The human trials on the use of dabrafenib and trametinib in the treatment of metastatic melanoma in patients with BRAF V600 mutation are now in phase 3, as reported by GlaxoSmithKline at the annual meeting of the ASCo (American Society of Clinical Oncology), Chicago, Illinois, and published in the New England Journal of Medicine: we report here the study inferred to these drugs
from Medical news:r. Rafael Amado, Head of Oncology R&D for GlaxoSmithKline, said: “The results from the clinical studies of dabrafenib and trametinib presented at this meeting represent important progress towards understanding how these investigational agents could benefit patients with advanced and metastatic melanoma. Importantly, trametinib is the first MEK inhibitor to demonstrate clinical benefit in a late phase melanoma trial. We are planning regulatory submissions for dabrafenib and trametinib as single agent therapies and have recently started a Phase III program to further investigate the effect of the combination in this disease.”
The BREAK3 Study – a Phase III, randomized, open-label study which compared the tolerability, safety and efficacy of dabrafenib to dacarbazine in individuals with Sage III (advanced) or Stage IV (metastatic) melanoma. The patients carry a BRAF V600 mutation. The primary endpoint was progression free survival. The study included 250 participants from the USA, Europe, Canada and Australia. Individuals with BRAF V600E mutation positive metastatic melanoma, who had been previously untreated were given dabrafenib. They were compared to those on dacarbazine. Those on dabrafenib had a 70% lower risk of disease progression or death (Hazard Ratio (HR) 0.30; p<0.0001) compared patients on chemotherapy. In the dabrafenib arm, progression free survival was 5.1 months, compared to 2.7 months in the dacarbazine arm. In the dabrafenib arm, the following adverse events were reported: hyperkeratosis (37%), headache (32%), pyrexia (25% Grade 1/2; 3% Grade 3), arthralgia (27%), skin papilloma (24%), alopecia (22%) and palmar-plantar erythrodysaesthesia syndrome (20%).
The METRIC Study – a Phase III trial of the MEK inhibitor, trametinib, in advanced/metastatic melanoma patients with with BRAF V600E or K mutation. They had had at least one previous regimen of chemotherapy, but no previous BRAF inhibitor treatment. The primary endpoint was progression free survival. The study involved 322 patients in the USA, Canada, Europe, Australia, New Zealand, and Argentina. Patients with BRAF V600E or K mutation positive metastatic melanoma were enrolled, some of them had been previously treated with chemotherapy. Those in the trametinib arm had a median progression free survival of 4.8 months, compared to 1.5 months in the chemotherapy arm This in the trametinib arm had a 55% lower risk of disease progression or death, compared to the patients in the chemotherapy arm. Overall survival benefit was significantly higher for those in the trametinib arm at the interim analysis The most commonly reported adverse events for those on trametinib were rash (57%), diarrhea (43%), fatigue (26%), and peripheral edema (26%). A much lower percentage reported hypertension, chorioretinopathy, and a drop in ejection fraction/ventricular dysfunction.
Dabrafenib side effects and clinical studies:
CLINICAL STUDIES: The approval of dabrafenib is based on results from one multicenter, international trial, specifically the pivotal, open-label Phase III BREAK-3 study that randomized 250 previously untreated adult patients with BRAF V600E mutation-positive unresectable or metastatic melanoma to receive dabrafenib or dacarbazine (chemotherapy) in a 3:1 ratio, respectively. The primary endpoint was progression-free survival (PFS) as assessed by the investigator. Other pre-specified endpoints included independent radiology review committee (IRRC) assessed PFS, confirmed objective response rate (ORR) and duration of response. Twenty-eight patients (44%) crossed over from the dacarbazine arm at the time of disease progression to receive dabrafenib. The study demonstrated a statistically significant increase in PFS in patients treated with dabrafenib, compared to dacarbazine (HR=0.33; [95% CI: 0.20, 0.54], p<0.0001). The median PFS was 5.1 months with dabrafenib (95% CI: 4.9, 6.9) compared to 2.7 months with dacarbazine (95% CI: 1.5, 3.2). The ORR with dabrafenib was 52 percent (95% CI: 44, 59) versus 17 percent with dacarbazine (95% CI: 9, 29). (joint aches) (27%), papilloma (warts) (27%), alopecia (hair loss) (22%), palmar-plantar erythrodysesthesia (redness, swelling, peeling or tenderness of hands or feet) (20%), rash (17%), back pain (12%), cough (12%), myalgia (muscle aches) (11%), constipation (11%) and nasopharyngitis (cold
-like symptoms) (10%). Dabrafenib was also prospectively evaluated in adult patients with BRAF V600E mutation-positive melanoma, metastatic to the brain. The single-arm, open-label Phase II trial enrolled patients into two cohorts. Patients in Cohort A (n=74) had received no prior local therapy for brain metastases, while patients in Cohort B (n=65) had received at least one local therapy for brain metastases, including but not limited to surgical resection, whole brain radiotherapy or stereotactic radiosurgery such as gamma knife, linear-accelerated-based radiosurgery, charged particles or CyberKnife. In addition, patients in Cohort B were required to have evidence of disease progression in a previously treated lesion or an untreated lesion. Additional eligibility criteria were at least one measurable lesion of 0.5 cm or greater in largest diameter on contrast-enhanced MRI, stable or decreasing corticosteroid dose, and no more than two prior systemic regimens for treatment of metastatic disease. The primary outcome measure was the estimation of the overall intracranial response rate (OIRR) in each cohort. The OIRR for Cohort A was 18 percent (95% CI: 9.7, 28.2). For Cohort B, the OIRR was also 18 percent (95% CI: 9.9, 30.0). The median duration of response was 4.6 months (95% CI: 2.8, Not Reached) and 4.6 months (95% CI: 1.9, 4.6) in Cohort A and Cohort B, respectively.
