FDA Actions & Updates

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

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.

Monday, September 25, 2017

The FDA has approved nivolumab injection for IV use for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. Approval for this indication has been granted under accelerated approval 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.

The burden of liver cancer in the U.S. is significant and is expected to increase in the decades to come. A recently released American Cancer Society (ACS) report notes that death rates for liver cancer are increasing at a faster pace than any other cancer, doubling since the mid-1980s (Ca Cancer J Clin 2017;67(4):273-289).

"Unfortunately, the majority of HCC patients are diagnosed with advanced-stage disease and are not candidates for potentially curative surgical interventions," said Adrian M. Di Bisceglie, MD, Co-Director of the Saint Louis University Liver Center and Chief of Hepatology. "More options are needed for advanced-stage HCC patients who have failed prior systemic therapy."

Hepatocellular carcinoma is often diagnosed in the advanced-stage where treatment options are limited and there is a high unmet need for patients who are intolerant to or who have progressed on sorafenib therapy.

"In recent years, there has been growing interest in leveraging immuno-oncology knowledge and discoveries to add to the treatment options available for patients with advanced-stage liver cancer," said Anthony B. El-Khoueiry, MD, lead investigator and Associate Professor of Clinical Medicine and Phase I Program Director at the Keck School of Medicine of University of Southern California (USC) and the USC Norris Comprehensive Cancer Center. "The approval of nivolumab provides us with an encouraging approach and a new treatment option for appropriate patients with HCC following prior systemic therapy."

CheckMate-040 included a phase I/II, open-label, multicenter study evaluating nivolumab in patients with HCC who progressed on or were intolerant to sorafenib. In this study, 154 patients received nivolumab 3 mg/kg administered intravenously every 2 weeks. The recommended dose is 240 mg administered as an IV infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. Efficacy outcome measures included confirmed overall response rate (as assessed by blinded independent central review using RECIST v1.1 and modified RECIST for HCC) and duration of response.

The median age of patients participating in the study was 63 (range: 19-81), all patients had received prior sorafenib therapy and 19 percent of patients had received two or more prior systemic therapies. Patients were enrolled regardless of PD-L1 expression level and whether or not they were infected with active Hepatitis B virus or active Hepatitis C virus. Data from CheckMate-040 were presented at the ASCO 2017 Annual Meeting in June.

In the CheckMate-040 trial, 14.3 percent (95% CI: 9.2-20.8; 22/154) of patients responded to treatment with nivolumab. The percentage of patients with a complete response was 1.9 percent (3/154) and the percentage of patients with a partial response was 12.3 percent (19/154). Among responders (n=22), responses ranged from 3.2 months to 38.2+ months; 91 percent of those patients had responses of 6 months or longer and 55 percent had responses of 12 months or longer. The median time to response was 2.8 months (range: 1.2-7.0). The overall response rate based on modified RECIST was 18.2 percent (95% CI: 12.4-25.2; 28/154). Complete response rate was 3.2 percent (5/154); partial response rate was 14.9 percent (23/154). Responses were observed across PD-L1 expression levels.