FDA News – June 2017

June 2017, Vol 7, No 6 - FDA Approvals, News & Updates

A brief overview of cancer drugs approved by the FDA between March 15, 2017, and April 29, 2017.

In This Article

Alunbrig, an Oral Kinase Inhibitor, Receives FDA Approval for NSCLC with ALK Mutation

On April 28, 2017, the FDA approved brigatinib (Alunbrig; Takeda), an oral kinase inhibitor, for the treatment of patients with metastatic non–small-cell lung cancer (NSCLC) with ALK mutation whose disease progressed during crizotinib therapy or who are intolerant to crizotinib therapy.

“In recent years, small molecule ALK inhibitors have revolutionized the treatment options for those with advanced ALK+ non-small cell lung cancer. Nevertheless, there is still a need for additional ALK inhibitors like brigatinib (Alunbrig), which have a manageable safety profile and may address mechanisms of clinical resistance,” said David Ross Camidge, MD, PhD, Director of Thoracic Oncology, University of Colorado, Denver.

The approval of brigatinib was based on results from ALTA, a 2-arm, open-label, multicenter, phase 2 clinical trial in which 222 adults with locally advanced or metastatic NSCLC with ALK mutation that progressed during crizotinib therapy received brigatinib 90 mg once daily or 180 mg once daily after a lead-in period with brigatinib 90 mg. All patients had confirmed ALK arrangement based on the Vysis ALK Break Apart FISH Probe Kit test.

The overall response rate was 48% (95% confidence interval [CI], 39-58) in patients who received brigatinib 90 mg and 53% (95% CI, 43-62) in patients who received brigatinib 180 mg. The median duration of response was 13.8 months in the 90-mg group and 13.8 months in the 180-mg group. In patients with measurable brain metastases, the intracranial objective response was 42% in the 90-mg group and 67% in the 180-mg group, with durations of response of not estimable and 5.6 months, respectively.

The most common (≥25%) adverse reactions with brigatinib 180 mg were nausea, diarrhea, fatigue, cough, and headache.

Serious adverse reactions occurred in 38% of patients who received 90 mg brigatinib and in 40% of patients who received 180 mg brigatinib, the most common of which included pneumonia and interstitial lung disease/pneumonitis. Fatal adverse reactions occurred in 3.7% of patients.

The recommended starting dose for brigatinib is 90 mg, orally, for the first 7 days; if tolerated, increase to 180 mg.

Brigatinib received a breakthrough therapy and an orphan drug designation for this indication and was reviewed under the FDA’s priority review status.

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Rydapt First Drug in Decades Approved by the FDA for Acute Myeloid Leukemia

On April 28, 2017, midostaurin (Rydapt; Novartis), a kinase inhibitor, became the first targeted therapy, and the first new drug in more than 20 years, to receive FDA approval, in combination with chemotherapy, for the treatment of adults with newly diagnosed acute myeloid leukemia (AML) plus the FLT3 mutation.

Midostaurin was approved with a companion diagnostic test, the LeukoStrat CDx FLT3 Mutation Assay, which detects the FLT3 mutation.

“Rydapt is the first targeted therapy to treat patients with AML, in combination with chemotherapy. The ability to detect the gene mutation with a diagnostic test means doctors can identify specific patients who may benefit from this treatment,” said Richard Pazdur, MD, Director of the FDA’s Office of Hematology and Oncology Products.

On the same day, the FDA also approved Rydapt for the treatment of adults with other types of rare blood disorders, including aggressive systemic mastocytosis, systemic mastocytosis with associated hematologic neoplasm, or mast-cell leukemia.

Midostaurin was approved based on results of a randomized clinical trial of 717 patients with newly diagnosed AML who received midostaurin plus chemotherapy or placebo plus chemotherapy. Patients who received midostaurin plus chemotherapy had superior overall survival (OS) compared with those receiving placebo plus chemotherapy (hazard ratio [HR], 0.77; 2-sided P = .016), although a median OS could not be reliably estimated. In addition, patients who received midostaurin plus chemotherapy had a significant improvement in event-free survival compared with the placebo group, 8.2 months versus 3 months, respectively (HR, 0.78; 2-sided P = .005).

