Dabrafenib plus trametinib in unselected advanced BRAF V600-mut melanoma: a non-interventional, multicenter, prospective trial.

OBJECTIVE: The efficacy of combined BRAF and MEK inhibition for BRAF V600-mutant melanoma in a broad patient population, including subgroups excluded from phase 3 trials, remains unanswered. This noninterventional study (DATUM-NIS) assessed the real-world efficacy, safety and tolerability of dabrafenib plus trametinib in Austrian patients with unresectable/metastatic melanoma. METHODS: This multicenter, open-label, non-interventional, post-approval, observational study investigated the effectiveness of dabrafenib plus trametinib prescribed in day-to-day clinical practice to patients ( N  = 79) with BRAF V600-mutant unresectable/metastatic melanoma with M1c disease (American Joint Committee on Cancer staging manual version 7), ECOG > 1, and elevated serum lactate dehydrogenase (LDH). The primary endpoint was 6-, 12- and 18-month progression-free survival (PFS) rates. Secondary endpoints were median PFS, disease control rate and overall survival (OS). RESULTS: The 6-, 12- and 18-month PFS rates were 76%, 30.6% and 16.2%, respectively. Subgroup analysis showed a significant PFS benefit in the absence of lung metastasis. The median PFS and OS were 9.1 (95% CI, 7.1-10.3) months and 17.9 (95% CI, 12.7-27.8) months, respectively. The 12- and 24-month OS rates were 62.7% and 26.8%, respectively. Subgroup analyses showed significant OS benefits in the absence of bone or lung metastasis and the presence of other metastases (excluding bone, lung, brain, liver and lymph nodes). Furthermore, S100 and Eastern Cooperative Oncology Group performance status (ECOG PS) showed a significant impact on survival. No new safety signals were observed. CONCLUSION: Despite an unselected population of melanoma patients with higher M1c disease, ECOG PS > 1 and elevated LDH, this real-world study demonstrated comparable efficacy and safety with the pivotal phase 3 clinical trials for dabrafenib-trametinib.

Failure of short-term psoralen and ultraviolet A light maintenance treatment to prevent early relapse in patients with chronic recurring plaque-type psoriasis.

BACKGROUND: Photochemotherapy using psoralen and ultraviolet A light (PUVA) is a highly effective treatment option for patients with severe psoriasis. Maintenance treatment has been advocated to provide for sustained remission. However, only a few studies have been conducted to assess the efficacy of maintenance treatment and these have provided inconsistent results. METHODS: We performed a prospective intrapatient left-right comparison study in 34 patients with chronic relapsing plaque psoriasis. PUVA treatment for clearing was given four times weekly. After complete or near-complete clearing, all patients were placed on a halfside maintenance schedule with irradiation twice weekly and then once weekly for 4 weeks each. The psoriasis area and severity index score was determined at baseline, end of the clearing phase and at 2-monthly intervals after discontinuation of treatment. RESULTS: Using a short-term maintenance protocol, a moderate delay in relapse of psoriasis was observed in only three patients (8.8%; 95% CI: 1.8-23.6%). In the remaining patients (91.2%), maintenance treatment had no effect on the length of remission. The mean time interval until relapse without and with maintenance irradiation was 4.5 +/- 3.4 and 4.6 +/- 3.4 months, respectively. CONCLUSION: Our data indicate that short-term maintenance treatment is not effective in preventing early relapse of psoriasis and should be avoided.

Randomized, double-blind comparison of 1 mg/L versus 5 mg/L methoxsalen bath-PUVA therapy for chronic plaque-type psoriasis.

BACKGROUND: Bath-psoralen plus ultraviolet A (PUVA) radiation therapy is increasingly replacing oral PUVA because of its superior short- and long-term safety profile. Several investigations in recent years have led to a refinement of the bath-PUVA protocol; however, the optimal therapeutic concentration of methoxsalen in the bath water has as yet not been delineated. OBJECTIVES: The therapeutic efficacy and tolerability of bath-PUVA by using two different dilutions of methoxsalen (1 mg/L vs 5 mg/L or 0.0001% vs 0.0005%) were compared in 46 patients with chronic plaque-type psoriasis in a prospective, randomized, double-blind study. METHODS: Scores of the Psoriasis Area and Severity Index excluding psoriasis of the head (PASI(TUL)) and the Plaque Severity Index (PSI) were assessed at baseline and at biweekly intervals thereafter until (near)complete clearance or maximal improvement. In addition, methoxsalen plasma levels were determined immediately after the psoralen bath during the first week of treatment and treatment-related side effects were recorded throughout the entire study period. RESULTS: The median baseline PASI(TUL) score decreased from 11.7 (7.5-32.8) to 3.3 (0.6-1.2) (-72%) in the 1 mg/L methoxsalen group and from 10.8 (6.6-20.7) to 1.4 (03.2) (-87%) in the 5 mg/L methoxsalen group (P < .01). The median baseline PSI score decreased from 9 (6-12) to 3.1 (0.6-10) (-66%) in the 1 mg/L methoxsalen group and from 9.3 (7.3-12) to 1.6 (0-3.6) (-83%) in the 5 mg/L methoxsalen group (P < .01). The median cumulative UVA exposure dose was 25.4 (5.3-81.5) J/cm2 for 5 mg/L methoxsalen and 71.9 (20.7-587.3) J/cm2 for 1 mg/L methoxsalen (P = .001). The number of exposures (22 [11-29] vs 23 [11-34]) and treatment duration (43 [19-68] vs 44 [23-66] days) was comparable for both methoxsalen dilutions (P = .97). Median psoralen plasma levels were 0 (0-26) ng/mL after the 1 mg/L and 30 (0-64) ng/mL after the 5 mg/L methoxsalen immersion (P = .001). Mild to moderate adverse events were more common in the 5 mg/L methoxsalen group. LIMITATIONS: The conclusions of this randomized controlled study are limited by the relatively small sample size. CONCLUSIONS: Our data indicate that in bath-PUVA treatment the use of a high (5 mg/L) methoxsalen concentration is substantially more effective in clearing chronic plaque-type psoriasis than a low (1 mg/L) concentration.