New Primary Malignancies. Cutaneous Malignancies: Across clinical trials of TAFINLAR® (dabrafenib) capsules administered with MEKINIST® (trametinib) tablets (“the combination”), the incidence of cu...
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 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 (n=36)1,2,4,5
Overall response rate
Median duration of response
CR, complete response; DOR, duration of response; IRC, independent review committee; NE, not estimable; PR, partial response.
aAt the time of the June 2019 data cutoff, 7 of 36 patients in the first-line population (Cohort C) and 4 of 57 patients in the second-line plus population (Cohort B) were still in follow-up. Results are subject to change pending longer trial follow-up.
Kaplan-Meier estimates of OS at an interim analysis of TAFINLAR + MEKINIST in first-line patients (n=36)4
Estimated OS rates
|Year||Estimated OS rate, %||95% CI|
Kaplan-Meier estimates of OS at 1, 2, and 3 years were not prespecified and are observational in nature; as such, there was no prespecified statistical procedure controlling for type 1 error.
Noncomparative analysis of median OS for TAFINLAR + MEKINIST (n=36)4,5
Noncomparative analysis of median PFS for TAFINLAR + MEKINIST (n=36)4,5
IRC, independent review committee; NE, not estimable; NSCLC, non-small cell lung cancer; 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. OS results from the August 2016 data cutoff should be considered immature; event rate of <50% at both data cutoffs; results are subject to change pending longer trial follow-up.
bAt the time of the June 2019 data cutoff, 7 of 36 patients in the first-line population (Cohort C) and 4 of 57 patients in the second-line plus population (Cohort B) were still in follow-up. Results are subject to change pending longer trial follow-up.
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
VIEW THIS INFORMATIVE VIDEO ABOUT TAFINLAR + MEKINIST NARRATED BY A KEY OPINION LEADER IN NSCLC
References: 1. Tafinlar [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2020. 2. Mekinist [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2020. 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. CDRB436E2201 Interim clinical study report. Novartis Pharmaceuticals Corp; 2017. 5. Data on file. CDRB436E2201 Interim clinical study report. Novartis Pharmaceuticals Corp; 2020.
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.
Across clinical trials of TAFINLAR administered with MEKINIST (“the combination”), the incidence of cutaneous squamous cell carcinomas (cuSCCs), including keratoacanthomas, occurred in 2% of patients. Basal cell carcinoma and new primary melanoma occurred in 3% and <1% of patients, respectively.
Perform dermatologic evaluations prior to initiation of the combination, every 2 months while on therapy, and for up to 6 months following discontinuation.
Based on its mechanism of action, TAFINLAR may promote the growth and development of malignancies with activation of monomeric G protein (RAS) through mutation or other mechanisms. Across clinical trials of TAFINLAR monotherapy and the combination, noncutaneous malignancies occurred in 1% of patients.
Monitor patients receiving the combination for signs or symptoms of noncutaneous malignancies. Permanently discontinue TAFINLAR for RAS-mutation–positive noncutaneous malignancies. No dose modification is required for MEKINIST in 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. Hemorrhage, including major hemorrhage defined as symptomatic bleeding in a critical area or organ, can occur with the combination. Fatal cases have been reported.
Across clinical trials of the combination, hemorrhagic events occurred in 17% of patients. Gastrointestinal hemorrhage occurred in 3% of patients who received the combination. Intracranial hemorrhage occurred in 0.6% of patients who received the combination. Fatal hemorrhage occurred in 0.5% of patients who received the combination. The fatal events were cerebral hemorrhage and brainstem hemorrhage.
Permanently discontinue TAFINLAR for all grade 4 hemorrhagic events and for any grade 3 hemorrhagic events that do not improve. Withhold TAFINLAR for grade 3 hemorrhagic events; if improved, resume at the next lower dose level. Permanently discontinue MEKINIST for all grade 4 hemorrhagic events and for any grade 3 hemorrhagic events that do not improve. Withhold 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 of the combination, colitis occurred in <1% of patients and gastrointestinal perforation occurred in <1% of patients. Monitor patients closely for colitis and gastrointestinal perforations.
Venous Thromboembolic Events. Across clinical trials of the combination, deep vein thrombosis (DVT) and pulmonary embolism (PE) occurred in 2% of patients.
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 MEKINIST for life-threatening PE. Withhold MEKINIST for uncomplicated DVT and PE for up to 3 weeks; if improved, MEKINIST may be resumed at a lower dose level.
Cardiomyopathy. Cardiomyopathy, including cardiac failure, can occur. Across clinical trials of the combination, cardiomyopathy, defined as a decrease in left ventricular ejection fraction (LVEF) ≥10% from baseline and below the institutional lower limit of normal (LLN), occurred in 6% of patients. Development of cardiomyopathy resulted in dose interruption or discontinuation of TAFINLAR in 3% and <1% of patients, respectively, and in 3% and <1% of patients receiving MEKINIST, respectively. Cardiomyopathy resolved in 45 of 50 patients who received the combination.
Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of the combination, 1 month after initiation, and 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 to baseline. For an asymptomatic absolute decrease in LVEF of 10% or greater 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): There were no cases of RVO across clinical trials of the combination. 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 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)/Pneumonitis. Across clinical trials of the combination, interstitial lung disease or pneumonitis occurred in 1% of patients.
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. Serious febrile reactions and fever of any severity complicated by hypotension, rigors or chills, dehydration, or renal failure, can occur. The incidence and severity of pyrexia are increased when TAFINLAR is administered with MEKINIST.
Across clinical trials of the combination, fever occurred in 58% of patients. Serious febrile reactions and fever of any severity complicated by hypotension, rigors or chills, dehydration, or renal failure occurred in 5% of patients. Fever was complicated by hypotension in 4%, dehydration in 3%, syncope in 2%, renal failure in 1%, and severe chills/rigors in <1% of patients.
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 Toxicities. Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS) and drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening or fatal, have been reported during treatment with the combination. Across clinical trials of the combination, other serious skin toxicity occurred in <1% of patients.
Monitor for new or worsening serious skin reactions. Permanently discontinue the combination for SCARs. For other skin toxicities, withhold TAFINLAR and/or MEKINIST for intolerable or severe skin toxicity. Resume TAFINLAR and/or MEKINIST at a lower dose in patients with improvement or recovery from skin toxicity within 3 weeks. Permanently discontinue TAFINLAR and/or MEKINIST if skin toxicity has not improved within 3 weeks.
Hyperglycemia. Across clinical trials of the combination, 15% of patients with a history of diabetes required more intensive hypoglycemic therapy. Grade 3 and grade 4 hyperglycemia occurred in 2% of patients.
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. Monitor patients with G6PD deficiency for signs of hemolytic anemia while taking TAFINLAR.
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.
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%).