Data on BRAFi combo's and effects of ipi before and after

Combined Vermurafenib and Cobimetinib in BRAF-Mutated Melanoma. 
Dreno, Atkinson, et al.  N Engl J Med 2014 September

Phase 3 study.  495 patients, previously untreated with unresectable BRAF V600 mutated melanoma got either vemurafenib and cobimetinib or vermurafenib and placebo.

	Vermurafenib and Cobimetinib	Vermurafenib and placebo
Progression free survival	9.9 months	6.2 months
Complete or partial response	68%	45%
Complete response	10%	4%
Overall survival at 9 months	81%	73%

Combined BRAF and MEK inhibition versus BRAF inhibition alone in Melanoma.
Long, Stryakoviskiy, et al.  N Engl J Med.  2014 September.

Phase 3 trial.  423 BRAF V600 of V600K mutation melanoma patients with unresectable Stage IIIC or  Stage IV disease.

	Dabrafenib and Trametinib	Dabrafenib and placebo
Progression free survival	9.3 months	8.8 months
Overall response at 6 months	93%	85%
Overall response rate	67%	51%
Fever	51%	28%

 

Combined Dabrafenib and Trametinib in patients with BRAFV600 mutant melanoma experiencing progression with single-agent BRAF inhibitor.
Johnson, Flaherty, Weber, Infante, Kim, Hamid, Sznol, Sosman, Daud, et al. J Clin Onc, 2014 Oct

Phase I/II study.   Group B = 26 patients treated with dabrafenib and trametinib after disease progression with BRAFi before study enrollment.  Group C = 45 patients treated with dabrafenib and trametinib after progression on dabrafenib monotherapy as cross over treatment.

	Group B	Group C
Overall response rate	15%	13%
Progression free survival	Treated with Dabrafenib less than 6 months – 3.9 months Treated with Dabrafenib more than 6 months – 1.8 months	3.6 months
Overall survival	Tx more than 6 months – 26% Tx less than 6 months – 0%	11.8 months

Conclusion:  Dabrafenib plus trametinib has modest clinical efficacy in patients with BRAF i resistant melanoma.  This may be a therapeutic strategy for patients who previously benefited from BRAF inhibitor monotherapy for more than 6 months but demonstrated minimal efficacy after rapid progression with BRAFi therapy.

Characteristics of pyrexia in BRAFV600E/K metastatic melanoma patients treated with combined dabrafenib and trametinib in phase 1/2 clinical trial.  Menzies, Ashworth, Flaherty, Weber, Infante, Hamid, Sosman, Daud, et al.  Ann Oncol. 2014 November

Pyrexia = fever, in this case defined as a temperature at or greater than 100.4 or related symptoms.
59% of patients developed pyrexia.  24% had symptoms with recorded increased temp.  Median onset of first pyrexia was in 19 days, median duration of 9 days.  Pyrexia patients had a median of two pyrexia events, but 21% had three or more events.  No baseline features predicted pyrexia and it was not associated with clinical outcome.

Objective responses can be obtained by CTLA-4 inhibition in metastatic melanoma after BRAF inhibitor failure.  Schreuer, Chevolet, et al.  Melanoma Research.  2014 November

64 patients with unresectable Stage III/IV BRAF V600 mutant melanoma.  33 had been treated with BRAFi before ipi.  31 patients were treated with ipi first.  In BRAFi first patients:  three complete responses and 6 partial responses, with median overall survival of 10 months from start of ipi therapy.  Ipi first patients:  no complete responses and 4 partial responses, with median overall survival from start of ipi therapy was 12.3 months.  Response rate did not differ significantly between the groups.

So....not really new news.  Combo's offer better results.  Fever occurs often and can be worse in the combos, but no patient specific features can predict who develops fevers and fever has not been associated with outcome, for better or worse.  In the final study, for all their numbers, there was apparently no statistical difference in response whether you took BRAFi followed by ipi or vice versa.  Best wishes - c