New Primary Malignancies. Cutaneous Malignancies: In the COMBI-d study in patients with unresectable or metastatic melanoma, the incidence of basal cell carcinoma in patients receiving TAFINLAR wit...
THE FIRST AND ONLY FDA-APPROVED TARGETED THERAPY FOR PATIENTS WITH BRAF V600E MUTATION-POSITIVE METASTATIC NSCLC1,2
A phase 2, multicenter, 3-cohort, nonrandomized, noncomparative, open-label trial assessed the efficacy and safety of TAFINLAR® (dabrafenib) capsules, alone or in combination with MEKINIST® (trametinib) tablets, in patients with BRAF V600E mutation-positive NSCLC (N=171)1-3*
The 3 cohorts were sequentially enrolled and studied in the following order: Cohort A (previously treated monotherapy), Cohort B (previously treated combination therapy), followed by Cohort C (first-line combination therapy).
Major efficacy outcomes studied: ORR and DOR1-3†
Additional outcomes: OS, PFS, and safety
DOR, duration of response; FDA, US Food and Drug Administration; NSCLC, non-small cell lung cancer; ORR, overall response rate; OS, overall survival; PFS, progression-free survival.
*Patients had no prior exposure to BRAF or mitogen-activated extracellular signal-regulated kinase (MEK) inhibitors and did not have epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) rearrangement (unless they had progression on prior tyrosine kinase inhibitor therapy).1,2
†The major efficacy outcomes were ORR per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1) as assessed by blinded independent review committee and DOR.1,2
PROFILE OF PATIENTS IN TAFINLAR + MEKINIST NSCLC STUDY
Patient characteristics across all 3 cohorts1,2
First-Line Patients: Response Rates
PROVEN RESPONSE RATES FOR TAFINLAR + MEKINIST IN FIRST-LINE PATIENTS
ORR based on independent review (n=36)
CR, complete response; ORR, overall response rate; PR, partial response.
DOR, duration of response; NE, not estimable.
First-Line Patients: Noncomparative Analysis of OS and PFS
Noncomparative analysis of median OS for TAFINLAR + MEKINIST (n=36)
NE, not estimable; OS, overall survival; PFS, progression-free survival.
aOS calculation takes into account 2 first-line patients enrolled prior to the opening of the first-line Cohort in April 2015 due to protocol deviation.
One of the patients died directly before the August 2016 data cutoff allowing for the calculation of a median OS.
Noncomparative analysis of PFS for TAFINLAR + MEKINIST (n=36)
NE, not estimable; NSCLC, non-small cell lung cancer; PFS, progression-free survival.
Efficacy in Previously Treated Patients: Response Rates
PROVEN RESPONSE RATES FOR TAFINLAR + MEKINIST IN PREVIOUSLY TREATED PATIENTS
Based on independent review (n=57) (August 2016 Data Cutoff)1,2
- Overall response rate: 63% (95% CI, 49-76) (complete response, 4%; partial response, 60%)
- Median duration of response (DOR): 12.6 months (95% CI, 5.8-not estimable) (n=36)
- Responders with DOR ≥6 months: 64%
Clinical Data Overview Video
PLEASE VIEW THIS INFORMATIVE VIDEO NARRATED BY THE LEAD INVESTIGATOR OF PIVOTAL STUDIES ON TAFINLAR + MEKINIST TREATMENT IN NSCLC PATIENTS
References: 1. Tafinlar [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2019. 2. Mekinist [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2019. 3. Planchard D, Smit EF, Groen HJM, et al. Dabrafenib plus trametinib in patients with previously untreated BRAFV600E-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial. Lancet Oncol. 2017;18(10):1307-1316. 4. Data on file. Clinical study report. CDRB436E2201. Novartis Pharmaceuticals Corp; 2017. 5. Data on file. Novartis Pharmaceuticals Corp; 2017.
TAFINLAR® (dabrafenib) capsules, in combination with MEKINIST® (trametinib) tablets, is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutation as detected by an FDA-approved test.
