FDA BRIEF: Week of March 13, 2017
KISQALI (ribociclib) tablets
Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA
INDICATION: In combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)- negative advanced or metastatic breast cancer.
UNMET NEED: Effective new treatment option for the continuing unmet need of the HR+/HER2- advanced breast cancer population.
REG PATHWAY: NDA
- Priority Review, Breakthrough Therapy Designation
- Post-marketing Requirements: Clinical trial to assess the efficacy and safety of an alternative dosing, clinical pharmacokinetic trial in severe renal impairment
MECHANISM OF ACTION: Inhibitor of cyclin-dependent kinase (CDK) 4 and 6 that are activated and play crucial role in cell cycle progression and cellular proliferation.
- Single randomized, double-blind, multicenter study (n=668), postmenopausal women with HR-positive, HER2-negative, advanced breast cancer with no prior therap, 21 days, 7 days off, KISQALI plus letrozole vs. placebo plus letrozole
- Primary Endpoint: Investigator-assessed progression-free survival (PFS) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
- Pre-planned interim analysis PFS: 27.8% vs. 44.9%, p< 0.0001
- Most common adverse reactions: Neutropenia, nausea, fatigue, diarrhea, leukopenia, alopecia, vomiting, constipation, headache, and back pain
- Most common grade 3 or 4 adverse reactions: Neutropenia, leukopenia, abnormal liver function tests, lymphopenia, and vomiting
- Warning and Precaution: Prolongation of QT interval
KEYTRUDA (pembrolizumab) injection
SUPPLEMENTARY INDICATION: treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or who have relapsed after 3 or more prior lines of therapy [see Clinical Studies (14.4)].
REG PATHWAY: Supplemental BLA
- Orphan Drug Designation, Breakthrough Therapy Designation, Priority Review, Accelerated Approval
- 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.
- Single multicenter, non-randomized, open-label study, n=210, patients with relapsed or refractory cHL, KEYTRUDA every 3 weeks until unacceptable toxicity or documented disease progression, or for up to 24 months
- Major efficacy outcome measures: Overall Response Rate (ORR), Complete Response Rate (CRR), duration of response, assessed by blinded independent central review
- ORR 69% (95% CI: 62, 75); median follow-up 9.4 months
- Median response duration: 11.1 months
- Efficacy in pediatric patients extrapolated from results observed in adults.
- Most common adverse reactions: Fatigue, pyrexia, cough, musculoskeletal pain, diarrhea, rash and hypertransaminasemia
- Additional common adverse reactions: Dyspnea, arthralgia, vomiting, nausea, pruritus, hypothyroidism, upper respiratory tract infections, headache, peripheral neuropathy, hyperbilirubinemia and increased creatinine
- Other immune-mediated adverse reactions: hyperthyroidism, pneumonitis, uveitis, myositis, myelitis and myocarditis
- Safety profile in the pediatric patients similar to adults