Metastatic Melanoma Treatment Efficacy

STRONG. DURABLE. SURVIVAL. With TAFINLAR + MEKINIST

MEK, mitogen-activated extracellular signal-regulated kinase.
*Based on IQVIA prescription data collected from December 2011 to August 2023.

Study Designs

COMBI-v

COMBI-v was a phase 3, multicenter, open-label, randomized (1:1), active-controlled trial of 704 patients with unresectable (stage IIIC) or metastatic (stage IV) BRAF V600E/K mutation–positive cutaneous melanoma. Patients were randomized to receive TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily (n=352) or single-agent vemurafenib 960 mg twice daily (n=352). Treatment was continued until disease progression or unacceptable toxicity. The primary end point was OS. Secondary end points included progression-free survival (PFS), overall response rate (ORR), duration of response (DOR), and safety.^1,2,5

COMBI-d

COMBI-d was a phase 3, multicenter, double-blind, randomized (1:1), active-controlled trial of 423 patients with unresectable (stage IIIC) or metastatic (stage IV) BRAF V600E/K mutation–positive cutaneous melanoma. Patients were randomized to receive TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily (n=211) or TAFINLAR 150 mg twice daily + placebo (n=212). Treatment was continued until disease progression or unacceptable toxicity. The primary end point was PFS. Secondary end points included OS, DOR, ORR, and safety. At the time of the primary analysis (August 2013), patients taking TAFINLAR + MEKINIST were progression free for a median of 9.3 months (95% CI, 7.7-11.1) vs 8.8 months (95% CI, 5.9-10.9) with TAFINLAR + matching placebo (HR, 0.75; 95% CI, 0.57-0.99; P=.035). In the interim analysis of COMBI-d, median OS was 25.1 months (95% CI, 19.2-NR) in the TAFINLAR + MEKINIST group and 18.7 months (95% CI, 15.2-23.1) in the TAFINLAR + placebo group (HR, 0.71; 95% CI, 0.55-0.92; P=.01).^1,2,7

Pooled COMBI-d/v

Pooled analysis of COMBI-d and COMBI-v consisted of 563 first-line patients with BRAF V600E/K mutation–positive unresectable or metastatic melanoma. All patients in the analysis received TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily in either COMBI-d (data cutoff, December 10, 2018) or COMBI-v (data cutoff, October 8, 2018). Median follow-up was 22 months (range, 0-76).^4,8

BRF113220

BRF113220 was an open-label phase 1 and 2 study of patients with unresectable stage IIIC or IV BRAF V600E/K mutation–positive melanoma. This study had 4 parts (A, B, C, D). Analysis only includes patients enrolled in Part C. Patients were randomly assigned 1:1:1 to receive either TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily, TAFINLAR 150 mg twice daily + MEKINIST 1 mg once daily, or TAFINLAR 150 mg monotherapy twice daily. Patients who progressed in the TAFINLAR monotherapy arm were allowed to cross over to the TAFINLAR 150-mg twice daily + MEKINIST 2-mg once daily arm. Efficacy and safety were analyzed at 4 and 5 years. End points included treatment response, DOR, PFS, OS, and safety.⁹

COMBI-MB

COMBI-MB was a phase 2, nonrandomized, open-label, multicenter, 4-cohort trial of 121 patients with BRAF V600E/K mutation–positive melanoma and at least 1 measurable intracranial lesion. Patients received TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily. Treatment was continued until disease progression or unacceptable toxicity. The primary end point was intracranial response rate, defined as the percentage of patients with a confirmed intracranial response per Response Evaluation Criteria In Solid Tumors v1.1, modified to allow up to 5 intracranial target lesions at least 5 mm in diameter, as assessed by independent review.^1,2,10

5-Year Overall Survival and Progression-Free Survival—COMBI-v

In COMBI-v—For the first-line treatment of patients with BRAF V600E/K unresectable or metastatic melanoma

THE STRENGTH OF DURABLE SURVIVAL⁴

36% OF PATIENTS WERE ALIVE AT 5 YEARS⁴

OS in COMBI-v^4,5

TAFINLAR + MEKINIST 5-year Overall Survival in COMBI-v

HR, hazard ratio; OS, overall survival.

