Fam-Trastuzumab Deruxtecan-Nxki for Unresectable or Metastatic HER2-Positive Breast Cancer
The FDA granted accelerated approval to fam-trastuzumab deruxtecan-nxki for patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting.
Efficacy was investigated in DESTINY-Breast01 (NCT03248492), a multicenter, single-arm trial enrolling 184 female patients with HER2-positive, unresectable, and/or metastatic breast cancer who had received two or more prior anti-HER2 therapies. Patients received fam-trastuzumab deruxtecan-nxki 5.4 mg/kg by intravenous infusion every 3 weeks until unacceptable toxicity or disease progression.
The main efficacy outcome measures were confirmed objective response rate (ORR) assessed by independent central review using RECIST 1.1 and response duration. ORR was 60.3 percent (95% CI: 52.9, 67.4), with a 4.3 percent complete response rate and a 56 percent partial response rate. Median response duration was 14.8 months (95% CI: 13.8, 16.9).
The safety was evaluated in a pooled analysis of 234 patients with unresectable or metastatic HER2-positive breast cancer who received at least one dose of fam-trastuzumab deruxtecan-nxki 5.4 mg/kg in DESTINY-Breast01 and Study DS8201-A-J101 (NCT02564900).
The most common adverse reactions (frequency >=20%) were nausea, fatigue, vomiting, alopecia, constipation, decreased appetite, anemia, neutropenia, diarrhea, leukopenia, cough, and thrombocytopenia.
The prescribing information includes a Boxed Warning to advise health professionals of the risk of interstitial lung disease (ILD) and embryo-fetal toxicity. Fatal outcomes due to ILD occurred in 2.6 percent of patients.
The recommended fam-trastuzumab deruxtecan-nxki dose is 5.4 mg/kg given as an intravenous infusion once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity.
Breakthrough Therapy Designation for Ivosidenib in R/R Myelodysplastic Syndrome
The FDA has granted Breakthrough Therapy Designation for ivosidenib for the treatment of adult patients with relapsed or refractory myelodysplastic syndrome (MDS) with a susceptible IDH1 mutation as detected by an FDA-approved test. MDS is a group of bone marrow disorders that can cause severe complications, such as infections and uncontrolled bleeding, and can lead to the development of acute myelogenous leukemia (AML).
Results from the MDS arm of the ongoing ivosidenib phase I dose-escalation and expansion study in hematologic malignancies were presented at the 2019 Society of Hematologic Oncology Annual Meeting. These demonstrate that ivosidenib administered as a monotherapy was well-tolerated and associated with durable remissions as well as the achievement and maintenance of transfusion independence in patients with relapsed or refractory MDS with an IDH1 mutation.
Among the 12 patients who received 500 mg of oral ivosidenib daily, the median treatment duration was 11.4 months. The median age was 72.5 years, and 42 percent of patients were age 75 or older. As of the Nov. 2, 2018, data cut-off, 75 percent (9/12) of patients had a response and 42 percent (5/12) had a complete response (CR). The median duration of CR had not been reached (95% CI, 2.8 months, NE). Of the patients who had a CR, 60 percent remained relapse-free at 12 months. In addition, nine (75%) patients were transfusion-independent for 56 days or longer during study treatment.
The most common adverse events (AEs) of any grade were back pain, diarrhea, fatigue, and rash. Grade 2 IDH differentiation syndrome was observed in 1 of 12 patients. No AEs resulted in permanent discontinuation of treatment.
Enzalutamide for Metastatic Castration-Sensitive Prostate Cancer
The FDA approved enzalutamide for patients with metastatic castration-sensitive prostate cancer (mCSPC). The organization previously approved enzalutamide for patients with castration-resistant prostate cancer.
Efficacy was investigated in ARCHES (NCT02677896), a trial enrolling 1,150 patients with mCSPC randomized (1:1) to receive either enzalutamide orally 160 mg once daily (N=574) or placebo orally once daily (N=576). All patients received a GnRH analog or had a prior bilateral orchiectomy.
The main efficacy outcome measure was radiographic progression-free survival (rPFS). Based on blinded independent central review, rPFS was defined as the time from randomization to radiographic disease progression at any time or death within 24 weeks after drug discontinuation.