The most common (≥20%) adverse reactions in patients with AML who received midostaurin included febrile neutropenia, nausea, mucositis, vomiting, headache, petechiae, musculoskeletal pain, epistaxis, device-related infection, hyperglycemia, and upper respiratory tract infection.

The most common (≥20%) adverse reactions in patients with aggressive systemic mastocytosis or mast-cell leukemia included nausea, vomiting, diarrhea, edema, musculoskeletal pain, abdominal pain, fatigue, upper respiratory tract infection, constipation, fever, headache, and shortness of breath.

Rydapt received a breakthrough therapy designation for AML plus the FLT3 mutation, as well as priority review and fast track for the mastocytosis indication.

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Stivarga First Drug in a Decade Approved by the FDA for Liver Cancer

On April 27, 2017, the kinase inhibitor regorafenib (Stivarga; Bayer HealthCare) received a new indication from the FDA for the treatment of patients with hepatocellular carcinoma (HCC) who had previously received sorafenib. This approval represents an important milestone in the treatment of liver cancer: it has been nearly 10 years since a new drug was approved by the FDA for liver cancer.

“This is the first time patients with HCC have had an FDA-approved treatment that can be used if their cancer has stopped responding to initial treatment with sorafenib,” said Richard Pazdur, MD, Director of the FDA’s Office of Hematology and Oncology Products.

The new indication of regorafenib for liver cancer was based on the RESORCE clinical trial, an international, randomized, double-blind, placebo-controlled study involving 573 adults with HCC that progressed after sorafenib therapy.

The major efficacy outcome measure was overall survival (OS); other outcome measures included progression-free survival (PFS), overall response rate (ORR), and duration of response.

The median OS was 10.6 months (95% confidence interval [CI], 19.1-12.1) in the regorafenib group versus 7.8 months (95% CI, 6.3-8.8) in the placebo group, a significant difference (P <.0001). The median PFS was 3.4 months in the regorafenib group compared with 1.5 months in the placebo group, also a significant difference (P <.0001). The ORR was 11% in the regorafenib group versus 4% in the placebo group.

The most common (≥20%) all-grade adverse reactions reported with regorafenib plus best supportive care in patients with liver cancer were pain, hand–foot skin reaction, asthenia or fatigue, diarrhea, decreased appetite or food intake, hypertension, infection dysphonia, fever, mucositis, weight loss, and rash.

Regorafenib includes a box warning about the potential for severe and fatal hepatotoxicity. Hepatic function should be monitored before and during treatment with regorafenib.

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Atezolizumab Approved as First-Line Treatment for Advanced Bladder Cancer in Some Patients

On April 17, 2017, atezo­lizumab (Tecentriq; Genentech), a PD-ligand 1 (PD-L1)-blocking antibody, received a new indication by the FDA as first-line treatment for patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin chemotherapy. This is the first immunotherapy and the first PD-L1 to receive FDA approval as first-line treatment for advanced bladder cancer in this subgroup of patients.

“It is encouraging to see continued progress in the treatment of advanced bladder cancer, which until last year had not seen any major advancements in more than 30 years. We are excited that Tecentriq is now a treatment option for people with advanced bladder cancer who are unable to receive a cisplatin-based chemotherapy as an initial treatment,” said Andrea Maddox Smith, Chief Executive Officer, Bladder Cancer Advocacy Network, in a press release.

This approval of atezolizumab was based on previously published results of the phase 2 IMvigor210 clinical trial. Atezolizumab was approved last year for patients with locally advanced or metastatic bladder cancer.

Serious side effects with atezo­lizumab include pneumonitis, hepatitis, colitis, hormonal issues, neuropathy, meningitis, encephalitis, and eye inflammation, as well as severe infections and severe infusion reactions.

