FDA Actions Yield Extended Approvals of Novel Agents, Advisory Committee Votes Favorably on Two Biosimilars and Pediatric Indication for CAR T-Cell Therapy

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DURING JULY, the U.S. Food and Drug Administration (FDA) and its Oncologic Drugs Advisory Committee (ODAC) made a number of approvals and recommendations on a variety of oncology products. 


ON JULY 1 7, the FDA approved neratinib (Nerlynx) for the extended adjuvant treatment of adult patients with early-stage HER2-overexpressed/amplified breast cancer, to follow adjuvant trastuzumab (Herceptin)-based therapy. 

Approval was based on the ExteNET trial (ClinicalTrials. gov identifier NCT00878709), a multicenter, randomized, double-blind, placebo-controlled trial of neratinib following adjuvant trastuzumab treatment. Women with early-stage HER2-positive breast cancer and within 2 years of completing adjuvant trastuzumab (N = 2,840) were randomized to receive either neratinib (n = 1,420) or placebo (n = 1,420) for 1 year. 

The major efficacy outcome measure was invasive disease–free survival, defined as the time between the randomization date and the first instance of invasive recurrence (local/regional, ipsilateral, or contralateral breast cancer), distant recurrence, or death from any cause, within 2 years and 28 days of follow-up. After 2 years, invasive disease–free survival was 94.2% in patients treated with neratinib compared with 91.9% in those receiving placebo (P = .008). 

The most common adverse reactions (> 5%) were diarrhea, nausea, abdominal pain, fatigue, vomiting, rash, stomatitis, decreased appetite, muscle spasms, dyspepsia, increased levels of aspartate transaminase and alanine transaminase, nail disorder, dry skin, abdominal distention, weight loss, and urinary tract infection. The most common adverse reaction leading to treatment discontinuation was diarrhea, observed in 16.8% of neratinib-treated patients. Hepatotoxicity or increases in liver transaminases led to drug discontinuation in 1.7% of neratinib-treated patients. 

The recommended dose of neratinib is 240 mg (6 tablets) given orally once daily with food, continuously for 1 year. Antidiarrheal prophylaxis should be initiated with the first neratinib dose and continued during the first 2 cycles (56 days) of treatment and as needed thereafter. 

Two Biosimilar Products 

ON JULY 13 , ODAC unanimously recommended approval of biosimilar versions of bevacizumab (Avastin) and trastuzumab (Herceptin). 

ODAC members voted 17 to 0 in favor of approving the bevacizumab biosimilar candidate, ABP 215 (Amgen), for 6 of bevacizumab’s indications. However, the committee did not consider whether Amgen’s data would support approval for two of bevacizumab’s indications for ovarian cancer, as they are covered by orphan drug exclusivity until 2021 and 2023. 

ODAC members voted 16 to 0 in favor of approving Mylan’s trastuzumab biosimilar candidate, MYL-1401O, for all of Herceptin’s indications, including an indication for metastatic gastric cancer, which is protected by orphan drug exclusivity through October 20, 2017. 

In the case of both biosimilar products, ODAC reviewers found there were no clinically meaningful differences between the reference products and the biosimilars, though some panel members expressed concerns about extrapolating data from studies in a single disease to multiple indications. 

CAR T-Cell Therapy With CTL019 

ON JULY 1 2 , ODAC met to discuss the biologics license application for the chimeric antigen receptor (CAR) T-cell therapy CTL019 (tisagenlecleucel) for the treatment of relapsed or refractory pediatric and young adult patients with B-cell ALL. The committee voted unanimously in favor of CTL019 for this indication.


Check out recent approvals by visiting the new podcast page from the Oncology Centers of Excellence—Drug Information Soundcast in Clinical Oncology (DISCO)—available at

CTL019 is an adoptive immunocellular cancer therapy using autologous peripheral blood T cells that have been reprogrammed with a transgene encoding a CAR to identify and eliminate CD19-expressing malignant and nonmalignant cells. The efficacy and safety of CTL019 have been evaluated in 3 trials involving over 150 pediatric and young adult patients with relapsed/ refractory B-cell ALL, with a maximum follow-up extending to 40.5 months. The data were summarized and submitted to the FDA in February 2017. 

A final decision from the FDA is expected in early October. 


ON JULY 11, the FDA approved blinatumomab (Blincyto) for the treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL) in adults and children. Blinatumomab is a bispecific CD19-directed CD3 T-cell engager that binds to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T cells. 

