FDA News - April 2017: Additional Items

JHOP Web Exclusives - FDA News & Updates, Online Only

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Keytruda Receives Accelerated Approval for Relapsed/Refractory Classical Hodgkin Lymphoma

On March 14, 2017, the FDA granted pembrolizumab (Keytruda; Merck), a PD-1 receptor blocking antibody, accelerated approval for the treatment of patients with refractory classical Hodgkin lymphoma, or for those whose disease relapsed after ≥3 lines of therapy.

“For the patients with classical Hodgkin lymphoma who are not cured with existing treatments, there are limited options, and treating their disease becomes more challenging. This approval is an important step forward in treating these patients, who are generally young and have a particularly poor prognosis,” said Craig Moskowitz, MD, Clinical Director, Division of Hematologic Oncology, Memorial Sloan Kettering Cancer Center, New York, NY.

Pembrolizumab received orphan drug and breakthrough therapy designations for this indication, which was approved under the FDA’s priority review process.

This approval was based on the Keynote-087 clinical trial that included 210 adults with relapsed or refractory classical Hodgkin lymphoma disease after autologous stem-cell transplantation and/or brentuximab vedotin and receiving a median of 4 therapies. After a median follow-up of 9.4 months, the overall response rate (ORR) was 69% (95% confidence interval [CI], 62-75); complete remission was 22%; and median duration of response was 11.1 months.

The most common (≥20%) all-grade adverse reactions in patients with classical Hodgkin lymphoma who received pembrolizumab included fatigue, pyrexia, cough, musculoskeletal pain, diarrhea, rash, and hypertransaminesemia. The most common grade 3 or 4 adverse reactions were fatigue (1%), pyrexia (1%), dyspnea (1%), musculoskeletal pain (1%), and diarrhea (1.4%).

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Kisqali, a New CDK4/CDK6 Inhibitor, Approved for First-Line Therapy in HR-Positive, HER2-Negative Advanced Breast Cancer

On March 13, 2017, ribociclib (Kisqali; Novartis) became the third CDK4/CDK6 inhibitor to be approved by the FDA. The FDA approved ribociclib, in combination with an aromatase inhibitor, for the treatment of postmeno­pausal women with hormone receptor (HR)-positive, HER2-negative advanced or metastatic breast cancer. Ribociclib received a breakthrough therapy designation and was approved under the FDA’s priority review process.

This approval was based on the phase 3 MONALEESA-2 clinical trial that included 668 treatment-naïve postmenopausal women with HR-positive, HER2-negative advanced breast cancer. The patients were randomized to ribociclib plus letrozole or placebo plus letrozole.

Ribociclib plus letrozole reduced mortality risk by 44%. The median progression-free survival (PFS) was not reached in the ribociclib plus letro­zole combination (95% CI, 19.3-not reached) and was 14.7 months with letrozole and placebo (P <.0001). The ORR was 52.7% versus 37.1%, respectively. In another analysis with an 11-month follow-up, the PFS was 25.3 months with the addition of ribociclib and 16 months with letrozole alone.

“These results affirm that combination therapy with a CDK4/6 inhibitor like ribociclib and an aromatase inhibitor should be a new standard of care for initial treatment of HR+ advanced breast cancer,” said Gabriel N. Hortobagyi, MD, Professor of Medicine, Department of Breast Medical Oncology, M.D. Anderson Cancer Center, Houston, and principal investigator of MONALEESA-2.

The most common all-grade adverse reactions with ribociclib plus letrozole included neutropenia (75%), leukopenia (33%), headache (22%), back pain (20%), nausea (52%), diarrhea (35%), vomiting (29%), constipation (25%), alopecia (33%), and fatigue (37%). Dose reductions because of adverse reactions were 45% with the active combination versus 3% with letrozole and placebo. Permanent discontinuation of therapy was reported in 7% of patients versus 2%, respectively.

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Xermelo First Oral Treatment Approved for Carcinoid Syndrome Diarrhea in Patients with NETs

On February 28, 2017, the FDA approved telotristat ethyl (Xermelo; Lexicon Pharmaceuticals), a tryptophan hydroxylase inhibitor, in combination with a somatostatin analog, for the treatment of carcinoid syndrome diarrhea in adults with neuroendocrine tumors (NETs) whose condition is inadequately controlled with somatostatin analog therapy. Telotristat ethyl received an orphan drug designation and was approved under the FDA’s fast track and priority review process.