Limitation of Use: TAFINLAR is not indicated for the treatment of patients with wild-type BRAF NSCLC.
IMPORTANT SAFETY INFORMATION
New Primary Malignancies.
Cutaneous Malignancies: In the COMBI-d study in patients with unresectable or metastatic melanoma, the incidence of basal cell carcinoma in patients receiving TAFINLAR with MEKINIST was 3.3% compared with 6% of patients receiving single-agent TAFINLAR. Among the 7 patients receiving TAFINLAR with MEKINIST who developed basal cell carcinoma, 2 experienced more than 1 occurrence (range: 1 to 3).
In the NSCLC study, cutaneous squamous cell carcinoma (cuSCC) occurred in 3.2% of patients receiving TAFINLAR with MEKINIST.
Perform dermatologic evaluations prior to initiation of therapy, every 2 months while on therapy and for up to 6 months following discontinuation of TAFINLAR.
Noncutaneous Malignancies: In the NSCLC study, noncutaneous malignancies occurred in 1.1% of patients receiving TAFINLAR with MEKINIST. Monitor patients closely for signs or symptoms of noncutaneous malignancies. Permanently discontinue TAFINLAR for monomeric G protein (RAS)-mutation–positive noncutaneous malignancies. No dose modification of MEKINIST is required for patients who develop noncutaneous malignancies.
Tumor Promotion in BRAF Wild-type Tumors. In vitro experiments have demonstrated paradoxical activation of mitogen-activated protein kinase (MAPK) signaling and increased cell proliferation in BRAF wild-type cells that are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation status prior to initiation of therapy.
Hemorrhage. Hemorrhages, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur. In the COMBI-d study, the incidence of hemorrhagic events in patients treated with the combination was 19% compared with 15% of patients receiving single-agent TAFINLAR. Gastrointestinal hemorrhage occurred in 6% of patients treated with the combination compared with 3% of patients receiving single-agent TAFINLAR. In the NSCLC study, fatal hemorrhagic events occurred in 2.2% of patients receiving TAFINLAR with MEKINIST.
Permanently discontinue TAFINLAR and MEKINIST for all grade 4 hemorrhagic events and for any grade 3 hemorrhagic events that do not improve. Withhold TAFINLAR and MEKINIST for grade 3 hemorrhagic events; if improved, resume at the next lower dose level.
Colitis and Gastrointestinal Perforation. Colitis and gastrointestinal perforation, including fatal outcomes, can occur. Across clinical trials with MEKINIST, colitis occurred in 0.6% of patients and gastrointestinal perforation occurred in 0.3% of patients, respectively. Monitor patients closely for colitis and gastrointestinal perforations.
Venous Thromboembolism. In the NSCLC study, deep venous thrombosis (DVT) and pulmonary embolism (PE) occurred in 4.3% (4/93) of patients receiving TAFINLAR with MEKINIST.
Advise patients to immediately seek medical care if they develop symptoms of DVT or PE such as shortness of breath, chest pain, or arm or leg swelling. Permanently discontinue TAFINLAR and MEKINIST for life-threatening PE. Withhold MEKINIST for uncomplicated DVT or PE for up to 3 weeks; if improved, MEKINIST may be resumed at a lower dose.
Cardiomyopathy. Cardiomyopathy, including cardiac failure, can occur. In the NSCLC clinical trial, cardiomyopathy, defined as a decrease in left ventricular ejection fraction (LVEF) below the institutional lower limit of normal (LLN) with an absolute decrease in LVEF >10% below baseline, occurred in 9% of patients receiving TAFINLAR with MEKINIST and resulted in dose interruption and permanent discontinuation of MEKINIST in 5% and 2.2% of patients, respectively; dose interruption and permanent discontinuation of TAFINLAR occurred in 3.2% and 2.2% of patients, respectively. Cardiomyopathy resolved in 4 of 8 patients receiving TAFINLAR with MEKINIST.
