Faculty Bibliography

Immunotherapy has revolutionized cancer therapy and has been named the cancer advance of the year for 2016. Checkpoint inhibitors have demonstrated unprecedented rates of durable responses in some of the most difficult-to-treat cancers; however, many treated patients do not respond, and the potential for serious side effects exists. There is a growing need to identify biomarkers that will improve the selection of patients who will best respond to therapy, further elucidate drug mechanisms of action, and help tailor therapy regimens. Biomarkers are being explored at the soluble, cellular, and genomic levels, and examples in immunotherapy include serum proteins, tumor-specific receptor expression patterns, factors in the tumor microenvironment, circulating immune and tumor cells, and host genomic factors. The search for reliable biomarkers is limited by our incomplete understanding of how immunotherapies modify the already complex immune response to cancer, as well as the contribution of immuno-editing to a dynamic and inducible tumor microenvironment and immune milieu. Furthermore, there has been little extension of any candidate assay into large, prospective studies, and the lack of standardization in measurement and interpretation restricts their validity. Both tumor-infiltrating lymphocytes and PD-L1 expression within the tumor microenvironment have been recognized as having both prognostic and predictive value for patients treated with immunotherapy. Alternately, a larger panel of gene signatures, chemokines, and other factors that correlate with response has been proposed. In this article, we will explore the status of current biomarker candidates.

BACKGROUND:In KEYNOTE-002, pembrolizumab significantly prolonged progression-free survival and was associated with a better safety profile compared with chemotherapy in patients with advanced melanoma that progressed after ipilimumab. We present health-related quality of life (HRQoL) outcomes from KEYNOTE-002. METHODS:Patients were randomly assigned 1:1:1 to pembrolizumab 2 or 10 mg/kg every 3 weeks (Q3W) or investigator-choice chemotherapy. HRQoL was assessed using the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire-Core 30 instrument. A constrained longitudinal data analysis model was implemented to assess between-arm differences in HRQoL scores. The study is registered with ClinicalTrials.gov, number NCT01704287. RESULTS:Of the 540 patients enrolled, 520 were included in the HRQoL analysis. Baseline global health status (GHS) was similar across treatment arms. Compliance rates at week 12 were 76.6% (n = 108), 82.3% (n = 121), and 86.4% (n = 133) for the control, pembrolizumab 2 mg/kg Q3W, and pembrolizumab 10 mg/kg Q3W arms, respectively. From baseline to week 12, GHS/HRQoL scores were maintained to a higher degree in the pembrolizumab arms compared with the chemotherapy arm (decrease of -2.6 for each pembrolizumab arm versus -9.1 for chemotherapy; P = 0.01 for each pembrolizumab arm versus chemotherapy). Fewer patients treated with pembrolizumab experienced deterioration in GHS at week 12 (31.8% for pembrolizumab 2 mg/kg, 26.6% for 10 mg/kg, and 38.3% for chemotherapy), with similar trends observed for the individual functioning and symptoms scales. CONCLUSIONS:HRQoL was better maintained with pembrolizumab than with chemotherapy in KEYNOTE-002, supporting the use of pembrolizumab in patients with ipilimumab-refractory melanoma.

UNLABELLED:In a phase II multicenter study, men with castration sensitive metastatic prostate cancer were treated with AT-101, a small molecule Bcl-2 inhibitor, and androgen deprivation therapy. At the end of 7 cycles of therapy in 55 patients, an undetectable PSA was achieved in 31%. However, the combination did not meet the pre-specified level of activity for further development. BACKGROUND:We conducted a phase II study in men with castration-sensitive metastatic prostate cancer to test the hypothesis that AT-101, a small molecule Bcl-2 inhibitor, has clinical activity in patients initiating androgen deprivation therapy (ADT) for metastatic prostate cancer. MATERIALS AND METHODS/METHODS:Patients with metastatic prostate cancer scheduled to start, or who had recently (within 6 weeks) initiated, ADT were enrolled. ADT with a luteinizing hormone-releasing hormone agonist and bicalutamide was started 6 weeks before initiation of oral AT-101, 20 mg/day for 21 days of a 28-day cycle. The primary endpoint of the study was the percentage of patients with an undetectable prostate-specific antigen (PSA) level (≤ 0.2 ng/mL) after 7.5 months (1.5 months of ADT alone plus 6 months of combined ADT and AT-101). To assess for an association between chromodomain helicase DNA binding protein 1 (CHD1) and drug sensitivity, fluorescence in situ hybridization with confocal microscopy was assessed in a subgroup of patients. RESULTS:A total of 55 patients were enrolled, with median age of 61 years and a median PSA level of 27.6 ng/dL. Of the 55 patients, 72% had a Gleason score ≥ 8. Three patients had visceral metastases, and the remaining patients had bone or nodal metastasis. An undetectable PSA level was achieved in 31% of the patients. Of the 31 patients, 12 experienced serious adverse events, 7 of which were considered related to study therapy. Most of the related adverse events were gastrointestinal and nervous system disorders. CHD1 assessment was feasible, with a nonsignificant association with therapeutic sensitivity in a small number of patients. CONCLUSION/CONCLUSIONS:The combination of ADT and AT-101 did not meet the prespecified level of activity for further development of this combination.