“The approval of Xermelo establishes a new treatment option for patients with carcinoid syndrome diarrhea that is inadequately controlled by SSA [somatostatin analog] therapy. Inhibition of tumoral serotonin production represents a novel approach for patients with this condition. Studies have shown that Xermelo can reduce the debilitating effects of carcinoid syndrome diarrhea and has a favorable efficacy and safety profile in patients who currently have limited treatment options,” said Matthew H. Kulke, MD, Director of the Program in Neuroendocrine and Carcinoid Tumors at Dana-­Farber Cancer Institute, and primary investigator of TELESTAR, the clinical trial that led to this approval.

The FDA approval was based on data from a study of 90 adults with a well-differentiated NET and carcinoid syndrome diarrhea that was not controlled with somatostatin analog therapy. Patients received telotristat ethyl as add-on therapy to a somato­statin analog or placebo as add-on therapy to a somatostatin analog. The primary efficacy measure was the change from baseline in the number of daily bowel movements, averaged over a 12-week period.

Overall, 33% of patients who received telotristat ethyl had an average reduction of 2 bowel movements daily versus 4% of patients who received placebo in addition to a somatostatin analog.

The most common (≥5%) adverse reactions in patients who received telotristat ethyl included nausea, headache, increased gamma glutamyl-transferase, depression, flatulence, decreased appetite, peripheral edema, and pyrexia. Telotristat ethyl can cause constipation, especially in patients who have <4 bowel movements daily, and should be discontinued in patients with severe constipation.

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Revlimid Receives New Indication for Maintenance Therapy in Multiple Myeloma After Autologous Stem-Cell Transplant

On February 22, 2017, the FDA granted expanded approval to Revlimid (lenalidomide; Celgene), a thalidomide analog, for multiple myeloma as maintenance therapy after autologous hematopoietic stem-cell transplant.

“Autologous stem cell transplant after induction therapy is part of the continuum of care for transplant-eligible multiple myeloma patients. However, most patients will still see their disease recur or progress after this treatment. Lenalidomide maintenance therapy, which has been shown to increase progression-free survival following autologous stem cell transplant in clinical trials, can be considered a standard of care for these patients,” said Philip McCarthy, MD, Director, Blood and Marrow Transplant Center, Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY.

This expanded indication was approved based on data from 2 clinical trials, CALGB-100104 and IFM-2002-02, with PFS as the main end point. The median PFS was approximately 15 months and 18 months longer with lenalidomide versus placebo, respectively. The median overall survival was 111 months with lenalidomide versus 84.2 months with placebo in the CALGB study, and 105.9 months versus 88.1 months, respectively, in the IFM study.

The most common (>20%) all-grade adverse events with lenalidomide in both studies were neutropenia, thrombocytopenia, leukopenia, anemia, upper respiratory tract infection, bronchitis, nasopharyngitis, cough, gastroenteritis, diarrhea, rash, fatigue, asthenia, muscle spasm, and pyrexia. The most common (>20%) grade 3 or 4 adverse reactions with lenalidomide included neutropenia, thrombocytopenia, and leukopenia. An increased incidence of second primary malignancies was reported in patients who received lenalidomide.

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Opdivo a New Option for Advanced or Metastatic Bladder Cancer

On February 2, 2017, the FDA accelerated the approval of nivolumab (Opdivo; Bristol-Myers Squibb), a PD-1 receptor blocking antibody, for the treatment of patients with locally advanced or metastatic urothelial carcinoma whose disease progressed during or after platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. Nivo­l­umab received a breakthrough therapy designation for this indication and was approved under the FDA’s priority review status.

This approval of nivolumab was based on a clinical trial including 270 patients with locally advanced or metastatic urothelial carcinoma that progressed during or after platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. Patients received nivolumab 3 mg/kg every 2 weeks until disease progression or until unacceptable toxicity.

The median duration of treatment was 3.3 months. The ORR was 19.6%: 7 patients had complete response, and 46 patients had partial responses. The estimated median response duration was 10.3 months; responses were ongoing at the data cutoff date.

Of the 270 patients, 46% had PD-L1 expression ≥1%; the other patients had PD-L1 expression <1%. The ORR was 25% in patients with PD-L1 expression ≥1% versus 15.1% in patients with PD-L1 expression <1%.

The most common (≥20%) all-grade adverse events included fatigue, musculoskeletal pain, nausea, and decreased appetite. Overall, 14 patients died from causes other than disease progression.

