Clinicopathologic features associated with efficacy and long-term survival in metastatic melanoma patients treated with BRAF or combined BRAF and MEK inhibitors.

BACKGROUND: The degree of response and the duration of survival of patients treated with mitogen-activated protein kinase (MAPK) inhibitors are highly variable. Whether baseline clinicopathologic factors can predict the clinical course with treatment is largely unknown. METHODS: For 142 consecutive immunotherapy- and MAPK inhibitor-naive patients with BRAF-mutant metastatic melanoma who were treated during clinical trials with BRAF inhibitors (n = 111) or a combination of dabrafenib and trametinib (n = 31), clinicopathologic factors were correlated with the response to MAPK inhibitors and survival. RESULTS: The median follow-up was 15.7 months (range, 0.6-60.5 months). The 2-, 3-, and 4-year overall survival (OS) rates were 43%, 24%, and 24%, respectively. A multivariate analysis demonstrated that the only clinicopathologic factors associated with longer progression-free survival (PFS) and OS were female sex and a normal pretreatment serum lactate dehydrogenase (LDH) level. The BRAF V600E genotype and an absence of primary melanoma ulceration were also independently associated with longer PFS but not OS. The median OS was 23.5 months for patients with normal LDH levels and 7.3 months for those with elevated LDH levels (hazard ratio, 0.31; P < .001). Complete responders had the best survival, but disease progression still occurred in 2 of 7 patients. CONCLUSIONS: Long-term survival occurs for a minority of patients receiving MAPK inhibitor treatment alone. Sex, serum LDH, BRAF genotype, and primary melanoma ulceration status are independent factors associated with treatment outcomes. Patients with a complete response to treatment have the best survival, but relapses still occur.

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.

Metastasis-specific patterns of response and progression with anti-PD-1 treatment in metastatic melanoma.

This study evaluated patterns of response as discerned by comprehensive metastasis-specific analysis in metastatic melanoma patients receiving anti-PD-1 antibodies. Bi-dimensional measurements of every metastasis in patients enrolled in the KEYNOTE-001 trial at a single institution were obtained at baseline and throughout treatment. Twenty-seven evaluable patients had 399 baseline metastases measurable on CT imaging. Complete response (CR) which occurred in 52.6% of metastases was smaller (mean 223 mm2 versus 760 mm2 , p < .01) and occurred more frequently in the lungs (65% versus 39.4%, p < .01). Response was heterogenous (new/progressing metastases alongside CR metastases) at first assessment in 4/14 patients with objective response (OR) as opposed to 7/13 patients with non-OR. CR of individual metastases is common and influenced by site and size. Most patients with OR demonstrate homogenous regression in all metastases at the first assessment. In contrast, patients with early heterogeneity had a poor outcome.

Apocynin but not allopurinol prevents and reverses adrenocorticotropic hormone-induced hypertension in the rat.

BACKGROUND: Adrenocorticotropic hormone (ACTH)-induced hypertension in the rat is accompanied by increased oxidative stress. This study examines the enzymatic source of reactive oxygen species in ACTH-hypertension. METHODS: Male Sprague-Dawley rats were divided into 10 groups of 10-20 rats per group. The NAD(P)H oxidase inhibitor apocynin (1.5 mmol/L in drinking water) or the xanthine oxidase inhibitor allopurinol (200 mg/kg/day via food) were administered daily. After 4 days, rats were co-administered ACTH (0.2 mg/kg/day) or saline by subcutaneous injection daily for 11 days (prevention study). In a reversal study, ACTH/saline was administered for 13 days and from day 8, apocynin or allopurinol was added for 5 days. Systolic blood pressure (SBP) was measured by the tail-cuff method and oxidative stress using plasma F2-isoprostane concentrations. Results were expressed as mean+/-SEM. RESULTS: ACTH increased SBP (P<.001) but apocynin or allopurinol alone had no effect. Apocynin (but not allopurinol) co-treatment prevented (142+/-3 ACTH, 120+/-4 mm Hg apocynin+ACTH, P'<0.001) and reversed ACTH-induced hypertension (133+/-4 to 118+/-5 mm Hg, P<.05). Plasma F2-isoprostane concentrations were increased in ACTH-treated rats compared with saline (11.9+/-1.0 vs 8.2+/-0.8 nmol/L, P<.01), and apocynin attenuated the ACTH-induced rise in plasma F2-isoprostane concentrations. Serum urate concentrations were undetectable in 75% of rats treated with allopurinol and were not affected by ACTH. CONCLUSIONS: Apocynin but not allopurinol prevented and reversed ACTH-induced hypertension in the rat. These results suggest superoxide production through NAD(P)H oxidase plays a role in ACTH-induced hypertension.

Arthritis and tenosynovitis associated with the anti-PD1 antibody pembrolizumab in metastatic melanoma.

We report the acute onset of polyarticular inflammatory arthritis in 2 patients receiving the immune check-point inhibitor, pembrolizumab (MK-3475), anti-PD1 drug for metastatic melanoma after 14 and 11 months therapy, respectively. The first patient had severe tenosynovitis, synovitis, bone marrow edema, and myositis, whereas the second patient had predominantly synovitis and tenosynovitis. Good symptomatic control was obtained with bisphosphonates and salazopyrin, avoiding the use of T-cell immunosuppressants. These cases raise important questions on whether anti-PD1 therapy allows preexisting autoimmune T-cell clones to escape tolerance by suppressing regulatory T cells or whether they allow autoimmunity to develop de novo. These conditions heighten our awareness of complications associated with the clinical use of these agents, and provide a prototypical model for future research into the understanding of autoimmunity.