Faculty Bibliography

IMPORTANCE/OBJECTIVE:The treatment of multiple brain metastases (MBM) from melanoma is controversial and includes surgical resection, stereotactic radiosurgery (SRS), and whole-brain radiation therapy (WBRT). Several new classes of agents have revolutionized the treatment of metastatic melanoma, allowing some subsets of patients to have long-term survival. Given this, management of MBM from melanoma is continually evolving. OBJECTIVE:To review the current evidence regarding the treatment of MBM from melanoma. EVIDENCE REVIEW/METHODS:The PubMed database was searched using combinations of search terms and synonyms for melanoma, brain metastases, radiation, chemotherapy, immunotherapy, and targeted therapy published between January 1, 1995, and January 1, 2015. Articles were selected for inclusion on the basis of targeted keyword searches, manual review of bibliographies, and whether the article was a clinical trial, large observational study, or retrospective study focusing on melanoma brain metastases. Of 2243 articles initially identified, 110 were selected for full review. Of these, the most pertinent 73 articles were included. FINDINGS/RESULTS:Patients with newly diagnosed MBM can be treated with various modalities, either alone or in combination. Level 1 evidence supports the use of SRS alone, WBRT, and SRS with WBRT. Although the addition of WBRT to SRS improves the overall brain relapse rate, WBRT has no significant impact on overall survival and has detrimental neurocognitive outcomes. Cytotoxic chemotherapy has largely been ineffective; targeted therapies and immunotherapies have been reported to have high response rates and deserve further attention in larger clinical trials. Further studies are needed to fully evaluate the efficacy of these novel regimens in combination with radiation therapy. CONCLUSIONS AND RELEVANCE/CONCLUSIONS:At this time, the standard management for patients with MBM from melanoma includes SRS, WBRT, or a combination of both. Emerging data exist to support the notion that SRS in combination with targeted therapies or immune therapy may obviate the need for WBRT; prospective studies are required to fully evaluate the efficacy of these novel regimens in combination with radiation therapy.

UNLABELLED:Macroautophagy (autophagy hereafter) may promote survival and growth of spontaneous tumors, including melanoma. We utilized a genetically engineered mouse model of melanoma driven by oncogenic BrafV600E and deficiency in the Pten tumor suppressor gene in melanocytes to test the functional consequences of loss of the essential autophagy gene autophagy-related-7, Atg7. Atg7 deficiency prevented melanoma development by BrafV600E and allelic Pten loss, indicating that autophagy is essential for melanomagenesis. Moreover, BrafV600E-mutant, Pten-null, Atg7-deficient melanomas displayed accumulation of autophagy substrates and growth defects, which extended animal survival. Atg7-deleted tumors showed increased oxidative stress and senescence, a known barrier to melanomagenesis. Treatment with the BRAF inhibitor dabrafenib decreased tumor growth and induced senescence that was more pronounced in tumors with Atg7 deficiency. Thus, Atg7 promotes melanoma by limiting oxidative stress and overcoming senescence, and autophagy inhibition may be of therapeutic value by augmenting the antitumor activity of BRAF inhibitors. SIGNIFICANCE/CONCLUSIONS:The essential autophagy gene Atg7 promotes development of BrafV600E-mutant, Pten-null melanomas by overcoming senescence, and deleting Atg7 facilitated senescence induction and antitumor activity of BRAF inhibition. This suggests that combinatorial BRAFV600E and autophagy inhibition may improve therapeutic outcomes in patients whose tumors have BRAFV600E/K mutations, an approach currently being explored in clinical trials.