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Tagrisso Receives Full Approval for NSCLC with EGFR T790M Mutation

On March 30, 2017, the FDA granted osimertinib (Tagrisso; AstraZeneca) full approval for the treatment of meta­static non–small-cell lung cancer (NSCLC) with the EGFR T790M mutation, as detected by an FDA-approved test, in patients whose disease progressed during or after EGFR tyrosine kinase inhibitor (TKI) therapy. Osimertinib received accelerated approval for this indication in November 2015.

The full approval of osimertinib was based on results from the AURA3 clinical trial, a randomized, multicenter, open-label, active-controlled study involving 419 patients with metastatic EGFR T790M mutation–positive NSCLC that progressed after first-line EGFR TKI therapy. Patients were randomized to receive osimertinib 80 mg orally once daily or platinum-based doublet chemotherapy with pemetrexed plus carboplatin or pemetrexed plus cisplatin.

The median progression-free survival was 10.1 months (95% confidence interval [CI], 8.3-12.3) with osimertinib versus 4.4 months (95% CI, 4.2-5.6) with chemotherapy (P <.001). The objective response rate was 65% with osimertinib versus 29% with chemotherapy (P <.001). The mediation duration of response was 11.0 months with osimertinib versus 4.2 months with chemotherapy.

In patients with measurable central nervous system (CNS) lesions on baseline brain scans, the CNS objective response rate was 57% in the osimertinib group versus 25% in the chemotherapy group. The CNS duration of response was not reached in the osimertinib group versus 5.7 months in the chemotherapy group.

The most common all-grade adverse reactions (≥20%) in patients who received osimertinib were diarrhea, rash, dry skin, nail toxicity, and fatigue. Serious adverse reactions were reported in 18% of patients who received osimertinib versus 26% of patients who received chemotherapy. One patient in the osimertinib group had a fatal reaction resulting from interstitial lung disease or pneumonitis.

The FDA previously granted osimertinib fast track and breakthrough therapy designation for this indication.

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Bavencio, a PD-L1 Inhibitor, First Nonchemotherapy Drug Approved for Merkel-Cell Carcinoma

On March 23, 2017, the FDA accelerated the approval of avelumab (Bavencio; EMD Serono/Pfizer), a PD ligand 1 (PD-L1)-blocking antibody, for the treatment of adults and pediatric patients aged ≥12 years with metastatic Merkel-cell carcinoma. This is the first nonchemotherapy drug approved by the FDA for this rare type of cancer.

“While skin cancer is one of the most common cancers, patients with a rare form called Merkel cell cancer have not had an approved treatment option until now,” said Richard Pazdur, MD, Director of the FDA’s Office of Hematology and Oncology Products. “The scientific community continues to make advances targeting the body’s immune system mechanisms for the treatment of various types of cancer. These advancements are leading to new therapies—even in rare forms of cancer where treatment options are limited or non-existent.”

The approval of avelumab was based on the efficacy and safety results from the JAVELIN Merkel 200 clinical trial, an open-label, single-arm, multicenter study involving 88 patients with metastatic Merkel-cell carcinoma that progressed during or after chemotherapy. Patients received Bavencio 10 mg/kg as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.

The major efficacy outcome measures were the overall response rate (ORR) and the duration of response. The ORR was 33% (95% confidence interval, 23.3-43.8), and the duration of response ranged from 2.8 months to approximately 23.3 months.

Of the 88 patients who were enrolled in the JAVELIN Merkel 200 clinical trial, the most common (≥20%) all-grade adverse reactions were fatigue, musculoskeletal pain, diarrhea, nausea, infusion-related reaction, rash, decreased appetite, and peripheral edema. Serious adverse reactions that occurred in more than 1 patient included acute kidney injury, anemia, abdominal pain, ileus, asthenia, and cellulitis.

Avelumab 10 mg/kg is administered as an intravenous infusion every 2 weeks.

Avelumab received orphan drug status and a breakthrough therapy designation for this indication and was reviewed under the FDA’s priority review status.

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