CI, 0.63-0.91; P = .0024). The median overall survival was 18.6 months (95% CI, 15.7-21.1) versus 13.9 months (95% CI, 12.0-18.7), respectively (P = .0384).

The most common adverse events (≥20%) with atezolizumab plus chemotherapy in patients with nonsquamous NSCLC were fatigue/asthenia, nausea, alopecia, constipation, diarrhea, and decreased appetite.

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FDA Approves Calquence for Adults with CLL or SLL

On November 21, 2019, the FDA accelerated the approval of acalabrutinib (Calquence; AstraZeneca) for adults with chronic lymphocytic leukemia (CLL) or with small lymphocytic lymphoma. This drug was approved 4 months earlier than the FDA PDUFA data. The FDA used its priority review for these 2 indications and granted ­acalabrutinib a breakthrough therapy designation for these indications.

This approval was done under Project Orbis, a new initiative by the FDA’s Oncology Center of Excellence. Project Orbis provides a framework for the concurrent submission and review of cancer drugs among international partners. The FDA, the Australian Therapeutic Goods Administration, and Health Canada collaborated on this review.

“Today, as part of a US, Australian, and Canadian collaboration known as Project Orbis, the US approved a new treatment option for those living with chronic lymphocytic leukemia or small lymphocytic lymphoma. The FDA’s Project Orbis provides a framework for concurrent submission and review of oncology drug applications among the FDA’s international partners,” said Richard Pazdur, MD, Director of the FDA’s Oncology Center of Excellence.The approval was based on 2 randomized, actively controlled clinical trials.

The ELEVATE-TN study included 535 newly diagnosed patients with CLL who were randomized to 1 of 3 arms: acalabrutinib monotherapy, acalabrutinib plus obinutuzumab, or obinutuzu­mab plus chlorambucil. With a median follow-up of 28.3 months, the hazard ratio (HR) for progression-free survival (PFS) was 0.10 (95% confidence interval [CI], 0.06-0.17; P <.0001) with acalabrutinib plus obinutuzumab and 0.20 (95% CI, 0.13-0.30; P <.0001) with acalabrutinib monotherapy compared with obinutuzumab plus chlorambucil.

The ASCEND study randomized 310 patients with relapsed or refractory CLL who received at least 1 systemic therapy to acalabrutinib or to the investigator’s choice of treatment (idelalisib plus rituximab therapy, or bendamustine plus rituximab therapy). With a median follow-up of 16.1 months, the PFS was significantly longer in the acal­abrutinib monotherapy arm compared with the investigator’s choice arm (HR, 0.31; 95% CI, 0.20-0.49; P <.0001).

In both studies, with a median follow-up of 28.3 months, the median PFS had not been reached in the acalabrutinib arm, and the median overall survival had not been reached in any arm.

The most common adverse reactions (≥30%) of any grade in patients with CLL were anemia, neutropenia, thrombocytopenia, headache, upper respiratory tract infection, and diarrhea.

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Zejula Receives FDA Approval for HRD-Positive Advanced Ovarian Cancer

On October 23, 2019, the FDA approved a new indication for the PARP inhibitor niraparib (Zejula; Tesaro) for the treatment of patients with homologous recombination deficiency repair (HRD)-positive advanced ovarian, fallopian tube, or primary peritoneal cancer, after receiving ≥3 chemotherapy regimens. HRD is defined by a deleterious or suspected deleterious BRCA mutation, or a genomic instability associated with disease progression more than 6 months after the tumor’s response to the last platinum-based chemotherapy. On the same day, the FDA also approved the Myriad myChoice CDx test to select patients for niraparib therapy based on the HRD tumor status.

The approval of niraparib for this indication was based on a single-arm clinical trial of 98 patients with HRD-positive advanced ovarian cancer. The FDA granted this application priority review. All patients received ≥3 previous lines of chemotherapy. Patients who had previously received a PARP inhibitor were excluded from the study. Patients without BRCA mutations had to have disease progression at least 6 months after the last dose of platinum-based therapy. HRD-positive status was determined by the Myriad myChoice CDx test. All patients received 300 mg of niraparib once daily, until disease progression or unacceptable toxicity.

The primary efficacy end points were objective response rate (ORR) and duration of response. In the cohort of 98 patients with HRD-positive status, the ORR was 24% (95% confidence interval [CI], 16-34). All the responses were partial. The estimated median duration of response was 8.3 months (95% CI, 6.5-not estimable).

Among patients with ovarian cancer and BRCA mutations (N = 63), the ORR was 39% (95% CI, 17-64) in those with platinum-sensitive disease; 29% (95% CI, 11-52) in those with platinum-resistant disease; and 19% (95% CI, 4-46) in those with platinum-refractory disease.

A total of 73% of patients had adverse reactions to niraparib that led to dose reduction or interruption. The most common (≥5%) side effects resulting in dose reduction or interruption were thrombocytopenia (40%), anemia (21%), neutropenia (11%), nausea (13%), vomiting (11%), fatigue (9%), and abdominal pain (5%).

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Last modified: July 22, 2021