BACKGROUND:Type 1 insulin-like growth factor receptor (IGF-IR) signaling is often dysregulated in cancer. Cixutumumab, a fully human IgG1 monoclonal antibody, blocks IGF-IR and inhibits downstream signaling. The current study determined the recommended dose, safety, and pharmacokinetic (PK) profile of weekly or every-2-week dosing of cixutumumab. PATIENTS AND METHODS/METHODS:Two open-label, multicenter phase I studies evaluated weekly (3-15 mg/kg) or every-2-weeks (6-15 mg/kg) dosing of cixutumumab in patients with advanced solid tumors. Serial blood samples for PK were collected up to 168-336 h (day 8-15) following the first administration of cixutumumab. Efficacy was evaluated as best overall tumor response. RESULTS:A total of 24 and 16 patients were enrolled in the weekly and every-2-week dosing studies, respectively. Treatment-emergent adverse events (≥10%) included hyperglycemia, fatigue, anemia, nausea, and vomiting. Severe adverse events (AE) were infrequent; one serious AE (grade 3 electrocardiogram QT prolongation) was deemed possibly cixutumumab-related (10 mg/kg every-2-weeks). One death occurred due to disease progression (6 mg/kg weekly cohort). Maximum serum concentrations increased with dose. A maximum tolerated dose was not identified; pre-determined target serum minimum concentrations (60 μg/mL) were achieved with ≥6 mg/kg weekly and ≥10 mg/kg every-2-week dosing. Cixutumumab terminal elimination half-life is approximately a week (individual range, t1/2 = 4.58-9.33 days based upon 10 mg/kg every 2 weeks). Overall, stable disease was achieved in 25% of all patients. CONCLUSIONS:Cixutumumab was associated with favorable safety and PK profiles. A dosing regimen of 10 mg/kg every 2 weeks was recommended for subsequent disease-focused clinical trials.

Melanoma is a type of skin cancer arising from melanocytes and is increasing in incidence. Although complete surgical excision of early stage lesions may be curative, metastatic melanoma continues to be a major therapeutic challenge. Advances in understanding the molecular pathways that promote tumorigenesis and the interactions between melanoma cells and the immune system have resulted in the approval of several newly targeted agents and immunotherapy strategies for the treatment of advanced disease. Oncolytic virus immunotherapy is a new approach that uses native or attenuated live viruses to selectively kill melanoma cells and induce systemic tumor-specific immune responses. A variety of viruses are now in clinical development with the attenuated oncolytic herpesvirus encoding granulocyte-macrophage colony stimulating factor, known as talimogene laherparepvec, recently demonstrating an improvement in durable response rate in patients with advanced melanoma compared with granulocyte-macrophage colony stimulating factor alone. A major advantage of talimogene laherparepvec and related agents is the limited toxicity and ability to use each individual tumor as a source of antigen to generate a highly specific antitumor immune response. These agents are easily administered in the out-patient setting and may be a reasonable option for patients with limited metastatic tumor burden, those with a good performance status and without extensive prior treatment, and in those who cannot tolerate more difficult therapeutic regimens. Further investigation into the impact on overall survival as monotherapy and combination of oncolytic virus immunotherapy with other forms of immunotherapy merit high priority for further clinical application of these novel agents for the treatment of melanoma and perhaps other cancers as well.

Our laboratory previously described the oncogenic properties of metabotropic glutamate receptor 1 (mGluR1) in melanocytes. mGluR1 transformed immortalized mouse melanocytes in vitro and induced vigorous tumor formation in vivo. Subsequently, we observed the activation of PI3K/AKT in mGluR1-mediated melanocytic tumorigenesis in vivo. In particular, we identified AKT2 being the predominant isoform contributing to the activation of AKT. Suppression of Grm1 or AKT2 using an inducible Tet-R siRNA system resulted in a 60 or 30% reduction, respectively, in in vivo tumorigenesis. We show that simultaneous downregulation of Grm1 plus AKT2 results in a reduction of approximately 80% in tumor volumes, suggesting that both mGluR1 and AKT2 contribute to the tumorigenic phenotype in vivo. The discrepancy between the mild in vitro transformation characteristics and the aggressive in vivo tumorigenic phenotypes of these stable mGluR1-melanocytic clones led us to investigate the possible involvement of other growth factors. Here, we highlight a potential crosstalk network between mGluR1 and tyrosine kinase, insulin-like growth factor 1 receptor (IGF-1R).

Glutamate-triggered signal transduction is thought to contribute widely to cancer pathogenesis. In melanoma, overexpression of the metabotropic glutamate receptor (GRM)-1 occurs frequently and its ectopic expression in melanocytes is sufficient for neoplastic transformation. Clinical evaluation of the GRM1 signaling inhibitor riluzole in patients with advanced melanoma has demonstrated tumor regressions that are associated with a suppression of the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathways. Together, these results prompted us to investigate the downstream consequences of GRM1 signaling and its disruption in more detail. We found that melanoma cells with enhanced GRM1 expression generated larger tumors in vivo marked by more abundant blood vessels. Media conditioned by these cells in vitro contained relatively higher concentrations of interleukin-8 and VEGF due to GRM1-mediated activation of the AKT-mTOR-HIF1 pathway. In clinical specimens from patients receiving riluzole, we confirmed an inhibition of MAPK and PI3K/AKT activation in posttreatment as compared with pretreatment tumor specimens, which exhibited a decreased density of blood vessels. Together, our results demonstrate that GRM1 activation triggers proangiogenic signaling in melanoma, offering a mechanistic rationale to design treatment strategies for the most suitable combinatorial use of GRM1 inhibitors in patients.