Assess LVEF by an echocardiogram or a multigated acquisition (MUGA) scan before initiation of therapy, 1 month after initiation then at 2- to 3-month intervals while on treatment. Withhold TAFINLAR for symptomatic cardiomyopathy or asymptomatic left ventricular dysfunction of >20% from baseline that is below institutional LLN. Resume TAFINLAR at the same dose level upon recovery of cardiac function to at least the institutional LLN for LVEF and absolute decrease ≤10% compared with baseline. For an asymptomatic absolute decrease in LVEF of ≥10% from baseline that is below the LLN, withhold MEKINIST for up to 4 weeks. If improved to normal LVEF value, resume at a lower dose. If no improvement to normal LVEF value within 4 weeks, permanently discontinue MEKINIST. For symptomatic cardiomyopathy or an absolute decrease in LVEF of >20% from baseline that is below LLN, permanently discontinue MEKINIST.
Retinal Vein Occlusion (RVO): Across all clinical trials including MEKINIST, the incidence of RVO was 0.2%. RVO may lead to macular edema, decreased visual function, neovascularization, and glaucoma.
Urgently (within 24 hours) perform ophthalmologic evaluation for patient-reported loss of vision or other visual disturbances. Permanently discontinue MEKINIST in patients with documented RVO.
Retinal Pigment Epithelial Detachment (RPED): RPED can occur. Retinal detachments may be bilateral and multifocal, occurring in the central macular region of the retina or elsewhere in the retina. In clinical trials, routine monitoring of patients to detect asymptomatic RPED was not conducted; therefore, the true incidence of this finding is unknown.
Perform ophthalmologic evaluation periodically, and at any time a patient reports visual disturbances. Withhold MEKINIST if RPED is diagnosed. If resolution of the RPED is documented on repeat ophthalmologic evaluation within 3 weeks, resume MEKINIST at the same or a reduced dose. If no improvement after 3 weeks, resume at a reduced dose or permanently discontinue MEKINIST.
Uveitis: Uveitis occurred in 2% of patients treated with the combination across metastatic melanoma trials. Treatment employed in clinical trials included steroid and mydriatic ophthalmic drops.
Monitor patients for visual signs and symptoms of uveitis (eg, change in vision, photophobia, and eye pain). If iritis is diagnosed, administer ocular therapy and continue TAFINLAR without dose modification. If severe uveitis (ie, iridocyclitis) or if mild or moderate uveitis does not respond to ocular therapy, withhold TAFINLAR and treat as clinically indicated. Resume TAFINLAR at the same or lower dose if uveitis improves to grade 0 or 1. Permanently discontinue TAFINLAR for persistent grade 2 or greater uveitis of >6 weeks.
Interstitial Lung Disease (ILD). In clinical trials of MEKINIST as a single agent, ILD or pneumonitis occurred in 2% of patients. In the NSCLC study, 2.2% of patients receiving TAFINLAR with MEKINIST developed pneumonitis.
Withhold MEKINIST in patients presenting with new or progressive pulmonary symptoms and findings including cough, dyspnea, hypoxia, pleural effusion, or infiltrates pending clinical investigations. Permanently discontinue MEKINIST for patients diagnosed with treatment-related ILD or pneumonitis.
Serious Febrile Reactions. The incidence and severity of pyrexia are increased when the combination is used compared with TAFINLAR as a single agent.
In patients treated with the combination in the metastatic melanoma studies, the incidence of fever was 54% and serious febrile reactions or fever of any severity complicated by severe rigors or chills, hypotension, dehydration, renal failure, or syncope occurred in 17%. About half of the patients taking combination therapy who experienced pyrexia had 3 or more discrete episodes. Fever was complicated by severe chills or rigors in 0.4%, dehydration in 1.8%, renal failure in 0.5%, and syncope in 0.7% in patients receiving the combination.