At the interim analysis (April 2014), the median OS was NR for patients taking TAFINLAR + MEKINIST (95% CI, 18.3-NR) vs 17.2 months for vemurafenib (95% CI, 16.4-NR)^5,6
- Risk of mortality reduced by 31% (HR, 0.69; 95% CI, 0.53-0.89; P=.005)
Crossover was permitted after an interim OS analysis demonstrating significant benefit in COMBI-v^4,†
Results at 24, 36, 48, and 60 months were not prespecified and are observational in nature; as such, there was no prespecified statistical procedure controlling for type 1 error

OS IS ONE OF THE MOST IMPORTANT MEASURES OF EFFICACY IN METASTATIC MELANOMA; TAFINLAR + MEKINIST has high OS rates at 4 and 5 years in a phase 3 trial⁴

^†COMBI-v was stopped early by the Independent Data Monitoring Committee after the preplanned interim analysis (222 events; 32%) conducted in April 2014 showed OS results that crossed the prespecified efficacy stopping boundary (P<.0214), at which point the interim analysis became final. Patients will continue to be followed until death, withdrawal of consent, loss to follow-up, or have had at least 5 years of follow-up.^5,6,11

THE STRENGTH TO DELAY PROGRESSION⁵

20% OF PATIENTS LIVING PROGRESSION FREE AT 5 YEARS⁴

PFS analysis of the intention-to-treat population in COMBI-v^4,5

TAFINLAR + MEKINIST progression-free survival analysis in COMBI-v

HR, hazard ratio; PFS, progression-free survival.

In the interim analysis, median PFS was 11.4 months (95% CI, 9.9-14.9) for TAFINLAR + MEKINIST and 7.3 months (95% CI, 5.8-7.8) for vemurafenib (HR, 0.56; 95% CI, 0.46-0.69; P<.001)¹
Results at 24, 36, 48, and 60 months were not prespecified and are observational in nature; as such, there was no prespecified statistical procedure controlling for type 1 error

TAFINLAR + MEKINIST CONTINUES TO BE THE MOST PRESCRIBED COMBINATION TARGETED THERAPY for patients with BRAF+ melanoma WORLDWIDE, as of December 2021^3,‡

^‡Based on IQVIA prescription data collected from December 2011 to December 2021.³

5-Year Response Rates–Pooled COMBI-d/v Analysis

In the pooled analysis of COMBI-d and COMBI-v—For the first-line treatment of patients with BRAF V600E/K unresectable or metastatic melanoma

DEPTH OF RESPONSE THAT LASTS^4,8

Response across pooled COMBI-d/v data^4,8

TAFINLAR + MEKINIST 5-year pooled analysis data

CR, complete response; DCR, disease control rate; ORR, overall response rate; SD, stable disease.
^aDCR is defined as CR + partial response + SD; SD is not a component of ORR and can reflect the natural progression of disease rather than a direct therapeutic effect.
^bTwo patients are excluded from this analysis because they had no measurable disease at baseline.⁴

In the primary analysis for COMBI-d, complete response (CR) for patients taking TAFINLAR + MEKINIST was 10%, partial response (PR) was 56%, and stable disease (SD) was 26%, for a total disease control rate (DCR) of 92%. For patients taking TAFINLAR monotherapy, CR was 9%, PR was 43%, and SD was 33%, for a total DCR of 84%⁷
In the interim analysis for COMBI-v, CR for patients taking TAFINLAR + MEKINIST was 13%, PR was 51%, and SD was 26%, for a total DCR of 91%. For patients taking vemurafenib, CR was 8%, PR was 44%, and SD was 30%, for a total DCR of 82%⁵
Results at 5 years were not prespecified and are observational in nature; as such, there was no prespecified statistical procedure controlling for type 1 error

EFFICACY PROVEN IN A LARGER PHASE 3 TRIAL PATIENT POPULATION THAN ANY OTHER COMBINATION TARGETED THERAPY^1,2,12-18

Time to Response

In BRF113220—For the first-line treatment of patients with BRAF V600E/K unresectable or metastatic melanoma

A STRONG START: GIVE YOUR PATIENTS A CHANCE FOR A RAPID RESPONSE

In a phase 1 and 2, open-label study of TAFINLAR + MEKINIST in patients with unresectable stage IIIC or IV BRAF V600E/K–mutant metastatic melanoma⁹

The primary end point was PFS; PFS in the TAFINLAR + MEKINIST group at 48 and 60 months was 13% (95% CI, 5%-25%) vs 3% (95% CI, 0%-11%) for TAFINLAR alone (HR, 0.44; 95% CI, 0.28-0.67)⁹

AMONG PATIENTS WHO RESPONDED, 50% HAD ALREADY ACHIEVED A RESPONSE BY 1.8 MONTHS⁹

There were no prespecified formal statistical tests for comparing the results of treatment with the combination of TAFINLAR + MEKINIST with treatment with TAFINLAR monotherapy for the efficacy end points, including end points of ORR, PFS, and OS. Therefore, no conclusions or statistical inferences can be drawn from this study.