PURPOSE/OBJECTIVE:This first-in-human study evaluated the safety, immunogenicity, pharmacokinetics, and antitumor activity of onartuzumab, a monovalent antibody against the receptor tyrosine kinase MET. EXPERIMENTAL DESIGN/METHODS:This 3+3 dose-escalation study comprised three stages: (i) phase Ia dose escalation of onartuzumab at doses of 1, 4, 10, 20, and 30 mg/kg intravenously every 3 weeks; (ii) phase Ia cohort expansion at the recommended phase II dose (RP2D) of 15 mg/kg; and (iii) phase Ib dose escalation of onartuzumab at 10 and 15 mg/kg in combination with bevacizumab (15 mg/kg intravenously every 3 weeks). Serum samples were collected for evaluation of pharmacokinetics, potential pharmacodynamic markers, and antitherapeutic antibodies. RESULTS:Thirty-four patients with solid tumors were treated in phase Ia and 9 in phase Ib. Onartuzumab was generally well tolerated at all dose levels evaluated; the maximum tolerated dose was not reached. The most frequent drug-related adverse events included fatigue, peripheral edema, nausea, and hypoalbuminemia. In the phase Ib cohort, onartuzumab at the RP2D was combined with bevacizumab and no dose-limiting toxicities were seen. Onartuzumab showed linear pharmacokinetics in the dose range from 4 to 30 mg/kg. The half-life was approximately 8 to 12 days. There were no apparent pharmacokinetic interactions between onartuzumab and bevacizumab, and antitherapeutic antibodies did not seem to affect the safety or pharmacokinetics of onartuzumab. A patient with gastric carcinoma in the 20-mg/kg dose cohort achieved a durable complete response for nearly 2 years. CONCLUSIONS:Onartuzumab was generally well tolerated as a single agent and in combination with bevacizumab in patients with solid tumors.

Squamous cell carcinoma of the skin (SCCS) is a common malignancy with potentially devastating consequences in patients with locally advanced or metastatic disease. Its rising incidence, primarily a result of an aging population and increased ultraviolet (UV) radiation exposure, characterize an emerging unmet need. A firm understanding of the biology of this disease, likely distinct from that of other squamous malignancies because of the influence of UV radiation, is necessary in the evaluation of treatment paradigms. Careful recognition of high-risk features pertaining to tumor and host characteristics is paramount to proper management. However, a lack of standardization in guidelines in this regard creates a challenge for physicians. Questions persist regarding additional evaluation and treatment for advanced disease such as the roles for sentinel lymph node biopsy and the adjuvant use of radiation and chemotherapy. With respect to advanced disease, multiple combinations of chemotherapy have been tested with variable success, but no rigorous randomized studies have been conducted. In addition, EGFR inhibitors such as cetuximab and erlotinib have displayed antitumor activity and as such, warrant further investigation. In sum, the treatment of locally advanced and metastatic SCCS is a ripe area for clinical investigation. This article summarizes the current understanding of disease biology and emerging questions in the management of this disease.

Ipilimumab is a fully human, monoclonal antibody directed against Cytotoxic T Lymphocyte Antigen-4 (CTLA-4) that has demonstrated a survival benefit and durable disease control in patients with advanced melanoma. Ipilimumab is associated with potentially serious immune-related adverse events, including autoimmune hepatitis. Because clinical trials of ipilimumab excluded patients with pre-existing hepatitis B or C infection, there is a paucity of data on the safety of ipilimumab administration to that patient population. Here, we report the largest case series to date of patients with hepatitis B or C who received ipilimumab for advanced melanoma. Two of the nine patients described in this case series experienced fluctuations in their liver function tests (LFTs) and were subsequently treated with corticosteroids. Although this is a small series, the rate of hepatotoxicity appears similar to what has been seen in the general population treated with ipilimumab, and the ability to administer ipilimumab did not appear to be affected by concomitant hepatitis B or C infection. The use of ipilimumab in patients with metastatic melanoma who have pre-existing hepatitis can be considered among other therapeutic options.