FDA Actions & Updates

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

Friday, July 20, 2018

Ivosidenib has been granted approval from the FDA for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (R/R AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test. Ivosidenib, an oral, targeted inhibitor of the IDH1 enzyme, is the first and only FDA-approved therapy for patients with R/R AML and an IDH1 mutation.

Given that the majority of patients with AML eventually relapse, R/R AML has a poor prognosis. The 5-year survival rate is approximately 27 percent (Genes Cancer 2011;2:95-107). For 6-10 percent of AML patients, the mutated IDH1 enzyme blocks normal blood stem cell differentiation, contributing to the genesis of acute leukemia.

"AML patients who relapse or are refractory to available therapies have few, if any, treatment options," said Hagop M. Kantarjian, MD, Professor and Chair of the Department of Leukemia at The University of Texas MD Anderson Cancer Center, Houston. "The clinical study demonstrated that [ivosidenib] has the potential to deliver strong, durable responses as a single agent and can help patients achieve and maintain transfusion independence. IDH inhibitors represent a new class of noncytotoxic, targeted therapies for AML patients with IDH mutations."

Safety & Efficacy Data

The FDA approval was based on the clinical data from an open-label, single-arm, multicenter dose-escalation and expansion trial of adult patients with R/R AML and an IDH1 mutation (Study AG120-C-001, NCT02074839). Ivosidenib was approved concurrently with the Abbott RealTime IDH1 companion diagnostic test for selection of patients with R/R AML for treatment with ivosidenib.  

The efficacy of ivosidenib was evaluated in 174 adult patients with R/R AML with an IDH1 mutation identified or confirmed by the Abbott RealTime IDH1 assay. Ivosidenib was given orally at a starting dose of 500 mg daily until disease progression, development of unacceptable toxicity, or undergoing hematopoietic stem cell transplantation. Patients had a median age of 67 years (range of 18-87) and received a median of two prior anticancer therapies (ranging from 1-6). More than half (63%) were refractory to previous therapy and 33% had secondary AML. The primary endpoint is the combined complete remission (CR) and complete remission with partial hematologic improvement (CRh) rate. CRh is defined as <5 percent of blasts in the bone marrow, no evidence of disease and partial recovery of peripheral blood counts (platelets >50,000/microliter and ANC >500/microliter).

In this trial, ivosidenib demonstrated:

  • CR+CRh rate of 32.8 percent (57 of 174 patients) (95% CI: 25.8, 40.3). 
  • The CR rate was 24.7 percent (43 of 174 patients) (95% CI 18.5, 31.8) and the CRh rate was 8 percent (14 of 174 patients) (95% CI 4.5, 13.1). 
  • Median duration of CR+CRh was 8.2 months (95% CI: range 5.6, 12 months). 
  • For patients who achieved a CR or CRh, the median time to best response of CR or CRh was 2.0 months (range, 0.9-5.6 months). 
  • Among the 110 patients who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline, 41 (37.3%) became independent of RBC and platelet transfusions during any 56-day post-baseline period. 
  • Of the 64 patients who were independent of both RBC and platelet transfusions at baseline, 38 (59.4%) remained transfusion independent during any 56-day post-baseline period.
  • Twenty-one of the 174 patients (12%) went on to stem cell transplant following ivosidenib treatment. 

The safety profile of single-agent ivosidenib was evaluated in 179 patients with R/R AML with an IDH1 mutation treated with a dose of 500 mg daily. The median duration of exposure to ivosidenib was 3.9 months (range 0.1 to 39.5 months). In the clinical trial, 19 percent (34/179) of patients treated with ivosidenib experienced differentiation syndrome, which can be fatal if not treated. QTc interval prolongation and Guillain-Barré Syndrome occurred in patients treated with ivosidenib. The most common adverse reactions (≥20%) of any grade were fatigue, leukocytosis, arthralgia, diarrhea, dyspnea, edema, nausea, mucositis, electrocardiogram QT prolonged, rash, pyrexia, cough, and constipation. The most frequent serious adverse reactions (≥5%) were differentiation syndrome (10%), leukocytosis (10%), and electrocardiogram QT prolonged (7%). ​

Wednesday, July 18, 2018

A new approval from the FDA was recently announced for ribociclib for women with HR+/HER2- advanced or metastatic breast cancer.

Ribociclib is now the only CDK4/6 inhibitor indicated for use with an aromatase inhibitor for the treatment of pre-, peri-, or postmenopausal women in the U.S., and also is indicated for use in combination with fulvestrant as both first- or second-line therapy in postmenopausal women.

