Early Breast Cancer Indication for Abemaciclib With Endocrine Therapy
The FDA approved abemaciclib with endocrine therapy (tamoxifen or an aromatase inhibitor) for the adjuvant treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, node-positive, early breast cancer at high risk of recurrence. Patients defined as high risk included those having either >=4 pALN (pathologic axillary lymph nodes) or 1-3 pALN and either tumor Grade 3 or a tumor size >=50 mm.
Abemaciclib was previously approved for the above high-risk population with the additional requirement of having a Ki-67 score >=20 percent. The new approval removes the Ki-67 testing requirement.
Efficacy was evaluated in monarchE (NCT03155997), a randomized (1:1), open-label, two-cohort multicenter trial including adult women and men with HR-positive, HER2-negative, node-positive, resected, early breast cancer with clinical and pathological features consistent with a high risk of recurrence. To be enrolled in Cohort 1, patients must have either >=4 pALN or 1-3 pALN and either tumor Grade 3 or a tumor size >=50 mm. To be enrolled in Cohort 2, patients could not be eligible for Cohort 1 and must have had 1-3 pALN and tumor Ki-67 score >=20 percent. Patients were randomized to either 2 years of abemaciclib plus physician's choice of standard endocrine therapy (tamoxifen or an aromatase inhibitor) or standard endocrine therapy alone.
The major efficacy outcome measure was invasive disease-free survival (IDFS). A statistically significant difference was observed in the intent-to-treat population, primarily attributed to patients in Cohort 1 (N=5,120 [91%]; IDFS HR: 0.653 [95% CI: 0.567, 0.753]). IDFS at 48 months was 85.5 percent (95% CI: 83.8, 87.0) for abemaciclib plus standard endocrine therapy and 78.6 percent (95% CI: 76.7, 80.4) for standard endocrine therapy alone. Overall survival data remains immature; however, in Cohort 2, more deaths were observed with abemaciclib plus standard endocrine therapy compared to standard endocrine therapy alone (10/253 vs. 5/264). Therefore, the indication was restricted to Cohort 1.
The most common adverse reactions (>=20%) were diarrhea, infections, neutropenia, fatigue, leukopenia, nausea, anemia, and headache. The recommended abemaciclib starting dose is 150 mg taken twice daily with tamoxifen or an aromatase inhibitor until completion of 2 years of treatment or until disease recurrence or unacceptable toxicity.
Dabrafenib + Trametinib for Pediatric Patients With Low-Grade Glioma & BRAF V600E Mutation
The FDA approved dabrafenib with trametinib for pediatric patients 1 year of age and older with low-grade glioma (LGG) with a BRAF V600E mutation who require systemic therapy. The FDA also approved new oral formulations of both drugs suitable for patients who cannot swallow pills. This represents the first FDA approval of a systemic therapy for the first-line treatment of pediatric patients with LGG with a BRAF V600E mutation.
Efficacy was evaluated in Study CDRB436G2201 (NCT02684058), a multicenter, open-label trial in patients with LGG (WHO Grades 1 and 2) requiring first systemic therapy. Patients were randomized 2:1 to dabrafenib plus trametinib (D+T) or carboplatin plus vincristine (C+V). BRAF mutation status was identified prospectively by local or central laboratory tests. Retrospective testing of available tumor samples by the central laboratory was also performed to evaluate mutation status. Patients received age- and weight-based dosing of D+T until they were no longer deriving benefit or experienced unacceptable toxicity. C+V were dosed based on body surface area at 175 mg/m2 and 1.5 mg/m2 (0.05 mg/kg for patients <12 kg), respectively, as one 10-week induction course, followed by eight 6-week cycles of maintenance therapy.
The major efficacy outcome measure was overall response rate (ORR) by independent review based on RANO LGG (2017) criteria. Additional efficacy outcome measures were progression-free survival (PFS) and overall survival (OS). The primary analysis was performed when all patients had completed at least 32 weeks of therapy.
In the LGG cohort, 110 patients were randomized to D+T (n=73) or C+V (n=37). ORR was 46.6 percent (95% CI: 34.8, 58.6) in the D+T arm and 10.8 percent (95% CI: 3.0, 25.4) for those receiving C+V (p= <0.001). DOR was 23.7 months (95% CI: 14.5, not estimable) in the D+T arm and not estimable (95% CI: 6.6, not estimable) in the C+V arm. PFS was 20.1 months (95% CI: 12.8, not estimable) and 7.4 months (95% CI: 3.6, 11.8) (HR=0.31 [95% CI: 0.17, 0.55]; p=<0.001) in the D+T and C+V arms, respectively. At the time of the interim analysis of OS conducted when all patients had completed at least 32 weeks of treatment or had discontinued earlier, there was one death on the C+V arm. The OS results at the interim analysis did not reach statistical significance.
In the pooled safety population of pediatric patients receiving D+T (N=166), the most common (>20%) adverse reactions were pyrexia (66%), rash (54%), headache (40%), vomiting (38%), musculoskeletal pain (36%), fatigue (31%), dry skin (31%), diarrhea (30%), nausea (26%), epistaxis and other bleeding events (25%), abdominal pain (24%), and dermatitis acneiform (23%). The most common (>2%) Grade 3 or 4 laboratory abnormalities were decreased neutrophil count (20%), increased alanine aminotransferase (3.1%), and increased aspartate aminotransferase (3.1%).
The recommended doses for dabrafenib and trametinib in pediatric patients are based on body weight. Dabrafenib is administered orally twice daily and trametinib is administered orally once daily. Dabrafenib and trametinib are administered until disease progression or unacceptable toxicity.
Orphan Drug Designation for LR 09 to Treat Leukemia Relapse After Allogeneic Stem Cell Transplant
The FDA has granted Orphan Drug Designation for LR 09, a novel metabolic immune checkpoint inhibitor, for the treatment of patients with hematological malignancies who are diagnosed with a relapse after allogeneic stem cell transplant (SCT). LR 09 is a novel, rationally designed form of the small molecule drug, ulodesine, a purine nucleoside phosphorylase (PNP) inhibitor that was originally developed for the treatment of autoimmune and inflammatory disorders. The decision to develop LR 09 for the treatment of relapse after stem cell transplantation follows the achievement of complete remission in a 3-year-old patient using a pharmacologically analogous PNP inhibitor whose U.S. development was later discontinued, and the discovery that inhibition of PNP activates (instead of suppressing) the immune system.
Recent research at the University of California, Los Angeles (UCLA) has revealed a novel, groundbreaking mode of action for LR 09 as a metabolic immune checkpoint inhibitor and supports its development for the treatment of patients experiencing relapse after allogeneic SCT. The data, published in the Journal of Clinical Investigation, has documented the immune-activating effects of LR 09 through the elevation of intracellular guanosine, TLR7 activation, and the activation and proliferation of T cells and germinal center B cells, resulting in the initiation of graft-versus-leukemia effects (2022; https://doi.org/10.1172/JCI160852). With its favorable safety profile demonstrated in earlier clinical development and its improved stability and manufacturing process versus earlier PNP inhibitors, the Orphan Drug Designation for the U.S. market adds to the promise of LR 09 as an oral immuno-oncology agent.