FDA Actions & Updates
The latest approvals, designations, and new indications from the U.S. Food and Drug Administration for oncology drugs.

Wednesday, March 15, 2017

The FDA has approved ribociclib, formerly known as LEE011, in combination with an aromatase inhibitor as initial endocrine-based therapy for treatment of postmenopausal women with hormone receptor positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) advanced or metastatic breast cancer.


Ribociclib is a CDK4/6 inhibitor approved based on a first-line phase III trial that met its primary endpoint early, demonstrating statistically significant improvement in progression-free survival (PFS) compared to letrozole alone at the first pre-planned interim analysis. Ribociclib was reviewed and approved under the FDA Breakthrough Therapy designation and Priority Review programs. The FDA approval is based on the superior efficacy and demonstrated safety of ribociclib plus letrozole versus letrozole alone in the pivotal Phase III MONALEESA-2 trial. The trial, which enrolled 668 postmenopausal women with HR+/HER2- advanced or metastatic breast cancer who received no prior systemic therapy for their advanced breast cancer, showed that ribociclib plus an aromatase inhibitor, letrozole, reduced the risk of progression or death by 44 percent over letrozole alone (median PFS not reached (95% CI: 19.3 months-not reached) versus 14.7 months (95% CI: 13.0-16.5 months); HR=0.556 (95% CI: 0.429-0.720); p<0.0001)


More than half of patients taking ribociclib plus letrozole remained alive and progression free at the time of interim analysis, therefore median PFS could not be determined. At a subsequent analysis with additional 11-month follow-up and progression events, a median PFS of 25.3 months for ribociclib plus letrozole and 16.0 months for letrozole alone was observed. Overall survival data is not yet mature and will be available at a later date.


"In the MONALEESA-2 trial, ribociclib plus letrozole reduced the risk of disease progression or death by 44 percent over letrozole alone, and more than half of patients (53%) with measurable disease taking ribociclib plus letrozole experienced a tumor burden reduction of at least 30 percent. This is a significant result for women with this serious form of breast cancer," said Gabriel N. Hortobagyi, MD, Professor of Medicine, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center and MONALEESA-2 Principal Investigator. "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."


Wednesday, March 15, 2017

The FDA has approved pembrolizumab for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or who have relapsed after three or more prior lines of therapy. Under the FDA’s accelerated approval regulations, this indication is approved based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. In refractory or relapsed cHL, pembrolizumab is approved for use in adult patients at a fixed dose of 200 mg and in pediatric patients at a dose of 2 mg/kg (up to a maximum of 200 mg). Pembrolizumab is administered intravenously every 3 weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Immune-mediated adverse reactions occurred with pembrolizumab including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis. Based on the severity of the adverse reaction, pembrolizumab should be withheld or discontinued and corticosteroids administered when appropriate. Immune-mediated complications, including fatal events, occurred in patients with cHL who underwent allogeneic hematopoietic stem cell transplantation (HSCT) after being treated with pembrolizumab. Follow patients closely for early evidence of transplant-related complications, and intervene promptly. pembrolizumab can also cause severe or life-threatening infusion-related reactions. Monitor patients for signs and symptoms of infusion-related reactions; for grade 3 or 4 reactions, stop infusion and permanently discontinue pembrolizumab. Based on its mechanism of action, it can cause fetal harm when administered to a pregnant woman. Female patients of reproductive potential should be advised of the potential hazard to a fetus.

The approval is based on data in 210 patients from the KEYNOTE-087 trial, which demonstrated an overall response rate (ORR) with pembrolizumab (200 mg every 3 weeks) of 69 percent (95% CI: 62, 75) with a complete remission rate (CRR) of 22 percent, and a partial remission rate (PRR) of 47 percent. The median follow-up time was 9.4 months. Among the 145 responding patients, the median duration of response was 11.1 months (range 0.0+ to 11.1 months).

“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,” said Craig Moskowitz, MD, Clinical Director, Division of Hematologic Oncology, Memorial Sloan Kettering Cancer Center. “This approval is an important step forward in treating these patients, who are generally young and have a particularly poor prognosis, and gives us the opportunity to help patients in their fight against this devastating disease.”

The accelerated FDA approval was based on data in 210 patients with relapsed or refractory cHL enrolled in the multicenter, nonrandomized, open-label KEYNOTE-087 study. Patients with active, non-infectious pneumonitis, an allogeneic HSCT within the past five years (or greater than five years but with symptoms of GVHD [graft-versus-host disease]), active autoimmune disease, a medical condition that required immunosuppression, or an active infection requiring systemic therapy were ineligible for the trial. Patients received pembrolizumab at a dose of 200 mg every three weeks until unacceptable toxicity or documented disease progression, or for up to 24 months in patients who did not progress. The major efficacy outcome measures (ORR, CRR, and duration of response) were assessed by blinded independent central review according to the 2007 revised International Working Group (IWG) criteria. Fifty-eight percent (58%) of patients were refractory to the last prior therapy, including 35 percent with primary refractory disease and 14 percent whose disease was chemo-refractory to all prior regimens. Additionally, 61 percent of patients had undergone prior auto-HSCT, 17 percent had no prior brentuximab use, and 36 percent had prior radiation therapy.

Efficacy analysis showed an ORR of 69 percent (95% CI: 62, 75) with a CRR of 22 percent and a PRR of 47 percent. The median follow-up time was 9.4 months. Among the 145 responding patients, the median duration of response was 11.1 months (range 0.0+ to 11.1 months).

