The nature and management of metastatic melanoma after progression on BRAF inhibitors: effects of extended BRAF inhibition.

BACKGROUND: The v-raf murine sarcoma viral oncogene homolog B (BRAF) inhibitor (BRAFi) drugs dabrafenib and vemurafenib have high response rates in BRAF-mutant, metastatic melanoma; however, 50% of patients progress by 7 months. In this study, the authors examined the nature and management of disease progression (PD) on BRAFi treatment, including characteristics and outcomes of patients who received continued BRAFi treatment beyond disease progression (TBP). METHODS: Clinicopathologic data at baseline and at the time of PD were collected for all patients with BRAF-mutant metastatic melanoma who received BRAFi monotherapy within clinical trials between July 2009 and September 2012. Management and survival after PD were examined, including continued BRAFi TBP (> 28 days beyond Response Evaluation Criteria in Solid Tumor [RECIST]-defined PD). RESULTS: Ninety-five of 114 BRAFi-treated patients had PD. Fifty-three of those 95 patients (56%) progressed in extracranial sites alone, 18% (17 of 95 patients) progressed in intracranial and extracranial sites simultaneously, and 16% (15 of 95 patients) progressed in intracranial sites alone. Twenty-nine of the 95 patients (31%) who had PD progressed in a single site or organ, 48% (46 of 95 patients) progressed in existing metastases only, and 18% (17 of 95 patients) had new metastases alone. At the time of PD, 35 of 95 patients (37%) received no subsequent systemic treatment, 20% (19 of 95 patients) changed systemic treatments, and 39% (37 of 95 patients) continued BRAFi TBP for a median of 97 days. BRAFi TBP and known prognostic factors (Eastern Cooperative Oncology Group performance status, lactate dehydrogenase, RECIST sum of the greatest dimensions of target lesions) were associated with overall survival (OS) from the time of PD; however, in multivariable analysis, BRAFi TBP improved OS (hazard ratio, 0.50; 95% confidence interval, 0.27-0.93; P = .029). CONCLUSIONS: Most BRAFi-treated patients progressed in existing extracranial sites, and 31% progressed in isolated sites. Compared with cessation, continued BRAFi TBP is associated with prolonged OS even after adjusting for potential prognostic factors at PD.

Patterns of response and progression in patients with BRAF-mutant melanoma metastatic to the brain who were treated with dabrafenib.

BACKGROUND: Dabrafenib has activity in patients with brain metastases, but little is known of the relative efficacy of treatment within and outside the brain. This study sought to examine the intracranial (IC) and extracranial (EC) patterns of response and progression in patients with active melanoma brain metastases treated with dabrafenib. METHODS: Clinicopathologic parameters were collected on patients with active brain metastases enrolled in the phase 1 and 2 studies of dabrafenib at a single institution. RECIST (Response Evaluation Criteria In Solid Tumors) response and progression-free survival (PFS) were prospectively assessed by disease site (IC versus EC). Treatments received after disease progression were also assessed. RESULTS: A total of 23 patients were studied. Response rates were similar in IC (78%) and EC (90%) sites (P = .416). IC and EC response was concordant in 71% of patients. Median site-specific PFS was identical in both IC and EC sites (23.6 weeks, P = .465), and exceeded whole-body PFS determined by RECIST (16.3 weeks). Of 20 patients with progressive disease (PD), 6 had IC PD only, 6 had EC PD only, and 8 had PD in both sites. In those with isolated intracranial PD, 5 of 6 underwent local therapy to the brain and continued on dabrafenib longer than 30 days. CONCLUSIONS: IC and EC melanoma metastases respond similarly to dabrafenib. There is no dominant site or pattern of disease progression in patients with brain metastases treated with dabrafenib. Salvage local therapy is possible in most patients after IC disease progression, with ongoing dabrafenib treatment possible in a subset of patients.

Inter- and intra-patient heterogeneity of response and progression to targeted therapy in metastatic melanoma.

BACKGROUND: MAPK inhibitors (MAPKi) are active in BRAF-mutant metastatic melanoma patients, but the extent of response and progression-free survival (PFS) is variable, and complete responses are rare. We sought to examine the patterns of response and progression in patients treated with targeted therapy. METHODS: MAPKi-naïve patients treated with combined dabrafenib and trametinib had all metastases ≥5 mm (lymph nodes ≥15 mm in short axis) visible on computed tomography measured at baseline and throughout treatment. RESULTS: 24 patients had 135 measured metastases (median 4.5/patient, median diameter 16 mm). Time to best response (median 5.5 mo, range 1.7-20.1 mo), and the degree of best response (median -70%, range +9 to -100%) varied amongst patients. 17% of patients achieved complete response (CR), whereas 53% of metastases underwent CR, including 42% ≥10 mm. Metastases that underwent CR were smaller than non-CR metastases (median 11 vs 20 mm, P<0.001). PFS was variable among patients (median 8.2 mo, range 2.6-18.3 mo), and 50% of patients had disease progression in new metastases only. Only 1% (1/71) of CR-metastases subsequently progressed. Twelve-month overall survival was poorer in those with a more heterogeneous initial response to therapy than less heterogeneous (67% vs 93%, P = 0.009). CONCLUSION: Melanoma response and progression with MAPKi displays marked inter- and intra-patient heterogeneity. Most metastases undergo complete response, yet only a small proportion of patients achieve an overall complete response. Similarly, disease progression often occurs only in a subset of the tumor burden, and often in new metastases alone. Clinical heterogeneity, likely reflecting molecular heterogeneity, remains a barrier to the effective treatment of melanoma patients.