Updated safety and efficacy results from a phase I/II study of the oral BRAF inhibitor dabrafenib (GSK2118436) combined with the oral MEK 1/2 inhibitor trametinib (GSK1120212) in patients with BRAFi-naive metastatic melanoma

Jeffrey S. Weber; Keith T. Flaherty; Jeffrey R. Infante; Gerald Steven Falchook; Richard Kefford; Adil Daud; Omid Hamid; Rene Gonzalez; Ragini Reiney Kudchadkar; Donald P. Lawrence; Howard A. Burris; Georgina V. Long; Alain Patrick Algazi; Karl D. Lewis; Kevin B. Kim; Igor Puzanov; Peng Sun; Shonda M. Little; Kiran Patel; Jeffrey Alan Sosman

Abstract

Background: In preclinical models, the BRAFi/MEKi combination has demonstrated enhanced activity against BRAF-mutant cancer cells compared with either drug alone, delayed emergence of BRAFi resistance, and prevented BRAFi-related proliferative skin lesions. A 3-part study investigating the dabrafenib/trametinib combination was conducted in patients (pts) with V600 BRAF mutant solid tumors. Interim data from the study were previously reported (Infante, ASCO 2011); updated safety and efficacy data are presented.

Methods: In Part 2, 125 pts with V600 BRAF mutant solid tumors enrolled, including 77 melanoma pts with no prior BRAFi, and measurable disease according to RECIST 1.1. Pts were treated on 4 escalating dose levels of dabrafenib/trametinib (mg BID/mg QD): 75/1, 150/1, 150/1.5, 150/2. Demographic and efficacy data for the 77 melanoma pts with no prior BRAFi and safety data for all 125 Part 2 pts are reported.

Results: Among 77 melanoma pts, median age was 52 years, 61% male, 57% ECOG PS of 0, 91% V600E, 65% M1c stage, 26% prior brain metastases, and 52% LDH > ULN. Confirmed ORR was 56% (95% CI: 44.1%-67.2%) with 4 CR, 39 PR, 29 SD and, 3 PD. Confirmed response rate for each dose level, respectively, was 67% (n=6), 64% (n=22), 48% (n=25), and 54% (n=24). Median PFS (months) for each dose level, respectively, was: 8.7, 8.3, 5.5; PFS is not mature for 150/2. Overall PFS was 7.4 (95% CI: 5.5-9.2). Among the 125 pts, there were 2 grade (G) 5 adverse events (AEs), pneumonia and hyponatraemia. The most common G3/4 AEs were pyrexia (n=6, 5%), fatigue (n=6, 5%) and dehydration (n=6, 5%). Skin toxicity ≥ G2 occurred in 17 (14%) pts. Cutaneous squamous cell carcinoma occurred in 3 (2%) pts and actinic keratoses in 2 (2%).

Conclusions: The combination of dabrafenib/trametinib has an acceptable safety profile, with a lower incidence of MEKi-related rash and BRAFi-induced hyperproliferative skin lesions compared with the single agents. The clinical activity of dabrafenib/trametinib observed in pts with V600 BRAF mutant metastatic melanoma is encouraging and will be investigated further in a phase III trial.

Original language	English
Pages (from-to)	8510-8510
Number of pages	1
Journal	Journal of Clinical Oncology
Volume	30
Issue number	Supplement 15
Publication status	Published - 20 May 2012
Externally published	Yes
Event	48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) - Chicago, United States Duration: 1 Jun 2012 → 6 Jun 2012

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Weber, J. S., Flaherty, K. T., Infante, J. R., Falchook, G. S., Kefford, R., Daud, A., Hamid, O., Gonzalez, R., Kudchadkar, R. R., Lawrence, D. P., Burris, H. A., Long, G. V., Algazi, A. P., Lewis, K. D., Kim, K. B., Puzanov, I., Sun, P., Little, S. M., Patel, K., & Sosman, J. A. (2012). Updated safety and efficacy results from a phase I/II study of the oral BRAF inhibitor dabrafenib (GSK2118436) combined with the oral MEK 1/2 inhibitor trametinib (GSK1120212) in patients with BRAFi-naive metastatic melanoma. Journal of Clinical Oncology, 30(Supplement 15), 8510-8510. http://ascopubs.org/doi/abs/10.1200/jco.2012.30.15_suppl.8510

