Therapeutic drug monitoring (TDM) provides valuable guidance for dose adjustment of antibiotics, immunosuppressives, antiepileptics, and other drugs, but its use for traditional anticancer therapies has been limited. Perhaps the most important obstacle is the impractical requirement of multiple blood samples to adequately define systemic exposure of drugs that have a short elimination half-life and are given by intermittent intravenous injections. However, the newer targeted anticancer therapies have different pharmacokinetic (PK) and dosing characteristics compared with traditional cytotoxic drugs, making it possible to estimate the steady-state drug exposure with a single trough-level measurement. Recent evidence indicates that certain PK parameters, including trough levels, are correlated with clinical outcomes for many of these agents, including imatinib, sunitinib, rituximab, and cetuximab. Although the current evidence is insufficient to mandate TDM in routine practice, a concerted investigation should be encouraged to determine whether the steady-state trough measurements of targeted agents will have a practical place in the clinical care of patients with cancer.

Agminated melanocytic nevus is an uncommon type of mole, characterized by a local group of macular or papular pigmented lesions, well demarcated, without a common pigmented background. This pattern has also been associated with Spitz nevi, dysplastic melanocytic nevi, and non-melanocytic lesions.We describe the onset of an acquired agminated melanocytic nevus after dabrafenib treatment. Our case highlights paradoxical MAPK activation in the setting of single-agent BRAF blockade and underscores the importance of characterizing the diverse side effects of selective BRAF inhibitors. This is the first case, to our knowledge, of agminated melanocytic nevus in association with dabrafenib.

The innovative blockade of immune checkpoints with targeted immunotherapies, such as monoclonal antibodies against programmed cell death-1, is pioneering the treatment for advanced melanoma. Potential adverse events of particular interest associated with immunotherapy are of an inflammatory or immune-related nature. Reported dermatological side effects mostly comprise nonspecific rash and pruritus. This is a report of a 75-year-old man with metastatic melanoma who was initially administered pembrolizumab at 10 mg/kg every 3 weeks. He developed spongiotic dermatitis that was partially treated with topical steroids after cycle 3. Pembrolizumab cycles were stopped because of disease progression after cycle 6. On the 30-day follow-up, the patient presented with extensive erythematous papules and plaques, in addition to a few intact and ruptured vesicles and bullae over the upper and lower limbs, especially over the knees and elbows. Both punch skin biopsies (haematoxylin and eosin and direct immunofluorescence studies) confirmed a bullous pemphigoid diagnosis. He was treated with a tapering dose of oral prednisone, resulting in rapid clinical improvement after only a week of treatment, which was switched to dexamethasone following the diagnosis of new brain metastases.

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.

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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; P5.029). 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. Cancer 2014;120:3142-53.

The MEK inhibitor trametinib is associated with the development of acneiform eruptions. When combined with dabrafenib the frequency of this side-effect is reduced.

CRA8503 Background: In preclinical models, the BRAF/MEK inhibitor (i) combination GSK436/GSK212 has demonstrated enhanced activity against BRAF-mutant cancer cells compared to either drug alone, delayed emergence of GSK436 resistance, and prevented proliferative skin lesions attributable to BRAFi exposure. Methods: Eligible patients (pts) had BRAF V600 mutation positive solid tumors. Part 1: pharmacokinetic (PK) drug-drug interaction (DDI) study. Part 2: Dose escalation of continuous daily dosing of the combination followed by expansion cohorts; Part 3: Randomized phase II trial in untreated stage IV melanoma. Results: 45 pts have received ≥ 1 dose of GSK212 + GSK436, including 43 melanoma (all BRAFi naïve), 1 NSCLC and 1 salivary duct carcinoma. PK results of 7 pts in Part 1 showed no effect of GSK212 on single dose of GSK436. There was no clinically meaningful DDI between GSK436 and GSK212 after repeat dosing of the combination (Part 2). GSK436 was dosed 75-150 mg BID in combination with GSK212 1.0, 1.5, 2.0 mg QD. The recommended dose was 2 mg QD GSK212 in combination with 150 mg BID GSK436. At 1.5 mg GSK212, there was one DLT, a recurrent grade (G) 2 neutrophilic panniculitis. The only G4 adverse event (AE) was a sepsis-like syndrome with fever/hypotension. G3 AEs included generalized rash (n=2, 4%) and neutropenia (n=2, 4%). Skin toxicity ≥ G2 occurred in 9 (20%) pts; of these, G2 rash (n=4, 8%) and G2 macular rash (n=1, 2%). No cutaneous squamous cell carcinoma (SCC) or hyperproliferative skin lesions have occurred at any dose level. Other common G2 toxicities were pyrexia (n=5, 11%), vomiting (n=2, 4%) and fatigue (n=2, 4%). Of 16 evaluable pts in Part 2, 13 pts had PR and 3 SD for an ORR of 81% (95% CI 54.4%-96.0%) and all but 2 pts remain on study. In 10 evaluable pts who received 150 mg BID GSK436 + ≥1 mg QD GSK212, 9 pts had PR and 1 SD. Conclusions: GSK212 at 2 mg QD combines safely with GSK436 150 mg BID, no SCC thus far and decreased frequency of rash compared to previous trials of single agent GSK436 and GSK212, respectively. The preliminary anti-tumor activity warrants further investigation; the randomized phase II trial (Part 3) is accruing.