primelines FDA Approvals July 2017 breast cancer melanoma ALL

Three New FDA Indications for Anti-Cancer Agents in July

In July, the US Food and Drug Administration (FDA) granted approval of neratinib for extended adjuvant therapy in early stage, human epidermal growth factor receptor 2 (HER2)-positive breast cancer, full approval of blinatumomab in relapsed or refractory acute lymphoblastic leukemia (ALL), and expanded the indication for ipilimumab in melanoma to pediatric patients.

  • Neratinib, First Approved Treatment for Extended Adjuvant Therapy in HER2-Positive Breast Cancer. On 17 July 2017, the FDA approved oral pan-HER targeted tyrosine kinase inhibitor neratinib (Nerlynx™, Puma Biotechnology) 240 mg daily, for use as extended adjuvant therapy following standard adjuvant trastuzumab for patients with early-stage HER2-positive breast cancer. This approval is based on results from the randomized, multicenter, double-blind, placebo-controlled phase III ExteNET trial of one year of neratinib after trastuzumab-based adjuvant therapy in HER2-positive early breast cancer. In the ExteNET trial, extended adjuvant anti-HER2 therapy with neratinib was associated with higher rates of 2-year invasive disease-free survival compared to placebo (94.2% vs 91.9%; HR 0.66, P = .008). Grade 3 diarrhea occurred in 40% of patients treated with neratinib, leading to treatment discontinuation in 16.8% of patients. However, in the phase II CONTROL trial, use of loperamide prophylaxis for 2 cycles substantially reduced the incidence, severity, and duration of neratinib-associated diarrhea. Thus the FDA approval includes the recommendation that patients receiving neratinib should be given antidiarrheal prophylaxis for the first 56 days of treatment and as needed thereafter.
  • Full Approval for Blinatumomab for Relapsed/Refractory ALL. On 11 July 2017, the CD19-targeting bispecific T-cell engager (BiTE) blinatumomab (Blincyto®, Amgen) received full FDA approval for relapsed/refractory B-cell precursor ALL in both adults and children, and the indication of blinatumomab was expanded to include Philadelphia chromosome (Ph)-positive disease. Blinatumomab was previously granted accelerated approval based on phase II data for Ph-negative relapsed/refractory B-cell precursor ALL. The full approval is based on the results from a randomized phase III TOWER trial, where blinatumomab treatment resulted in a 3.3 month improvement in overall survival compared to standard of care (7.7 months vs 4.0 months; HR 0.71, P = .012). Extension of the indication to include Ph-positive disease was based on the phase II ALCANTARA trial, where complete remission with partial or complete hematologic recovery was achieved in 36% of patients with Ph-positive ALL who were resistant or intolerant to second-generation TKIs. No new safety signals were reported in the above trials. However, the prescribing information for blinatumomab includes a boxed warning for cytokine release syndrome and neurologic toxicities.
  • Ipilimumab Indication in Melanoma Now Expanded for Pediatric Patients. On 24 July 2017, the FDA expanded indication of ipilimumab (Yervoy®, Bristol-Meyers Squibb) for unresectable or metastatic melanoma to include pediatric patients aged 12 years and older. Previously ipilimumab had only been approved for adults 18 years and older. Inclusion of adolescents in the ipilimumab indication was based on two small trials investigating ipilimumab in patients with melanoma ranging from 2 and 21 years of age. Of the 17 patients with melanoma aged 12 years or older treated with ipilimumab on these trials, two patients experienced objective responses, including a partial response lasting 16 months. The safety profile of ipilimumab in pediatric patients was similar to that seen in trials in adults. The approved dose of ipilimumab in patients aged ≥12 is 3 mg/kg every 3 weeks for four doses.

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