Weber, Jeffrey S. ; Flaherty, Keith T. ; Infante, Jeffrey R. et al. / Updated safety and efficacy results from a phase I/II study of the oral BRAF inhibitor dabrafenib (GSK2118436) combined with the oral MEK 1/2 inhibitor trametinib (GSK1120212) in patients with BRAFi-naive metastatic melanoma. In: Journal of Clinical Oncology. 2012 ; Vol. 30, No. Supplement 15. pp. 8510-8510.

@article{e9844c24755540f2841aca7574704658,

title = "Updated safety and efficacy results from a phase I/II study of the oral BRAF inhibitor dabrafenib (GSK2118436) combined with the oral MEK 1/2 inhibitor trametinib (GSK1120212) in patients with BRAFi-naive metastatic melanoma",

abstract = "Background: In preclinical models, the BRAFi/MEKi combination has demonstrated enhanced activity against BRAF-mutant cancer cells compared with either drug alone, delayed emergence of BRAFi resistance, and prevented BRAFi-related proliferative skin lesions. A 3-part study investigating the dabrafenib/trametinib combination was conducted in patients (pts) with V600 BRAF mutant solid tumors. Interim data from the study were previously reported (Infante, ASCO 2011); updated safety and efficacy data are presented. Methods: In Part 2, 125 pts with V600 BRAF mutant solid tumors enrolled, including 77 melanoma pts with no prior BRAFi, and measurable disease according to RECIST 1.1. Pts were treated on 4 escalating dose levels of dabrafenib/trametinib (mg BID/mg QD): 75/1, 150/1, 150/1.5, 150/2. Demographic and efficacy data for the 77 melanoma pts with no prior BRAFi and safety data for all 125 Part 2 pts are reported. Results: Among 77 melanoma pts, median age was 52 years, 61% male, 57% ECOG PS of 0, 91% V600E, 65% M1c stage, 26% prior brain metastases, and 52% LDH > ULN. Confirmed ORR was 56% (95% CI: 44.1%-67.2%) with 4 CR, 39 PR, 29 SD and, 3 PD. Confirmed response rate for each dose level, respectively, was 67% (n=6), 64% (n=22), 48% (n=25), and 54% (n=24). Median PFS (months) for each dose level, respectively, was: 8.7, 8.3, 5.5; PFS is not mature for 150/2. Overall PFS was 7.4 (95% CI: 5.5-9.2). Among the 125 pts, there were 2 grade (G) 5 adverse events (AEs), pneumonia and hyponatraemia. The most common G3/4 AEs were pyrexia (n=6, 5%), fatigue (n=6, 5%) and dehydration (n=6, 5%). Skin toxicity ≥ G2 occurred in 17 (14%) pts. Cutaneous squamous cell carcinoma occurred in 3 (2%) pts and actinic keratoses in 2 (2%). Conclusions: The combination of dabrafenib/trametinib has an acceptable safety profile, with a lower incidence of MEKi-related rash and BRAFi-induced hyperproliferative skin lesions compared with the single agents. The clinical activity of dabrafenib/trametinib observed in pts with V600 BRAF mutant metastatic melanoma is encouraging and will be investigated further in a phase III trial.",

author = "Weber, {Jeffrey S.} and Flaherty, {Keith T.} and Infante, {Jeffrey R.} and Falchook, {Gerald Steven} and Richard Kefford and Adil Daud and Omid Hamid and Rene Gonzalez and Kudchadkar, {Ragini Reiney} and Lawrence, {Donald P.} and Burris, {Howard A.} and Long, {Georgina V.} and Algazi, {Alain Patrick} and Lewis, {Karl D.} and Kim, {Kevin B.} and Igor Puzanov and Peng Sun and Little, {Shonda M.} and Kiran Patel and Sosman, {Jeffrey Alan}",

year = "2012",

month = may,

day = "20",

language = "English",

volume = "30",

pages = "8510--8510",

journal = "Journal of Clinical Oncology",

issn = "0732-183X",

publisher = "American Society of Clinical Oncology",

number = "Supplement 15",

note = "48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) ; Conference date: 01-06-2012 Through 06-06-2012",