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Imbruvica First Nonchemotherapy Drug Approved for Relapsed/Refractory Marginal Zone Lymphoma

On January 19, 2017, the FDA granted accelerated approval to ibrutinib (Imbruvica; Pharmacyclics), a kinase inhibitor, for the treatment of patients with marginal zone lymphoma who require systemic therapy and have received at least 1 previous anti-CD20–based therapy. Ibrutinib is the first nonchemotherapy drug approved by the FDA for marginal zone lymphoma.

“In the phase 2 trial, Imbruvica demonstrated impressive response rates and duration of response in relapsed/refractory marginal zone lymphoma patients. The hematology-oncology community welcomes a new option like Imbruvica, which helps fill a significant treatment gap for previously treated MZL [marginal zone lymphoma] patients who are in need of non-chemotherapy options,” said Ariela Noy, MD, Hematologic Oncologist, Memorial Sloan Kettering Cancer Center, New York, NY, and lead investigator of the study.

This approval was based on the phase 2 PCYC-1121 clinical trial involving 63 patients with 3 subtypes of marginal zone lymphoma, including mucosa-­associated lymphoid tissue, nodal, or splenic, who received oral ibrutinib 560 mg once daily until disease progression or until unacceptable toxicity.

The complete response rate was 3.2% and the partial response rate was 42.9%. The median time to response was 4.5 months. The median duration of response had not been reached after a median follow-up of 19.4 months.

The most common (≥20) all-grade adverse reactions included decreased platelets, fatigue, decreased hemoglobin, diarrhea, bruising, musculoskeletal pain, hemorrhage, rash, nausea, peripheral edema, arthralgia, decreased neutrophils, cough, dyspnea, and upper respiratory tract infection. The most common grade 3 or 4 adverse events included decreased hemoglobin (13%), decreased neutrophils (13%), and pneumonia (10%).

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Rubraca Receives Accelerated Approval for Advanced Ovarian Cancer

On December 19, 2016, the FDA accelerated the approval of rucaparib (Rubraca; Clovis Oncology), a PARP inhibitor, for advanced ovarian cancer that is associated with BRCA mutation in patients who had received ≥2 chemotherapies. At the same time, the FDA approved a companion diagnostic test, the FoundationFocus CDxBRCA test, for the diagnosis of a BRCA genetic mutation in patients with ovarian cancer; this is the first next-generation sequencing diagnostic test to be approved by the FDA.

“Recurrent ovarian cancer remains one of the most difficult cancers to treat and for so many years, medical advances in this space have been limited. Today’s approval of Rubraca for the treatment of advanced ovarian cancer demonstrates the value of treatment with PARP inhibitors and represents an important advance for women diagnosed with either germline or somatic BRCA-mutated tumors who have been treated with two or more chemotherapies,” said Robert L. Coleman, MD, Vice Chair, Clinical Research, Ann Rife Cox Chair in Gynecology, Department of Gynecologic Oncology and Reproductive Medicine, M.D. Anderson Cancer Center, Houston, and a principal investigator of the study that led to this approval.

This approval was based on data from 2 clinical trials, and the efficacy was assessed in 106 patients with advanced ovarian cancer that progressed after ≥2 chemotherapies. All patients received oral rucaparib 600 mg twice daily. A total of 57 (54%) patients achieved an ORR; the median duration of response was 9.2 months. The ORR was also assessed after patients were categorized based on a platinum-resistant (ORR, 25%), platinum-refractory (0%), or platinum-sensitive (66%) status.

Overall, 67 patients had tumor tissue samples analyzed by the companion diagnostic test, which verified BRCA mutations in 64 (96%) of these patients. The response rate was similar in patients with BRCA1 or BRCA2 mutation.

The safety of rucaparib was assessed in 377 patients with advanced ovarian cancer. The most common (≥20%) all-grade adverse reactions included nausea (77%), fatigue or asthenia (77%), dysgeusia (39%), diarrhea (34%), anemia (44%), abdominal pain (32%), dyspnea (21%), vomiting (46%), decreased appetite (39%), constipatiosssssn (40%), and thrombocytopenia (39%). Fatigue or asthenia led to rucaparib discontinuation in 10% of patients.

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

On March 27, 2017, the FDA accelerated the approval of niraparib (Zejula; Tesaro), a PARP inhibitor, for maintenance treatment of adults with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer 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, Acting Director of the FDA’s Center for Drug Evaluation and Research and 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.

Niraparib received breakthrough therapy designation for this indication, and an orphan drug designation for recurrent epithelial ovarian cancer.

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

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. The median PFS was 9.3 months in patients without a BRCA mutation who received niraparib versus 3.9 months in patients who received 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 (≥1%) 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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Last modified: August 11, 2017