FDA Actions & Updates

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

Thursday, October 19, 2017

The FDA has approved axicabtagene ciloleucel, a cell-based gene therapy, to treat adult patients with certain types of large B-cell lymphoma who have not responded to or who have relapsed after at least two other kinds of treatment. A CAR-T cell therapy, axicabtagene ciloleucel, is the second gene therapy approved by the FDA and the first for certain types of non-Hodgkin lymphoma (NHL).

"Today marks another milestone in the development of a whole new scientific paradigm for the treatment of serious diseases. In just several decades, gene therapy has gone from being a promising concept to a practical solution to deadly and largely untreatable forms of cancer," said FDA Commissioner Scott Gottlieb, MD. "This approval demonstrates the continued momentum of this promising new area of medicine and we're committed to supporting and helping expedite the development of these products.

"We will soon release a comprehensive policy to address how we plan to support the development of cell-based regenerative medicine," he continued. "That policy will also clarify how we will apply our expedited programs to breakthrough products that use CAR-T cells and other gene therapies. We remain committed to supporting the efficient development of safe and effective treatments that leverage these new scientific platforms."

Approximately 72,000 new cases of NHL are diagnosed in the U.S. each year, and diffuse large B-cell lymphoma (DLBCL) represents approximately one in three newly diagnosed cases. Axicabtagene ciloleucel is approved for use in adult patients with large B-cell lymphoma after at least two other kinds of treatment failed, including DLBCL, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma. The treatment is not indicated for the treatment of patients with primary central nervous system lymphoma.

"The approval of [axicabtagene ciloleucel] brings this innovative class of CAR-T cell therapies to an additional group of cancer patients with few other options – those adults with certain types of lymphoma that have not responded to previous treatments," said Peter Marks, MD, PhD, Director of the FDA's Center for Biologics Evaluation and Research (CBER).

The safety and efficacy of axicabtagene ciloleucel were established in a multicenter clinical trial of more than 100 adults with refractory or relapsed large B-cell lymphoma. The complete remission rate after treatment was 51 percent.

Treatment with axicabtagene ciloleucel has the potential to cause severe side effects. It carries a boxed warning for cytokine release syndrome (CRS) and for neurologic toxicities. Both CRS and neurologic toxicities can be fatal or life-threatening. Other side effects include serious infections, low blood cell counts, and a weakened immune system. Side effects from treatment with axicabtagene ciloleucel usually appear within the first 1-2 weeks, but some side effects may occur later.

Because of the risk of CRS and neurologic toxicities, axicabtagene ciloleucel is being approved with a risk evaluation and mitigation strategy, which includes elements to assure safe use. The FDA is requiring that hospitals and their associated clinics that dispense axicabtagene ciloleucel be specially certified. As part of that certification, staff involved in the prescribing, dispensing, or administering of the therapy are required to be trained to recognize and manage CRS and nervous system toxicities. Also, patients must be informed of the potential serious side effects and of the importance of promptly returning to the treatment site if side effects develop.

To further evaluate the long-term safety, the FDA is also requiring a post-marketing observational study involving patients treated with axicabtagene ciloleucel.

The FDA granted axicabtagene ciloleucel Priority Review and Breakthrough Therapy designations. The treatment also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.


Sunday, October 15, 2017

The FDA has granted Fast Track designation for the development of gilteritinib for adult patients with FLT3 mutation-positive (FLT3+) relapsed or refractory acute myeloid leukemia (AML).

Fast Track designation is designed to facilitate the development, and expedite the FDA review, of drugs to treat serious and life-threatening conditions so that, if approved, the compounds can reach the market expeditiously.

AML most commonly experienced in older adults. According to the American Cancer Society, in 2016 there were approximately 21,000 new patients diagnosed with AML in the U.S. and about 10,000 cases resulted in death.