Withhold TAFINLAR for temperature of ≥101.3ºF or fever complicated by hypotension, rigors or chills, dehydration, or renal failure, and evaluate for signs and symptoms of infection. Withhold MEKINIST for a temperature of >104ºF or fever complicated by hypotension, rigors or chills, dehydration, or renal failure, and evaluate for signs and symptoms of infection. Monitor serum creatinine and other evidence of renal function during and following severe pyrexia. Upon resolution, resume at same or lower dose. Administer antipyretics as secondary prophylaxis when resuming TAFINLAR and/or MEKINIST if the patient had a prior episode of severe febrile reaction or fever associated with complications. Administer corticosteroids (eg, prednisone 10 mg daily) for at least 5 days for second or subsequent pyrexia if temperature does not return to baseline within 3 days of onset of pyrexia, or for pyrexia associated with complications such as hypotension, severe rigors or chills, dehydration, or renal failure, and there is no evidence of active infection.
Serious Skin Toxicity. Across clinical trials of the combination in unresectable metastatic melanoma, serious skin toxicity occurred in 0.7% of patients.
In the COMBI-d study, the overall incidence of any skin toxicity was 55% for patients receiving the combination. No serious or severe cases of skin toxicity occurred in patients treated with the combination. Reductions in the dose of MEKINIST were required in 5% of patients receiving the combination, and no patient required permanent discontinuation of TAFINLAR or MEKINIST for skin toxicity.
Withhold TAFINLAR and MEKINIST for intolerable or severe skin toxicity. Resume TAFINLAR and MEKINIST at a lower dose level in patients with improvement or recovery from skin toxicity within 3 weeks. Permanently discontinue TAFINLAR and MEKINIST if skin toxicity has not improved within 3 weeks.
Hyperglycemia. In the COMBI-d study, 27% of patients with a history of diabetes receiving the combination and 13% of patients receiving single-agent TAFINLAR required more intensive hypoglycemic therapy. The incidence of grade 3 and grade 4 hyperglycemia based on laboratory values was 5% and 0.5% of patients treated with the combination, respectively. For patients receiving single-agent TAFINLAR, 4.3% of patients had grade 3 hyperglycemia based on laboratory values and no patients had grade 4 hyperglycemia.
Monitor serum glucose levels upon initiation, and as clinically appropriate in patients with preexisting diabetes or hyperglycemia. Initiate or optimize antihyperglycemic medications as clinically indicated.
Glucose-6-Phosphate Dehydrogenase Deficiency. TAFINLAR, which contains a sulfonamide moiety, confers a potential risk of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Closely observe patients with G6PD deficiency for signs of hemolytic anemia.
Embryo-fetal Toxicity. TAFINLAR and MEKINIST can cause fetal harm when administered to a pregnant woman. Advise female patients of reproductive potential to use effective nonhormonal contraception during treatment, and for 4 months after treatment, since TAFINLAR can render hormonal contraceptives ineffective.
Most Common Adverse Reactions. In the NSCLC clinical trial, the most commonly occurring adverse reactions (≥20%) in patients receiving the combination were pyrexia (55%), fatigue (51%), nausea (45%), vomiting (33%), diarrhea (32%), dry skin (31%), decreased appetite (29%), edema (28%), rash (28%), chills (23%), hemorrhage (23%), cough (22%), and dyspnea (20%). The most common grade 3 or 4 adverse reactions (incidence ≥2%) were pyrexia (5%), fatigue (5%), dyspnea (5%), hemorrhage (3.2%), rash (3.2%), vomiting (3.2%), and diarrhea (2.2%).
Other Clinically Important Adverse Reactions. The other clinically important adverse reactions observed in ≤10% of patients with NSCLC receiving the combination were pancreatitis and tubulointerstitial nephritis.
Laboratory Abnormalities. In the NSCLC clinical trial, the most common treatment-emergent laboratory abnormalities occurring at ≥20% of patients receiving the combination were hyperglycemia (71%), increased blood alkaline phosphatase (64%), increased aspartate aminotransferase (AST) (61%), hyponatremia (57%), leukopenia (48%), anemia (46%), neutropenia (44%), lymphopenia (42%), hypophosphatemia (36%), increased alanine aminotransferase (ALT) (32%), and creatinine (21%). The most common grade 3 or 4 laboratory abnormalities (incidence ≥10%) were hyponatremia (17%), lymphopenia (14%), and anemia (10%).