BRAFi: What predicts resistance? Discontinuation after complete remission? Dabrafenib/trametinib combo and quality of life?

The status of PD-L1 and tumor-infiltrating immune cells predict resistance and poor prognosis in BRAFi-treated melanoma patients harboring mutant BRAFV600.  Massi, Brusa, Merelli, et al. Ann Oncol, June 2, 2015. 

BRAF inhibitors improve survival in metastatic melanoma patients but the duration of clinical benefit is limited by development of drug resistance.  Here, we investigated whether the expression of Programmed Death-Ligand 1 (PD-L1) and the density of tumor-infiltrating mononuclear cells (TIMC) predict the occurrence of resistance, hence affecting the clinical outcome in BRAFi-treated melanoma patients. 
PD-L1 expression (cut-off - 5%) and TIMC were analyzed...from 80 consecutive melanoma patients treated with BRAFi at a single institution.  46 and 34 patients received vemurafenib and dabrafenib, respectively.  Membraneous expression of PD-L1 was detected in 35% of patients.  After analysis:  ABSENCE of tumoral PD-L1 staining and the presence of TIMC were associated with a better response to treatment.  Median PFS and OS were 10 and 15 months respectively.  Additionally, analysis demonstrated, PD-L1 expression and absence of TIMC correlated with SHORTER PFS.  Our results provide the first proof-of-principle evidence for the predictive and prognostic relevance of PD-L1 expression and density of immune cell infiltration of BRAF V600 mutated melanoma treated with BRAFi.

Thoughts:
1.  The study used a 5% cut-off for PD-L1 expression, while many studies use 1%, not sure that matters.
2. According to this study, patients treated with BRAF inhibitors did better if their tumors were negative for PD-L1 and loaded with TIMC.
3.  Now...these results can't (yet) be determined to mean that BRAFi was undermined by the presence of PD-L1 or facilitated by the presence of TIMC.  It is just one more study that demonstrates the presence of PD-L1 and absence of TIMC are bad prognostic indicators...unless...at least in the case of the PD-L1...you are taking anti-PD1 drugs.
4.  Notice...one more time...PD-L1 was present in 35% of patients.
5.  Clearly, we have lots to learn.

Complete remission of metastatic melanoma upon BRAF inhibitor treatment - what happens after discontinuation?  Tolk, Stzger, Mohr, et al.  Melanoma Res. June 8, 2015.

Treatments with BRAFi leads to complete remission in 3-6% of patients with BRAF mutant melanoma.  In cases of complete remission, it is unclear whether BRAFi therapy should be continued.  We retrospectively analyzed the clinical course of patients with metastatic melanoma who discontinued BRAFi therapy after achieving CR.  In 12 patients, CR of melanoma was diagnosed after a median BRAFi treatment duration of 13 (0.3-32 months) months.  Reasons for d/c were side effects in 7 and patient demand in 5.  Six patients are still in CR after a median 17 months (2-26 months) after discontinuation of BRAF inhibition.  Six patients developed a melanoma recurrence after a median of 3 (range 2-17) months of discontinuation of BRAFi therapy.  Subsequently, these patients were again treated with a BRAFi, which resulted in 3 CR, one stable disease, and one progressive disease, and one patient who could not be assessed.  Melanoma patients achieving CR during BRAFi therapy represent a heterogenous group.  Discontinuation of BRAFi therapy after CR has to be balanced carefully with the potential risk of nonresponding to BRAFi retreatment in the case of relapse.

Thoughts:
1.  While BRAFi provides a beneficial response in approximately 70-80% of BRAF positive patients, apparently only 3-6% of those gain complete remission.
2.  But, if you do....it seems that half of those will maintain remission (for at least 17 months...so far) after discontinuation of BRAFi.
3.  The half who do recur after stopping BRAFi, appear to have a 50% chance of regaining complete remission on retreatment. 
4.  These are very small numbers...but something to think about.

Health-related quality of life impact in a randomized phase III study of the combination of dabrafenib and trametinib vs dabrafenib monotherapy in patients with BRAF V600 metastatic melanoma.  Schadendorf, Amonkar, Stroyakovskiy, et al.  Eur J Cancer, March 17, 2015.

The COMBI-d trial that combined dabrafenib and trametinib vs dabrafenib monotherapy showed that patients taking the combo experienced significantly prolonged progression-free survival.  These same patients were evaluated regarding quality of life using an established questionnaire.  Questionnaire completion rates were more than 95% at baseline, less than 85% to week 40 and less than 70% at disease progression.  Baseline scores across both arms were comparable for all dimensions.  Global health dimension scores were significantly better at weeks 8, 16, and 24 for patients receiving the combo during treatment and at progression.  Pain scores were improved and meaningful in patients receiving the combo for all follow-up assessments vs those receiving monotherapy.  For other symptoms (nausea, vomiting, diarrhea, dyspnea, constipation) scores trended in favor of monotherapy.  This analysis demonstrates that the combo of dabrafenib and trametinib provides better preservation of quality of life measures and pain improvements vs dabrafenib monotherapy, while delaying progression.

Thoughts:
Given the better results and decreased side effects noted in the COMBI-d study when dabrafenib was combined with trametinib...improved quality of life is not really a surprise, but still nice to know.  For a refresher regarding BRAFi:  BRAFi for melanoma - dabrafenib, vemurafenib, and the dabrafenib/trametinib combo  For more info:  Data on BRAFi combo's

Wishing you all my best. - c