FDA News – June 2017

June 2017, Vol 8, No 3 - FDA Approvals, News & Updates


A brief overview of cancer drugs approved by the FDA between March 15, 2017, and May 30, 2017.

In This Article


Keytruda First Cancer Drug Approved for Any Solid Tumor Based on a Biomarker Instead of Tumor Site

On May 23, 2017, the FDA granted accelerated approval to pembrolizumab (Keytruda; Merck) for the treatment of metastatic, microsatellite instability–high (MSI-H) or mismatch repair–deficient (dMMR) solid tumors that have progressed after previous treatment and have no appropriate alternative treatments, or for colorectal cancer that has progressed after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. This is the first time the FDA approved a cancer drug for use in any solid tumor with a specific genetic feature.

“This is an important first for the cancer community. Until now, the FDA has approved cancer treatments based on where in the body the cancer started—for example, lung or breast cancers. We have now approved a drug based on a tumor’s biomarker without regard to the tumor’s original location,” said Richard Pazdur, MD, Director of the FDA’s Oncology Center of Excellence.

The FDA approval of pembrolizu­mab for this indication was based on data from patients with MSI-H or dMMR solid tumors who participated in 1 of 5 uncontrolled, open-label, multicohort, multicenter, single-arm clinical trials. The overall response rate was 39.6%, and 78% of patients who responded to pembrolizumab had a duration of response lasting ≥6 months. The median duration of response had not been reached at the time of the analysis.

Pembrolizumab can cause serious immune-mediated adverse events, including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis. Complications or death related to allogeneic hematopoietic stem-cell transplantation has occurred after therapy with pembrolizumab.

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Imfinzi a New PD-L1 Approved for Bladder Cancer After Platinum-Based Chemotherapy

On May 1, 2017, the FDA accelerated the approval of durvalumab (Imfinzi; AstraZeneca) for the treatment of locally advanced or metastatic urothelial carcinoma in patients whose disease progressed during or after platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment. On the same day, the FDA approved the Ventana PD-L1 Assay as a complementary diagnostic test to assess PD-L1 levels in urothelial carcinoma tissue.

“The usual course of treatment for patients with advanced bladder cancer begins with a standard platinum-containing chemotherapy. Patients who have disease progression during or following chemotherapy are left with few other treatment options. The approval of Imfinzi to treat this population of select patients signifies hope for those who are currently suffering, or may find themselves with limited options in the future,” said Nicholas J. Vogelzang, MD, FACP, FASCO, Clinical Pro­fessor, University of Nevada School ­of Medicine.

The FDA also granted durvalumab priority review and breakthrough therapy designation for this indication.

This approval was based on a single-­arm clinical trial involving 182 patients with locally advanced or metastatic urothelial carcinoma that progressed after previous platinum-containing chemotherapy. Of the 182 patients, 95 had high PD-L1 levels. The median follow-up time was 5.6 months. The overall response rate was 17% in all patients, 26.3% in patients with high PD-L1 expression, 21.4% in patients with PD-L1 expression that was not evaluable, and 4.1% in patients with low or no PD-L1 expression.

The median duration of response was 12.3 months in patients with low or no PD-L1 expression and was not reached in patients with high PD-L1 expression, and patients whose PD-L1 was not evaluable.

The most common (≥15%) all-grade adverse reactions included fatigue, musculoskeletal pain, constipation, decreased appetite, nausea, peripheral edema, and urinary tract infection. Grade 3 or 4 adverse events were reported in 43% of patients who received durvalumab, including pneumonitis, hepatitis, colitis, thyroid disease, adrenal insufficiency, and diabetes.

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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 of brigatinib and in 40% of patients who received 180 mg of 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.

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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 Oncology Center of Excellence.

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.

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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 Oncology Center of Excellence.

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 in the regorafenib group versus 7.8 months 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.

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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-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 inhibitor 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 IMvigor 210 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, 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.

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.

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Zejula a New Maintenance Treatment Option for Recurrent Epithelial Ovarian Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cancer

On March 27, 2017, the FDA accelerated the approval of niraparib (Zejula; Tesaro), a PARP inhibitor, for maintenance treatment of 3 types of cancers—recurrent epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer—in adults who had a complete or partial response to platinum-based chemotherapy.

“Maintenance therapy is an important part of a cancer treatment regimen for patients who have responded positively to a primary treatment,” said Richard Pazdur, MD, Director of the FDA’s Oncology Center of Excellence. “Zejula offers patients a new treatment option that may help delay the future growth of these cancers, regardless of whether they have a specific genetic mutation,” he added.

The FDA approval was based on a randomized clinical trial of 553 patients with recurrent epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer, who had received ≥2 platinum-based chemotherapies and had a complete or a partial response to the most recent chemotherapy regimen.

All patients were tested for BRCA mutation with the FDA-approved BRAC­Analysis CDx test. The median progression-free survival (PFS) was 21 months in patients with a BRCA mutation who received niraparib versus 5.5 months in patients who received placebo. Among patients without a BRCA mutation, the median PFS was 9.3 months with niraparib versus 3.9 months with placebo.

The most common (≥10%) all-grade adverse events with niraparib were thrombocytopenia, anemia, neutropenia, leukopenia, palpitations, nausea, constipation, vomiting, abdominal pain or distention, mucositis or stomatitis, diarrhea, dyspepsia, dry mouth, fatigue/asthenia, decreased appetite, urinary tract infection, elevations in AST or ALT levels, myalgia, back pain, arthralgia, headache, dizziness, dysgeusia, insomnia, anxiety, nasopharyngitis, dyspnea, cough, rash, and hypertension.

The most common grade 3 or 4 adverse reactions included neutropenia, nausea, constipation, diarrhea, urinary tract infection, elevations in AST or ALT levels, dyspnea, and hypertension.

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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), 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 Oncology Center of Excellence. “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 and the duration of response. The overall response rate 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.

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