Radiographic disease progression was defined by identification of 2 or more new bone lesions on a bone scan with confirmation (Prostate Cancer Working Group 2 criteria) and/or progression in soft tissue disease. Time to new antineoplastic therapy was an additional endpoint.
Median rPFS was not reached (NR) in the enzalutamide arm compared to 19.4 months (95% CI: 16.6, NR) in the placebo arm (HR 0.39; 95% CI: 0.30, 0.50; p<0.0001). A statistically significant improvement was also reported on the enzalutamide arm compared to placebo in time to initiation of a new antineoplastic therapy (HR 0.28; 95% CI: 0.20, 0.40; p<0.0001). Overall survival data were not mature at the time of rPFS analysis.
The most common adverse reactions (>= 5%) that occurred more frequently (>= 2% over placebo) in enzalutamide-treated patients in ARCHES were hot flush, asthenia/fatigue, hypertension, fractures, and musculoskeletal pain.
The recommended dose is 160 mg (four 40 mg capsules) administered orally once daily, with or without food.
Breakthrough Therapy Designation for Tucatinib in HER2-Positive Breast Cancer
The FDA has granted Breakthrough Therapy designation to tucatinib, in combination with trastuzumab and capecitabine, for treatment of patients with locally advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have been treated with trastuzumab, pertuzumab and T-DM1.
The positive topline results of the pivotal HER2CLIMB clinical trial were announced in October 2019, and additional data were presented at the 2019 San Antonio Breast Cancer Symposium (SABCS) and were simultaneously published in the New England Journal of Medicine. Tucatinib is an oral, small molecule tyrosine kinase inhibitor (TKI).
This Breakthrough Therapy Designation was based on data from the pivotal HER2CLIMB clinical trial, which compared tucatinib in combination with trastuzumab and capecitabine to trastuzumab and capecitabine alone in patients with locally advanced unresectable or metastatic HER2-positive breast cancer.
Patients had previously received trastuzumab, pertuzumab, and ado-trastuzumab emtansine (T-DM1). Patients had received a median of four prior lines of therapy overall and three in the metastatic setting. Forty-seven percent of the patients enrolled in the trial had brain metastases at the time of enrollment.
Data presented at SABCS and published in NEJM include the primary endpoint of progression-free survival (PFS) as assessed by blinded independent central review in the first 480 patients enrolled in the trial. The primary endpoint of PFS showed that the addition of tucatinib was superior to trastuzumab and capecitabine alone, with a 46 percent reduction in the risk of disease progression or death (HR=0.54 (95% CI: 0.42, 0.71); p<0.00001). The trial met the two key secondary endpoints at interim analysis.
The tucatinib arm demonstrated an improvement in overall survival, with a 34 percent reduction in the risk of death (HR=0.66 [95% CI: 0.50, 0.88]; p=0.0048), compared to the control arm. For patients with brain metastases at baseline, the tucatinib arm also demonstrated superior PFS, with a 52 percent reduction in the risk of disease progression or death, compared to the control arm (HR=0.48 [95% CI: 0.34, 0.69]; p<0.00001).
Tucatinib in combination with trastuzumab and capecitabine was generally well tolerated. The most common adverse events occurring in more than 20 percent of patients in the tucatinib arm versus the control arm included diarrhea, palmar-plantar erythrodysaesthesia syndrome, nausea, fatigue, and vomiting. Discontinuation of tucatinib and placebo due to adverse events was 5.7 percent in the tucatinib arm and 3.0 percent in the control arm.
Greater than or equal to grade 3 diarrhea was seen in 12.9 percent of the patients in the tucatinib arm versus 8.6 percent in the control arm. Antidiarrheal prophylaxis was not required per protocol. Antidiarrheals were used in less than half of all cycles where diarrhea was reported. In both treatment arms, when used, the duration of antidiarrheal treatment was short (median of 3 days/cycle).
Greater than or equal to grade 3 aspartate aminotransferase (AST) was seen in 4.5 percent of the patients in the tucatinib arm versus 0.5 percent in the control arm, and alanine aminotransferase (ALT) elevation in 5.4 percent vs. 0.5 percent, respectively. Discontinuations due to liver transaminase elevations were infrequent in both arms (ALT: 1.0 vs. 0.5 percent; AST: 0.7 vs. 0.5 percent).
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