Vanderbilt University Medical Center, Nashville, TN
Jeffrey Alan Sosman , Adil Daud , Jeffrey S. Weber , Kevin Kim , Richard Kefford , Keith Flaherty , Jeffrey R. Infante , Omid Hamid , Jonathan S. Cebon , Lynn Mara Schuchter , Robert R. McWilliams , Mario Sznol , William Howard Sharfman , Alain Patrick Algazi , Karl D. Lewis , Shonda M Little , Peng Sun , Georgina Long , Kiran Patel , Rene Gonzalez
Background: Dual inhibition of the MAP kinase (MAPK) pathway with dabrafenib (D) and trametinib (T) in combination has demonstrated clinical benefit compared to D alone in a randomized Phase II trial in V600 BRAF-mutant MM pts, thus delaying the development of BRAFi resistance. Little is known about the efficacy of D + T after BRAFi resistance has been acquired. This analysis evaluates the ability of D + T combination to treat acquired resistance compared to the D + T combination as first-line treatment. Methods: These data from a phase I/II study include 1. BRAFi-resistant group: pts who received 150/2 D+T in Part B (n=26) and Part C (n=43) following progression on BRAFi monotherapy (mono); 2. BRAFi-naïve group: pts who received initial 150/2 D+T in Part B (n=24) and Part C (n=54). Results: Baseline characteristics (ECOG PS, M staging, LDH) were similar across all groups.In the Part B BRAFi-resistant group, 93% of pts previously received D or vemurafenib and all pts received D prior to D+T in Part C. In BRAFi-resistant group, prior best response of CR/PR (38%, 56%), SD (35%, 27%), PD (27%, 7%) was observed in Parts B and C respectively. In BRAFi-resistant group, the ORR and PFS with D+T was lower than initial D+T in BRAFi-naive group. Median duration of response (DoR) in BRAFi-resistant group cannot be calculated due to small no. of pts responding. Median DoR for BRAFi-naïve pts was 11.3 mo and 10.5 mo in Parts B and C respectively. In Part C, the 12-mo overall survival rates in BRAFi-naïve (150/2) pts was 79% vs 70% for pts initially on D mono, despite 80% pts crossing over to D+T combination. Conclusions: The clinical activity for 150/2 D+T combination is consistently superior in BRAFi-naive group vs BRAFi-resistant group in both Parts B and C. Dual MAPK blockade can delay clinical resistance to BRAF inhibition. However, once BRAFi resistance has occurred, the combination of BRAFi + MEKi is far less effective. Clinical trial information: NCT01072175.
BRAFi resistant | BRAFi naive | |||
---|---|---|---|---|
Cohort | Part B | Part C | Part B | Part C |
Treatment group | 150/2 combination N=26 |
Mono X-over 150/2 combination N=43 |
150/2 combination N=24 |
150/2 combination N=54 |
PFS, median, months | 3.6 | 3.6 | 10.8 | 9.4 |
ORR, % | 15% | 9% | 63% | 76% |
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