Pembrolizumab was discontinued due to adverse reactions in five percent of 210 patients with cHL and treatment was interrupted due to adverse reactions in 26 percent of patients. Fifteen percent (15%) of patients had an adverse reaction requiring systemic corticosteroid therapy. Serious adverse reactions occurred in 16 percent of patients. The most frequent serious adverse reactions (≥1%) included pneumonia, pneumonitis, pyrexia, dyspnea, GVHD, and herpes zoster. Two patients died from causes other than disease progression; one from GVHD after subsequent allogeneic HSCT and one from septic shock. The most common adverse reactions (occurring in ≥20% of patients) were fatigue (26%), pyrexia (24%), cough (24%), musculoskeletal pain (21%), diarrhea (20%), and rash (20%).

There is limited experience in pediatric patients. Efficacy for pediatric patients was extrapolated from the results in the adult cHL population. In a study of 40 pediatric patients with advanced melanoma, PD-L1–positive advanced, relapsed, or refractory solid tumors or lymphoma, patients were treated with pembrolizumab for a median of 43 days (range 1-414 days), with 24 patients (60%) receiving treatment for 42 days or more. The safety profile in pediatric patients was similar to that seen in adults treated with pembrolizumab. Toxicities that occurred at a higher rate (≥15% difference) in these patients when compared to adults under 65 years of age were fatigue (45%), vomiting (38%), abdominal pain (28%), hypertransaminasemia (28%), and hyponatremia (18%).


Friday, March 10, 2017

Two supplemental Biologics License Applications (sBLAs) have been accepted for review by the FDA for pembrolizumab, an anti-PD-1 therapy, in patients with locally advanced or metastatic urothelial cancer.

Specifically, the application for first-line use was accepted and granted Priority Review for the treatment of these patients who are ineligible for cisplatin containing therapy. The application for second-line use also was accepted and granted Priority Review for these patients with disease progression on or after platinum-containing chemotherapy. The PDUFA, or target action, date for both applications is June 14, 2017.

The FDA previously granted Breakthrough Therapy Designation to pembrolizumab for the second-line treatment of patients with locally advanced or metastatic urothelial cancer with disease progression on or after platinum-containing chemotherapy.

The applications, which are seeking approval for pembrolizumab monotherapy at a dose of 200 mg administered by IV every 3 weeks, are based on data from the phase II KEYNOTE-052 trial and the phase III KEYNOTE-045 trial, respectively.

KEYNOTE-052 is an open-label study investigating pembrolizumab as a first-line treatment in patients with locally advanced or metastatic urothelial cancer who are ineligible for cisplatin-containing therapy. KEYNOTE-045 is a randomized study investigating pembrolizumab as a second-line therapy compared to investigator-choice chemotherapy (paclitaxel, docetaxel, vinflunine) in patients with locally advanced or metastatic urothelial cancer that has recurred or progressed on or after platinum containing chemotherapy. In October 2016, the trial met its co-primary endpoint of overall survival and was stopped early at the recommendation of an independent Data Monitoring Committee.

Pembrolizumab is being evaluated in over 30 tumor types in more than 400 clinical trials, at least half of which combine the drug with other cancer treatments. Pembrolizumab is a humanized monoclonal antibody that works by increasing the ability of the body's immune system to help detect and fight tumor cells. It blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes that may affect both tumor cells and healthy cells. Pembrolizumab is administered as an IV infusion over 30 minutes every 3 weeks for the approved indications.


Friday, March 10, 2017

The FDA has granted Orphan Drug Designation to CX-4945 for the treatment of cholangiocarcinoma.

CX-4945 is a novel small molecule drug that inhibits protein kinase CK2, which plays an important role in the DNA damage repair mechanisms of cancer cells.

The study drug has demonstrated favorable safety, pharmacokinetic, and pharmacodynamic characteristics in the treatment of advanced cholangiocarcinoma, a disease for which there are limited effective therapies. This cancer is difficult to detect in its early stages, and the survival rate at 5 years is only around 20 percent.

Orphan Drug Designation is granted by the FDA to novel drugs or biologics that treat rare diseases or conditions affecting fewer than 200,000 patients in the U.S. This Orphan Drug Designation will expedite the development of CX-4945 in the treatment of cholangiocarcinoma.​


Friday, March 10, 2017

The Investigational New Drug (IND) application to initiate phase II/III trials has been accepted by the

FDA for plinabulin for the prevention of chemotherapy-induced neutropenia.

"The primary endpoint for this trial is the duration of severe neutropenia in docetaxel-treated patients in the first chemotherapy cycle, after randomization to either plinabulin or pegfilgrastim," said

Douglas Blayney, MD, FACP, Professor of Medicine at Stanford University and principal investigator for the neutropenia registrational trial. "With approximately 200 chemotherapy patients slated to complete this trial, the study was designed based on the highly statistically significant data we derived from the phase II data in a lung cancer study. Plinabulin has great potential to improve the care of cancer patients worldwide."

Plinabulin is a novel small molecule with immune-enhancing effects and anti-cancer activity that is given by IV infusion—1 hour after chemotherapy—and has the potential to be a safe, cost effective, and convenient alternative to G-CSF, the current standard of care for chemotherapy-induced neutropenia, with much less bone pain and a more favorable safety profile. Recent data presented at the 2016 American Society of Hematology annual meeting also showed that plinabulin reduced the clinical sequelae associated with docetaxel-induced neutropenia—i.e., infections, sepsis, hospitalizations, and the need for docetaxel dose reductions (Abstract 2508).

More than 60,000 patients are hospitalized each year for chemotherapy induced severe neutropenia, which is associated with fever, infections, and death in up to 18 percent of these cases.

When severe neutropenia occurs, the chemotherapy dose has to be reduced or interrupted until it subsides. This reduction or interruption causes patients to receive suboptimal chemotherapy cancer treatment.