}

Weber, JS, Flaherty, KT, Infante, JR, Falchook, GS, Kefford, R, Daud, A, Hamid, O, Gonzalez, R, Kudchadkar, RR, Lawrence, DP, Burris, HA, Long, GV, Algazi, AP, Lewis, KD, Kim, KB, Puzanov, I, Sun, P, Little, SM, Patel, K & Sosman, JA 2012, 'Updated safety and efficacy results from a phase I/II study of the oral BRAF inhibitor dabrafenib (GSK2118436) combined with the oral MEK 1/2 inhibitor trametinib (GSK1120212) in patients with BRAFi-naive metastatic melanoma', Journal of Clinical Oncology, vol. 30, no. Supplement 15, pp. 8510-8510. <http://ascopubs.org/doi/abs/10.1200/jco.2012.30.15_suppl.8510>

Updated safety and efficacy results from a phase I/II study of the oral BRAF inhibitor dabrafenib (GSK2118436) combined with the oral MEK 1/2 inhibitor trametinib (GSK1120212) in patients with BRAFi-naive metastatic melanoma. / Weber, Jeffrey S.; Flaherty, Keith T.; Infante, Jeffrey R. et al.
In: Journal of Clinical Oncology, Vol. 30, No. Supplement 15, 20.05.2012, p. 8510-8510.

Research output: Contribution to journal › Meeting abstract › peer-review

TY - JOUR

T1 - Updated safety and efficacy results from a phase I/II study of the oral BRAF inhibitor dabrafenib (GSK2118436) combined with the oral MEK 1/2 inhibitor trametinib (GSK1120212) in patients with BRAFi-naive metastatic melanoma

AU - Weber, Jeffrey S.

AU - Flaherty, Keith T.

AU - Infante, Jeffrey R.

AU - Falchook, Gerald Steven

AU - Kefford, Richard

AU - Daud, Adil

AU - Hamid, Omid

AU - Gonzalez, Rene

AU - Kudchadkar, Ragini Reiney

AU - Lawrence, Donald P.

AU - Burris, Howard A.

AU - Long, Georgina V.

AU - Algazi, Alain Patrick

AU - Lewis, Karl D.

AU - Kim, Kevin B.

AU - Puzanov, Igor

AU - Sun, Peng

AU - Little, Shonda M.