Efficacy in Patients With Brain Metastases

In COMBI-MB–For the first-line treatment of patients with BRAF V600E/K unresectable or metastatic melanoma

THE STRENGTH OF AN INTRACRANIAL RESPONSE

MORE THAN HALF OF PATIENTS WITH BRAIN METASTASES SHOWED AN INTRACRANIAL RESPONSE WITH TAFINLAR + MEKINIST¹⁰

COMBI-MB: Clinical Results (Cohort A)¹⁰

TAFINLAR + MEKINIST efficacy in patients with brain metastases

CR, complete response; PR, partial response.

50% of patients in COMBI-MB had an intracranial response (95% CI, 41%-60%), with a complete response rate of 4.1% and a partial response rate of 46%^1,2

Watch a video exploring how TAFINLAR + MEKINIST is redefining what's possible for patients with brain metastases

NEXT: Safety Profile

References: 1. Tafinlar. Prescribing information. Novartis Pharmaceuticals Corp. 2. Mekinist. Prescribing information. Novartis Pharmaceuticals Corp. 3. Data on file. BRAF inhibitors—worldwide numbers. RITM2438789. Novartis Pharmaceuticals Corp; 2022. 4. Supplement to: Robert C, Grob JJ, Strovakovskiy D, et al. Five-year outcomes with dabrafenib plus trametinib in metastatic melanoma. N Engl J Med. 2019;381(7):626-636. doi:10.1056/NEJMoa1904059 5. Robert C, Karaszewska B, Schachter J, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015;372(1):30-39. doi:10.1056/NEJMoa1412690 6. Data on file. Clinical study report. MEK116513. Novartis Pharmaceuticals Corp; January 15, 2015. 7. Long GV, Stroyakovskiy D, Gogas H, et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med. 2014;371(20):1877-1888. doi:10.1056/NEJMoa1406037 8. Robert C, Grob JJ, Strovakovskiy D, et al. Five-year outcomes with dabrafenib plus trametinib in metastatic melanoma. N Engl J Med. 2019;381(7):626-636. doi:10.1056/NEJMoa1904059 9. Long GV, Eroglu Z, Infante J, et al. Long-term outcomes in patients with BRAF V600–mutant metastatic melanoma who received dabrafenib combined with trametinib. J Clin Oncol. 2018;36(7):667-673. doi:10.1200/JCO.2017.74.1025 10. Davies MA, Saiag P, Robert C, et al. Dabrafenib plus trametinib in patients with BRAF V600-mutant melanoma brain metastases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial. Lancet Oncol. 2017;18(7):863-873. doi:10.1016/S1470-2045(17)30429-1 11. Supplement to: Robert C, Karaszewska B, Schachter J, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015;372(1):30-39. doi:10.1056/NEJMoa1412690 12. Zelboraf. Prescribing information. Genentech Inc. 13. Cotellic. Prescribing information. Genentech Inc. 14. Braftovi. Prescribing information. Array BioPharma Inc. 15. Mektovi. Prescribing information. Array BioPharma Inc. 16. Long GV, Grob JJ, Nathan P, et al. Factors predictive of response, disease progression, and overall survival after dabrafenib and trametinib combination treatment: a pooled analysis of individual patient data from randomised trials. Lancet Oncol. 2016;17(12):1743-1754. doi:10.1016/S1470-2045(16)30578-2 17. Larkin J, Ascierto PA, Dréno B, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014;371(20):1867-1876. doi:10.1056/NEJMoa1408868 18. Dummer R, Ascierto PA, Gogas HJ, et al. Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2018;19(5):603-615. doi:10.1016/S1470-2045(18)30142-6

IMPORTANT SAFETY INFORMATION

INDICATIONS