SIDE EFFECTS: TAFINLAR® (dabrafenib) results in an increased incidence of cutaneous squamous cell carcinoma, keratoacanthoma and melanoma. In the pivotal trial of dabrafenib, cuSCC occurred in 7% (14/147) of patients treated with dabrafenib and in none of the patients treated with dacarbazine. Across clinical trials of dabrafenib (n=586), the incidence of cuSCC was 11%. The median time to first cuSCC was 9 weeks (range: 1 to 53 weeks). Of those, patients who developed a cuSCC, approximately 33% developed one or more cuSCC with continued dabrafenib. The median time between diagnosis of the first cuSCC and the second cuSCC was 6 weeks. In the pivotal trial of dabrafenib, the incidence of new primary malignant melanomas was 2% (3/187) for patients receiving dabrafenib while no chemotherapy-treated patient was diagnosed with new primary malignant melanoma.
Tumor Promotion in BRAF Wild-Type Melanoma: In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells which are exposed to BRAF inhibitors Serious Febrile Drug Reactions
In the pivotal trial of Tafinlar (dabrafenib), serious febrile drug reactions, defined as serious cases of fever or fever of any severity accompanied by hypotension, rigors or chills, dehydration, or renal failure in the absence of another identifiable cause (e.g., infection) occurred in 3.7% (7/187) of patients treated with dabrafenib and in none of the patients treated with dacarbazine. The incidence of fever (serious and non-serious) was 28% in patients treated with dabrafenib and 10% in patients treated with dacarbazine. In patients treated with dabrafenib, the median time to initial onset of fever (any severity) was 11 days (range: 1 to 202 days), and the median duration of fever was 3 days (range 1 to 129 days).
Hyperglycemia
Hyperglycaemia requiring an increase in the dose of, or initiation of insulin or oral hypoglycaemic agent therapy, can occur with Tafinlar (dabrafenib). In the pivotal trial of dabrafenib, 5 of 12 patients with a history of diabetes required more intensive hypoglycaemic therapy while taking dabrafenib. The incidence of Grade 3 hyperglycaemia based on laboratory values was 6% (12/187) in patients treated with dabrafenib compared to none of the dacarbazine-treated patients.
Uveitis and Iritis
Uveitis (including iritis) occurred in 1% (6/586) of patients treated with Tafinlar (dabrafenib) across clinical trials.
Glucose-6-Phosphate Dehydrogenase Deficiency
Tafinlar (dabrafenib), which contains a sulfonamide moiety, confers a potential risk of haemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency.
Embryofoetal Toxicity
Based on its mechanism of action, Tafinlar (dabrafenib) can cause foetal harm when administered to a pregnant woman. Dabrafenib was teratogenic and embryotoxic in rats at doses three times greater than the human exposure at the recommended clinical dose.
Most Common Adverse Reactions
The most common adverse reactions (greater than or equal to 10%) of any grade included hyperkeratosis (37%), headache (32%), pyrexia (28%), arthralgia (27%), papilloma (27%), alopecia (22%), palmar-plantar erythrodysesthesia (20%), rash (17%), back pain (12%), cough (12%), constipation (11%), myalgia (11%), and nasopharyngitis (10%).
The most common serious adverse reactions (greater than or equal to 2%) of grades 3 and 4 include cuSCC (4%), back pain (3%), pyrexia (3%), constipation (2%), and palmar-plantar erythrodysesthesia (2%).
Drug Interactions
Effects of Other Drugs or
n Dabrafenib
Drugs that Inhibit or Induce Drug-Metabolising Enzymes: Dabrafenib is primarily metabolised by CYP2C8 and CYP3A4. Strong inhibitors or inducers of CYP3A4 or CYP2C8 may increase or decrease, respectively, concentrations of dabrafenib.
Drugs that Affect Gastric pH: Drugs that alter the pH of the upper GI tract (e.g., proton pump inhibitors, H2-receptor antagonists, antacids) may alter the solubility of dabrafenib and reduce its bioavailability. However, no formal clinical trial has been conducted to evaluate the effect of gastric pH-altering agents on the systemic exposure of dabrafenib.
Effects of Dabrafenib on Other Drugs
Dabrafenib induces CYP3A4 and may induce other enyzmes including CYP2B6, CYP2C8, CYP2C9, CYP2C19, and UDP glucuronosyltransferases (UGT) and may induce transporters. Dabrafenib decreased the maximum concentration (Cmax) and area under the curve (AUC) of midazolam (a substrate of CYP3A4) by 61% and 74%, respectively. Coadministration of Tafinlar with other substrates of these enzymes, including warfarin, dexamethasone, or hormonal contraceptives, can result in decreased concentrations and loss of efficacy.
Females and Males of Reproductive Potential
Tafinlar (dabrafenib) may impair fertility in males.