AU - Patel, Kiran

AU - Sosman, Jeffrey Alan

PY - 2012/5/20

Y1 - 2012/5/20

N2 - Background: In preclinical models, the BRAFi/MEKi combination has demonstrated enhanced activity against BRAF-mutant cancer cells compared with either drug alone, delayed emergence of BRAFi resistance, and prevented BRAFi-related proliferative skin lesions. A 3-part study investigating the dabrafenib/trametinib combination was conducted in patients (pts) with V600 BRAF mutant solid tumors. Interim data from the study were previously reported (Infante, ASCO 2011); updated safety and efficacy data are presented. Methods: In Part 2, 125 pts with V600 BRAF mutant solid tumors enrolled, including 77 melanoma pts with no prior BRAFi, and measurable disease according to RECIST 1.1. Pts were treated on 4 escalating dose levels of dabrafenib/trametinib (mg BID/mg QD): 75/1, 150/1, 150/1.5, 150/2. Demographic and efficacy data for the 77 melanoma pts with no prior BRAFi and safety data for all 125 Part 2 pts are reported. Results: Among 77 melanoma pts, median age was 52 years, 61% male, 57% ECOG PS of 0, 91% V600E, 65% M1c stage, 26% prior brain metastases, and 52% LDH > ULN. Confirmed ORR was 56% (95% CI: 44.1%-67.2%) with 4 CR, 39 PR, 29 SD and, 3 PD. Confirmed response rate for each dose level, respectively, was 67% (n=6), 64% (n=22), 48% (n=25), and 54% (n=24). Median PFS (months) for each dose level, respectively, was: 8.7, 8.3, 5.5; PFS is not mature for 150/2. Overall PFS was 7.4 (95% CI: 5.5-9.2). Among the 125 pts, there were 2 grade (G) 5 adverse events (AEs), pneumonia and hyponatraemia. The most common G3/4 AEs were pyrexia (n=6, 5%), fatigue (n=6, 5%) and dehydration (n=6, 5%). Skin toxicity ≥ G2 occurred in 17 (14%) pts. Cutaneous squamous cell carcinoma occurred in 3 (2%) pts and actinic keratoses in 2 (2%). Conclusions: The combination of dabrafenib/trametinib has an acceptable safety profile, with a lower incidence of MEKi-related rash and BRAFi-induced hyperproliferative skin lesions compared with the single agents. The clinical activity of dabrafenib/trametinib observed in pts with V600 BRAF mutant metastatic melanoma is encouraging and will be investigated further in a phase III trial.

AB - Background: In preclinical models, the BRAFi/MEKi combination has demonstrated enhanced activity against BRAF-mutant cancer cells compared with either drug alone, delayed emergence of BRAFi resistance, and prevented BRAFi-related proliferative skin lesions. A 3-part study investigating the dabrafenib/trametinib combination was conducted in patients (pts) with V600 BRAF mutant solid tumors. Interim data from the study were previously reported (Infante, ASCO 2011); updated safety and efficacy data are presented. Methods: In Part 2, 125 pts with V600 BRAF mutant solid tumors enrolled, including 77 melanoma pts with no prior BRAFi, and measurable disease according to RECIST 1.1. Pts were treated on 4 escalating dose levels of dabrafenib/trametinib (mg BID/mg QD): 75/1, 150/1, 150/1.5, 150/2. Demographic and efficacy data for the 77 melanoma pts with no prior BRAFi and safety data for all 125 Part 2 pts are reported. Results: Among 77 melanoma pts, median age was 52 years, 61% male, 57% ECOG PS of 0, 91% V600E, 65% M1c stage, 26% prior brain metastases, and 52% LDH > ULN. Confirmed ORR was 56% (95% CI: 44.1%-67.2%) with 4 CR, 39 PR, 29 SD and, 3 PD. Confirmed response rate for each dose level, respectively, was 67% (n=6), 64% (n=22), 48% (n=25), and 54% (n=24). Median PFS (months) for each dose level, respectively, was: 8.7, 8.3, 5.5; PFS is not mature for 150/2. Overall PFS was 7.4 (95% CI: 5.5-9.2). Among the 125 pts, there were 2 grade (G) 5 adverse events (AEs), pneumonia and hyponatraemia. The most common G3/4 AEs were pyrexia (n=6, 5%), fatigue (n=6, 5%) and dehydration (n=6, 5%). Skin toxicity ≥ G2 occurred in 17 (14%) pts. Cutaneous squamous cell carcinoma occurred in 3 (2%) pts and actinic keratoses in 2 (2%). Conclusions: The combination of dabrafenib/trametinib has an acceptable safety profile, with a lower incidence of MEKi-related rash and BRAFi-induced hyperproliferative skin lesions compared with the single agents. The clinical activity of dabrafenib/trametinib observed in pts with V600 BRAF mutant metastatic melanoma is encouraging and will be investigated further in a phase III trial.

M3 - Meeting abstract

SN - 0732-183X

VL - 30

SP - 8510

EP - 8510

JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

IS - Supplement 15

T2 - 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO)

Y2 - 1 June 2012 through 6 June 2012

ER -