Gilteritinib is an investigational compound that has demonstrated inhibitory activity against FLT3 internal tandem duplication as well as FLT3 tyrosine kinase domain, two common types of FLT3 mutations that are seen in approximately one-third of patients with AML. Further, gilteritinib has also demonstrated inhibition of AXL, which is reported to be associated with therapeutic resistance.

Gilteritinib is currently being investigated in various AML patient populations through four ongoing phase III trials, including the registrational ADMIRAL trial in relapsed/refractory FLT3+ AML.​

Monday, October 9, 2017

The FDA has granted Breakthrough Therapy Designation (BTD) for osimertinib for the first-line treatment of patients with metastatic epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC).

The FDA granted the BTD based on data from the phase III FLAURA trial of osimertinib versus standard-of-care EGFR tyrosine kinase inhibitor (TKI) therapy in previously untreated patients with locally advanced or metastatic EGFR mutation-positive NSCLC. In the trial, median progression-free survival was 18.9 months for osimertinib compared with 10.2 months for EGFR-TKIs (erlotinib or gefitinib). Improvements were seen in all pre-specified subgroups, including patients with and without brain metastases.

In the FLAURA trial, the safety profile of osimertinib was consistent with previous experience. In patients treated with osimertinib, the most common adverse events (AEs) were diarrhea (58%, any grade [2% Grade 3]) and dry skin (32%, any grade [<1% Grade 3]), and in the comparator arm group the most common AEs were diarrhea (57%, any grade [2% Grade 3]) and dermatitis acneiform (48%, any grade [5% Grade 3]). Of the patients on osimertinib, 34 percent had a grade 3 AE, compared to 45 percent in the comparator arm, and 13 percent of patients on osimertinib had an AE leading to treatment discontinuation compared to 18 percent in the comparator arm.

On Sept. 28, 2017, the U.S. NCCN Clinical Practice Guidelines in Oncology were updated to include the use of osimertinib in the first-line treatment of patients with locally advanced or metastatic EGFR mutation-positive NSCLC. The use of osimertinib for the first-line treatment of patients with locally advanced or metastatic EGFR mutation-positive NSCLC is not yet FDA approved.

Osimertinib is currently approved in more than 50 countries, including the U.S., E.U., Japan, and China, as second-line treatment for patients with advanced NSCLC who progress following treatment with an EGFR-TKI due to the EGFR T790M resistance mutation. Osimertinib once-daily tablets are approved by the FDA for the treatment of patients with metastatic EGFR T790M mutation-positive NSCLC, as detected by an FDA-approved test, whose disease has progressed on or after an EGFR TKI therapy.



Thursday, September 28, 2017

The FDA approved abemaciclib to treat adult patients who have hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer that has progressed after endocrine therapy. Abemaciclib is approved to be given in combination with an endocrine therapy, called fulvestrant, after the cancer had grown on endocrine therapy. It is also approved to be given on its own, if patients were previously treated with endocrine therapy and chemotherapy after the cancer had spread (metastasized).

"[Abemaciclib] provides a new targeted treatment option for certain patients with breast cancer who are not responding to treatment, and unlike other drugs in the class, it can be given as a stand-alone treatment to patients who were previously treated with endocrine therapy and chemotherapy," said Richard Pazdur, MD, Director of the FDA's Oncology Center of Excellence and Acting Director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research.

Abemaciclib works by blocking certain molecules (known as cyclin-dependent kinases 4 and 6), involved in promoting the growth of cancer cells. There are two other drugs in this class that are approved for certain patients with breast cancer, palbociclib approved in February 2015 and ribociclib approved in March 2017.

Breast cancer is the most common form of cancer in the U.S. The NCI estimates approximately 252,710 women will be diagnosed with breast cancer this year, and 40,610 will die of the disease. Approximately 72 percent of patients with breast cancer have tumors that are HR-positive and HER2-negative.