Antibodies that target the immune checkpoint receptor programmed cell death protein 1 (PD-1) have resulted in prolonged and beneficial responses toward a variety of human cancers. However, anti-PD-1 therapy in some patients provides no benefit and/or results in adverse side effects. The factors that determine whether patients will be drug sensitive or resistant are not fully understood; therefore, genomic assessment of exceptional responders can provide important insight into patient response. Here, we identified a patient with endometrial cancer who had an exceptional response to the anti-PD-1 antibody pembrolizumab. Clinical grade targeted genomic profiling of a pretreatment tumor sample from this individual identified a mutation in DNA polymerase epsilon (POLE) that associated with an ultramutator phenotype. Analysis of The Cancer Genome Atlas (TCGA) revealed that the presence of POLE mutation associates with high mutational burden and elevated expression of several immune checkpoint genes. Together, these data suggest that cancers harboring POLE mutations are good candidates for immune checkpoint inhibitor therapy.

IMPORTANCE/OBJECTIVE:Ipilimumab and other immune therapies are effective treatment options for patients with advanced melanoma but cause frequent immune-related toxic effects. Autoimmune diseases are common, and the safety and efficacy of ipilimumab therapy in patients with preexisting autoimmune disorders is not known. OBJECTIVE:To determine the safety and efficacy of ipilimumab therapy in patients with advanced melanoma with preexisting autoimmune disorders. DESIGN, SETTING, AND PARTICIPANTS/METHODS:Retrospective review of patients with advanced melanoma and preexisting autoimmune disorders who received ipilimumab at 9 academic tertiary referral centers from January 1, 2012, through August 1, 2015. The data analysis was performed on August 24, 2015. EXPOSURE/METHODS:Ipilimumab therapy. MAIN OUTCOMES AND MEASURES/METHODS:Safety, in terms of frequency of autoimmune flares and conventional immune-related adverse events (irAEs), and efficacy, in terms of response rates and overall survival, were evaluated descriptively. RESULTS:Of the 30 patients who received ipilimumab (17 [57%] male; median [range] age, 59.5 [30-80] y), 6 had rheumatoid arthritis, 5 had psoriasis, 6 had inflammatory bowel disease, 2 had systemic lupus erythematosus, 2 had multiple sclerosis, 2 had autoimmune thyroiditis, and 7 had other conditions. Thirteen patients (43%) were receiving immunosuppressive therapy at the time of initiation of ipilimumab therapy, most commonly low-dose prednisone or hydroxychloroquine. With ipilimumab treatment, 8 patients (27%) experienced exacerbations of their autoimmune condition necessitating systemic treatment; all were managed with corticosteroids. Conventional grade 3 to 5 irAEs occurred in 10 patients (33%) and were reversible with corticosteroids or with infliximab therapy in 2 cases. One patient with baseline psoriasis died of presumed immune-related colitis after a 1-week delay prior to reporting symptoms. Fifteen patients (50%) had neither autoimmune disease flares nor irAEs. Six patients experienced an objective response (20%), including 1 with a durable complete response. CONCLUSIONS AND RELEVANCE/CONCLUSIONS:To our knowledge, this is the largest series of patients with preexisting autoimmune disease treated with immune checkpoint inhibitors. Ipilimumab was clinically active and was associated with exacerbations of autoimmune disease and conventional ipilimumab-induced irAEs that were readily manageable with standard therapies when started in a timely fashion. Ipilimumab therapy may be considered in this setting with vigilant clinical monitoring.

Mucosal melanoma is an exceedingly rare variant of cutaneous melanoma that, due to its rarity, is poorly described and infrequently studied. Primary sites of origin include the head and neck, anorectum and vulvovaginal regions. It is uniquely different from cutaneous melanoma with respect to epidemiology, etiology, pathogenesis and prognosis. The etiology and pathogenesis remain unclear. Unlike cutaneous melanoma, exposure to UV light is not an apparent risk factor. Furthermore, distinct molecular features including a lower incidence of BRAF oncogene mutations but a higher incidence of KIT oncogene mutations suggest divergent genetic etiologies. Mucosal melanomas generally present at a later stage, are more aggressive and carry a worse prognosis regardless of the stage at diagnosis. Establishing standardized treatment guidelines has been challenging due to the rarity of the disease. Early detection provides the best chance at survival but is often difficult due to anatomic location. Surgery remains the primary therapeutic intervention if complete resection is technically feasible given the anatomic location. Radiotherapy may be used to achieve local control when resection is not feasible, or adjuvantly to enhance locoregional control, but most studies have failed to demonstrate an improvement in overall survival. There are no consensus guidelines on the optimal systemic therapy, and regimens are often extrapolated from data based on therapies used to treat advanced cutaneous melanoma. Clinical trials, particularly utilizing newer targeted therapies and immunotherapies, are investigating novel treatment approaches.

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.

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.

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.