The FDA reviewed this supplemental New Drug Application (sNDA) under its Real-Time Oncology Review and Assessment Aid pilot programs and approved the application in less than 1 month after submission.

This approval is based on the pivotal MONALEESA-7 and MONALEESA-3 phase III clinical trials that demonstrated prolonged progression-free survival (PFS) and improvements as early as 8 weeks for ribociclib-based regimens compared to endocrine therapy alone.

In MONALEESA-7, ribociclib plus an aromatase inhibitor and goserelin nearly doubled the median PFS compared to an aromatase inhibitor and goserelin alone (27.5 months compared to 13.8 months; HR=0.569; 95% CI: 0.436-0.743) in pre- or perimenopausal women. In MONALEESA-3, ribociclib plus fulvestrant demonstrated a median PFS of 20.5 months compared to 12.8 months for fulvestrant alone (HR=0.593; 95% CI: 0.480-0.732) across the overall population of first-line and second-line postmenopausal women.

"These MONALEESA clinical trial program data add to the body of evidence that CDK 4/6 inhibition, in the case of these studies with ribociclib, gives women diagnosed with HR+/HER2- advanced breast cancer an important first-line treatment option," said Dennis J. Slamon, MD, Director of Clinical/Translational Research, University of California, Los Angeles Jonsson Comprehensive Cancer Center. "Based on phase III trial results that consistently showed clinical benefit, physicians should be encouraged to re-evaluate treatment for advanced breast cancer in the first-line setting."

Approximately 155,000 people in the U.S. are living with metastatic breast cancer. Up to one-third of patients with early-stage breast cancer will subsequently develop advanced disease, for which there is currently no cure. Advanced breast cancer in premenopausal women is a biologically distinct and more aggressive disease, and it is the leading cause of cancer death in women 20-59 years old.

"Premenopausal women diagnosed with advanced breast cancer often face unique social challenges and a poorer prognosis. For the first time in nearly 20 years, we have results from a dedicated clinical trial among these women," said Jennifer Merschdorf, CEO, Young Survival Coalition. "With this approval, some younger women now have a new therapy indicated specifically for them that may help extend their lives without progression of disease."

Wednesday, July 18, 2018

The FDA has granted Breakthrough Therapy Designation for atezolizumab in combination with bevacizumab as a first-line treatment for patients with advanced or metastatic hepatocellular carcinoma (HCC). The designation is based on data from a phase Ib study assessing the safety and clinical activity of the combination therapy.

Breakthrough Therapy Designation is designed to expedite the development and review of medicines intended to treat serious or life-threatening diseases and to help ensure people have access to them through FDA approval as soon as possible.

Data from a phase Ib study in HCC was recently presented at the 2018 ASCO Annual Meeting. These data showed that after a median follow-up of 10.3 months, responses (independent review facility [IRF] per RECIST v1.1) were seen in 15 (65%) of 23 efficacy-evaluable participants. Responses were seen in all subgroups, including on the basis of the cause of their disease (etiology: Hepatitis B, Hepatitis C, and non-viral), region (Asia [excluding Japan] or Japan/U.S.), baseline alpha-fetoprotein levels (high/low). or spread of tumor beyond the liver (yes/no).

Assessment by investigators (INV) assessed per RECIST v1.1 demonstrated a response rate of 61 percent (14 out of 23 participants). Median progression-free survival (PFS), duration of response (DoR), time to progression (TTP), and overall survival (OS) have not yet been reached after a median follow-up of 10.3 months; results will be presented at a future medical congress when updated data from an expanded cohort are available.

In the safety-evaluable population (n=43), 28 percent of participants (n=12) experienced grade 3-4 treatment-related adverse events (AEs), and no treatment-related grade 5 AEs were observed. No new safety signals were identified beyond the established safety profiles for the individual medicines.

Earlier this year, IMbrave150 (NCT03434379), an open-label, multicenter, randomized phase III study was initiated to investigate the combination of atezolizumab and bevacizumab versus sorafenib in people with previously-untreated, locally advanced, unresectable, or metastatic HCC. This study is currently enrolling.

Friday, July 13, 2018

Nivolumab (3 mg/kg) plus low-dose ipilimumab (1 mg/kg) (injections for IV use) received approval from the FDA for the treatment of adult and pediatric patients 12 years and older with microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (mCRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.

Approval for this indication has been granted under Accelerated Approval based on overall response rate (ORR) and duration of response (DOR). Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

This approved indication was based on data from the ongoing phase II CheckMat-142 study evaluating the nivolumab plus ipilimumab combination in patients with MSI-H or dMMR mCRC previously treated with a fluoropyrimidine-, oxaliplatin- or irinotecan-based chemotherapy.  The application was granted Priority Review and Breakthrough Therapy Designation by the FDA.