The safety and efficacy of abemaciclib in combination with fulvestrant were studied in a randomized trial of 669 patients with HR-positive, HER2-negative breast cancer that had progressed after treatment with endocrine therapy and who had not received chemotherapy once the cancer had metastasized. The study measured the length of time tumors did not grow after treatment (progression-free survival). The median progression-free survival for patients taking abemaciclib with fulvestrant was 16.4 months compared to 9.3 months for patients taking a placebo with fulvestrant.

The safety and efficacy of abemaciclib as a stand-alone treatment were studied in a single-arm trial of 132 patients with HR-positive, HER2-negative breast cancer that had progressed after treatment with endocrine therapy and chemotherapy after the cancer metastasized. The study measured the percent of patients whose tumors completely or partially shrank after treatment (objective response rate). In the study, 19.7 percent of patients taking Verzenio experienced complete or partial shrinkage of their tumors for a median 8.6 months.


Tuesday, September 26, 2017

The FDA has approved pembrolizumab, an anti-PD-1 therapy, for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy.

This indication is approved under the FDA's accelerated approval regulations 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.

"Historically, advanced gastric cancer has been particularly challenging to treat, and new treatment options are needed for these patients," said Charles S. Fuchs, MD, MPH, lead investigator and Director of Yale Cancer Center. "The results observed in the diverse population of heavily pretreated advanced gastric or GEJ patients from the KEYNOTE-059 clinical trial demonstrate that pembrolizumab in the third-line setting has the potential to shift how we care for certain patients facing this difficult-to-treat disease."

The accelerated approval for pembrolizumab was based on data from a global, multicenter, non-randomized, open-label multi-cohort trial, KEYNOTE-059, that enrolled 259 patients with gastric or GEJ adenocarcinoma who progressed on at least two prior systemic treatments for advanced disease. Previous treatment must have included a fluoropyrimidine and platinum doublet; HER2/neu-positive patients must have previously received treatment with approved HER2/neu-targeted therapy. Patients with active autoimmune disease or a medical condition that required immunosuppression or with clinical evidence of ascites by physical exam were ineligible.

Patients received pembrolizumab at a dose of 200 mg every 3 weeks until unacceptable toxicity or disease progression that was symptomatic, rapidly progressive, required urgent intervention, occurred with a decline in performance status, or was confirmed at least 4 weeks later with repeat imaging. Patients without disease progression were treated for up to 24 months. Assessment of tumor status was performed every 6-9 weeks. The major efficacy outcome measures were objective response rate (ORR) according to RECIST 1.1, as assessed by independent central review, and duration of response.

Among the 259 patients, 55 percent (n=143) had tumors that expressed PD-L1 with a CPS ≥1 and microsatellite stable (MSS) tumor status or undetermined microsatellite instability (MSI) or mismatch repair (MMR) status. The baseline characteristics of these 143 patients were: median age 64 years (47% age 65 or older); 77 percent male; 82 percent white, 11 percent Asian; and ECOG performance status (PS) of 0 (43%) and 1 (57%). Eighty-five percent had M1 disease and seven percent had M0 disease. Fifty-one percent had two and 49 percent had three or more prior lines of therapy in the recurrent or metastatic setting.

For the 143 patients, the ORR was 13.3 percent (95% CI: 8.2, 20.0) – with a complete response rate of 1.4 percent and a partial response rate of 11.9 percent. Among the 19 responding patients, the duration of response ranged from 2.8+ to 19.4+ months, with 11 patients (58%) having responses of 6 months or longer and five patients (26%) having responses of 12 months or longer.

Among the 259 patients, seven (3%) had tumors that were determined to be MSI-High. An objective response was observed in four patients, including one complete response. The duration of response ranged from 5.3+ to 14.1+ months.

Adverse reactions occurring in patients with gastric cancer were similar to those occurring in patients with melanoma or non-small cell lung cancer (NSCLC). The most common adverse reactions for pembrolizumab (reported in ≥20% of patients) were fatigue, musculoskeletal pain, decreased appetite, pruritis, diarrhea, nausea, rash, pyrexia, cough, dyspnea, and constipation.