Blinatumomab received accelerated approval in December 2014 for the treatment of Philadelphia chromosome–negative relapsed or refractory B-cell precursor ALL. This newly approved supplemental biologics license application provides the confirmation of clinical benefit required under the accelerated approval and also expands the indication to include Philadelphia chromosome–positive relapsed or refractory B-cell precursor ALL. 

The phase III trial that confirmed clinical benefit was a randomized, open-label, multicenter clinical trial (TOWER, NCT02013167), comparing blinatumomab to standard-of-care chemotherapy in 405 patients with relapsed or refractory B-cell precursor ALL. Blinatumomab was administered at 9 g/d on days 1 to 7 and 28 μg/d on days 8 to 28 for cycle 1 in a 42-day cycle, at 28 g/d on days 1 to 28 for cycles 2 to 5 in 42-day cycles, and at 28 g/d on days 1 to 28 for cycles 6 to 9 in 84-day cycles. Standard-of-care chemotherapy included fludarabine, cytarabine, and granulocyte colony-stimulating factor (FLAG); high-dose cytarabine (HiDAC); high-dose methotrexate (HDMTX)-based combinations; or clofarabine/clofarabine-based regimens. 

The trial demonstrated a statistically significant improvement in overall survival for patients treated with blinatumomab compared to those treated with standard-of-care chemotherapy (P = .012). The estimated median overall survival was 7.7 months in the blinatumomab arm and 4.0 months in the standard-of-care chemotherapy arm (hazard ratio = 0.71, P = .012). An independent data monitoring committee recommended the study end early for efficacy based on these results, as prespecified in an interim analysis. 

The inclusion of Philadelphia chromosome–positive relapsed or refractory B-cell precursor ALL in the indication was based on a single-arm, multicenter study (ALCANTARA, NCT02000427) enrolling 45 patients with Philadelphia chromosome–positive ALL. Patients either had disease resistant to second-generation tyrosine kinase inhibitors or were intolerant to second-generation tyrosine kinase inhibitors and had disease resistant to imatinib. In this population, 36% of the patients achieved a complete remission with complete or partial hematologic recovery. The median duration of remission was 6.7 months. 

No new major adverse reactions of blinatumomab were identified in the above clinical trials. Dosage and administration schedule of blinatumomab is based on weight for patients weighing < 45 kg and fixed dose for those weighing ≥ 45 kg. Patients should be premedicated with dexamethasone. Hospitalization is recommended at the beginning of the first and second cycles. 

Cooling Cap 

ON JULY 3, the FDA cleared the expanded use of a cooling cap (DigniCap Cooling System), to reduce hair loss during chemotherapy. This is the first cooling cap cleared by the agency for use in patients with solid tumor cancers. 

“We are pleased to expand the use of this product for cancer patients with solid tumors to potentially minimize chemotherapy-induced hair loss,” said Binita Ashar, MD, Director of the Division of Surgical Devices in the FDA’s Center for Devices and Radiological Health. “Managing the side effects of chemotherapy is a critical component to overall health and quality of life.” 

Hair loss due to cancer treatment is usually temporary, but minimizing or relieving these kinds of side effects is considered important to overall treatment. The DigniCap Cooling System is indicated to reduce the frequency and severity of hair loss during chemotherapy in patients with solid tumor cancers in which alopecia-inducing chemotherapeutic agents and doses are used. It is a computer-controlled system used during treatment. The cap is worn on the patient’s head and circulates liquid to cool the scalp during chemotherapy treatment. It is covered by a second cap made from neoprene, a type of rubber, which holds the cooling cap in place and acts as an insulation cover to prevent loss of cooling. 

The cooling is intended to constrict blood vessels in the scalp, which reduces the amount of chemotherapy that reaches cells in the hair follicles. The cold temperature also decreases the activity of the hair follicles and slows down cell division, making them less affected by chemotherapy. The combined actions are thought to reduce the effect chemotherapy has on the cells, which may reduce hair loss. The DigniCap may not work with some chemotherapy regimens. 

The FDA granted marketing authorization of the DigniCap in 2015 for use in patients with breast cancer. For that authorization, the efficacy of the cooling system was studied in 122 women with stage I and stage II breast cancer who were undergoing chemotherapy, using recognized chemotherapy regimens that have been associated with hair loss. The study demonstrated that more than 66% of patients treated with the cooling cap reported losing less than half their hair. 

In support of the expanded use of the device, the manufacturer also submitted evidence from published, peer-reviewed articles that analyzed the application of the DigniCap to patients with solid tumors in other areas of the body besides the breast. The FDA concluded these studies provided valid scientific evidence to support the safety and efficacy of the expanded indication for the DigniCap. ■