The  nivolumab + ipilimumab cohort of the CheckMate-142 trial enrolled MSI-H/dMMR mCRC patients who had received at least one prior line of therapy for metastatic disease, and efficacy was analyzed for both patients who had received prior treatment with a fluoropyrimidine, oxaliplatin and irinotecan (82 of the total 119 patients) as well as for all enrolled patients.

Among the 82 patients who received prior treatment with a fluoropyrimidine, oxaliplatin, and irinotecan, 46 percent (95% CI: 35-58; n=38/82) responded to treatment with nivolumab + ipilimumab as assessed by Independent Radiographic Review Committee (IRRC). The percentage of these patients with a complete response was 3.7 percent (n = 3/82), and the percentage of patients with a partial response was 43 percent (n = 35/82). Among these 38 responders, the median DOR was not reached (range: 1.9-23.2+ months); 89 percent of those patients had responses of 6 months or longer, and 21 percent had responses of 12 months or longer. This trial is ongoing.

Among all enrolled patients, 49 percent (95% CI: 39-58; n = 58/119) responded to treatment with nivolumab + ipilimumab; 4.2 percent (n = 5/119) experienced a complete response, while 45 percent (n = 53/119) experienced a partial response. Among these 58 responders, the median DOR was not reached (range: 1.9-23.2+ months); 83 percent of those patients had responses of 6 months or longer, and 19 percent had responses of 12 months or longer. In the combination cohort, 51 of 58 responders were ongoing at the time of database lock; 78 percent of these ongoing responders had not reached 12 months of follow-up from the date of onset of response.

The recommended dosing schedule includes the nivolumab + low-dose ipilimumab combination nivolumab (3 mg/kg), administered as an IV infusion over 30 minutes, followed by ipilimumab (1 mg/kg), administered as an IV infusion over 30 minutes, on the same day, every 3 weeks for four doses), followed by nivolumab maintenance therapy (240 mg, administered as an IV infusion over 30 minutes, every 2 weeks) after completion of four doses of the combination until disease progression or unacceptable toxicity. 

In the nivolumab + ipilimumab cohort of CheckMate-142, 86 percent of patients received all four doses of nivolumab + ipilimumab. Nivolumab was discontinued in 13 percent of patients and delayed in 45 percent of patients due to an adverse reaction. Serious adverse reactions occurred in 47 percent of patients.

"Metastatic colorectal cancers with dMMR or MSI-H biomarkers can be difficult to treat and some patients may need additional options," said Heinz-Josef Lenz, MD, FACP, L. Terrence Lanni Chair in Gastrointestinal Cancer Research, Keck School of Medicine of University of Southern California and principal investigator of the study at USC Norris Comprehensive Cancer Center. "The FDA's approval of an I-O/I-O combination provides us with an encouraging approach to address this challenging disease in patients who have progressed following treatment with three standard chemotherapy options."

Tuesday, June 26, 2018

The FDA has accepted for Priority Review a supplemental New Drug Application (sNDA) for ibrutinib in combination with rituximab as a new treatment option for Waldenström's macroglobulinemia (WM), a rare and incurable form of blood cancer.

If approved, the sNDA would expand the prescribing information of ibrutinib, a first-in-class Bruton's tyrosine kinase (BTK) inhibitor, in WM beyond its current approved use as a single agent for all lines of therapy to include combination use with rituximab. As a single-agent therapy, ibrutinib is the first and only FDA-approved treatment available for patients with WM.

The sNDA is supported by data from the phase III iNNOVATE (PCYC-1127) trial assessing ibrutinib in combination with rituximab, versus rituximab alone, in patients with previously untreated and relapsed/refractory WM (N Engl J Med 2018; 378:2399-2410).

The study enrolled 150 patients with relapsed/refractory and treatment-naïve Waldenström's macroglobulinemia. Patients were randomized to receive intravenous rituximab 375 mg/m2 once weekly for four consecutive weeks, followed by a second four-weekly rituximab course following a 3-month interval. All patients received either ibrutinib 420 mg or placebo once daily continuously until criteria for permanent discontinuation were met. The primary endpoint was progression-free survival, with secondary objectives including overall response rate, hematological improvement measured by hemoglobin, time-to-next treatment, overall survival, and number of participants with adverse events as a measure of safety and tolerability within each treatment arm.

WM is a rare and incurable form of non-Hodgkin's lymphoma (NHL). There are about 2,800 new cases of WM in the U.S. each year. In January 2015, ibrutinib received FDA approval for all lines of treatment in WM and is the first and only FDA-approved therapy specifically indicated for this disease.