February 26, 2016 – Two new treatments for oncologic indications have been approved by the American Food and Drug Administration (FDA). Thus, the FDA approved Obinutuzumab (Gazyva) for use in combination with bendamustine followed by Obinutuzumab (Gazyva) monotherapy for the treatment of patients with follicular lymphoma (FL) who relapsed after, or are refractory to, a rituximab-containing regimen. Obinutuzumab (Gazyva) was previously approved for use in combination with chlorambucil for the treatment of patients with previously untreated chronic lymphocytic leukaemia. Similarly, the FDA approved Everolimus (Afinitor) for the treatment of adult patients with progressive, well-differentiated non-functional, neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin with unresectable, locally advanced or metastatic disease.
In the case of Obinutuzumab (Gazyva), this new approval was based on demonstration of an improvement in progression-free survival (PFS) in a randomized, open-label, multicenter trial in patients with FL who had no response to or have progressed during or within 6 months of a Rituximab-containing regimen. This trial compared 6 cycles of Obinutuzumab (Gazyva) plus bendamustine combination therapy followed by continued Obinutuzumab (Gazyva) monotherapy for up to 2 years with 6 cycles of bendamustine therapy. Efficacy was assessed in 321 patients with follicular lymphoma randomized to either Obinutuzumab (Gazyva) plus bendamustine (n=155) or bendamustine (n=166). The median age was 63 years (range
34-87). Patients had received a median of 2 prior therapies (range 1-10). The independent review assessed median PFS was 13.8 months in the bendamustine arm while the median PFS was not reached in the Obinutuzumab (Gazyva) plus bendamustine arm [HR 0.48 (95% CI: 0.34-0.68), log-rank test p-value < 0.0001). This trial also enrolled 46 patients with marginal zone lymphoma and 28 with small lymphocytic lymphoma who were also included in the safety analysis.
The most common adverse reactions (greater than or equal to 10%) in the safety population treated with Obinutuzumab (Gazyva) plus bendamustine followed by Obinutuzumab (Gazyva) monotherapy were infusion reactions, neutropenia, nausea, fatigue, cough, diarrhea, constipation, pyrexia, thrombocytopenia, vomiting, upper respiratory tract infection, decreased appetite, arthralgia, sinusitis, anemia, asthenia and urinary tract infection. Serious adverse reactions were reported in 38% of patients treated with Obinutuzumab (Gazyva) plus bendamustine followed by Obinutuzumab (Gazyva). The most common serious adverse reactions (greater than 2%) were febrile neutropenia, neutropenia, infusion related reactions, sepsis, pneumonia and pyrexia.
In the case of Everolimus (Afinitor), the approval was based on demonstration of improvement in progression-free survival (PFS) in a multicenter, randomized (2:1), placebo-controlled trial of Everolimus (Afinitor) 10 mg orally once daily plus best supportive care (BSC) to placebo plus BSC. The clinical trial enrolled 302 patients with unresectable, locally advanced or metastatic, well differentiated (low or intermediate grade), non-functional (no current or prior history of carcinoid symptoms), neuroendocrine tumors (NET) of gastrointestinal or lung origin. All patients were required to have evidence of disease progression within 6 months prior to randomization. The major efficacy outcome measure was progression-free
survival (PFS) based on independent radiological assessment per RECIST. Median PFS were 11 months and 3.9 months in the Everolimus (Afinitor) and placebo arms, respectively [HR 0.48 (95% CI: 0.35, 0.67), p <0.001, stratified log rank test]. Overall response rates were 2% in the Everolimus (Afinitor) arm and 1% in the placebo arm. At the planned interim analysis, there was no statistically significant difference in overall survival between arms.
Safety data were evaluated in 300 patients who received at least one dose of investigational drug. The median exposure duration to Everolimus (Afinitor) was 9.3 months; 64% of patients were treated for greater than or equal to 6 months and 39% were treated for greater than or equal to12 months. Everolimus (Afinitor) was discontinued for adverse reactions in 29% of patients and dose reduction or delay was required in 70% of Everolimus (Afinitor)-treated patients. Serious adverse reactions occurred in 42% of Everolimus (Afinitor)-treated patients and included 3 fatal events (cardiac failure, respiratory failure, and septic shock). The most common adverse reactions (incidence greater than or equal to 30%) were stomatitis, infections, diarrhea, peripheral edema, fatigue and rash. The most common laboratory abnormalities (incidence greater than or equal to 50%) were anemia, hypercholesterolemia, lymphopenia, elevated aspartate transaminase (AST) and fasting hyperglycemia.
For both, Obinutuzumab (Gazyva) and Everolimus (Afinitor), in their respective new indications, the full prescribing information from FDA are available here and here, respectively.
Ph.D.; Professor in Pharmacology and Toxicology.
Senior expert in theragenomic and personalized medicine and individualized drug safety.
Senior expert in pharmaco- and toxicogenetics.
Senior expert in human safety of drugs, chemicals, environmental pollutants, and dietary ingredients.
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