The introduction of LAG-3 checkpoint blockade in melanoma: immunotherapy landscape beyond PD-1 and CTLA-4 inhibition.

Despite major advances with immunotherapy and targeted therapy in the past decade, metastatic melanoma continues to be a deadly disease for close to half of all patients. Over the past decade, advancement in immune profiling and a deeper understanding of the immune tumor microenvironment (TME) have enabled the development of novel approaches targeting and a multitude of targets being investigated for the immunotherapy of melanoma. However, to date, immune checkpoint blockade has remained the most successful with programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitors, alone or in combination, yielding the most robust and durable clinical outcome in patients with metastatic melanoma. The highest rate of durable responses is achieved with the combination with PD-1 and CTLA-4 inhibition, and is effective in a variety of settings including brain metastases; however, it comes at the expense of a multitude of life-threatening toxicities occurring in up to 60% of patients. This has also established melanoma as the forefront of immuno-oncology (IO) drug development, and the search for novel checkpoints has been ongoing with multiple relevant targets including T-cell immunoglobulin and mucinodomain containing-3 (TIM-3), LAG-3, V-domain immunoglobulin suppressor T-cell activation (VISTA), T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT), among others. Lymphocyte activation gene-3 (LAG-3), which is a co-inhibitory receptor on T cells that suppress their activation, has revolutionized immunomodulation in melanoma. The 'game changing' results from the RELATIVITY-047 trial validated LAG-3 blockade as a relevant biological target and established it as the third clinically relevant immune checkpoint. Importantly, LAG-3 inhibition in combination with PD-1 inhibition offered impressive efficacy with modest increases in toxicity over single agent PD-1 inhibitor and has been U.S. Food and Drug Administration approved for the first-line therapy of patients with metastatic melanoma. The efficacy of this combination in patients with untreated brain or leptomeningeal metastases or with rare melanoma types, such as uveal melanoma, remains to be established. The challenge remains to elucidate specific mechanisms of response and resistance to LAG-3 blockade and to extend its benefits to other malignancies. Ongoing trials are studying the combination of LAG-3 antibodies with PD-1 inhibitors in multiple cancers and settings. The low toxicity of the combination may also allow for further layering of additional therapeutic approaches such as chemotherapy, oncolytic viruses, cellular therapies, and possibly novel cytokines, among others.

Novel Immunotherapeutics: Perspectives on Checkpoints, Bispecifics, and Vaccines in Development.

Over the past decade, the advent of molecular techniques and deeper understanding of the tumor microenvironment (TME) have enabled the development of a multitude of immunotherapy targets and approaches. Despite the revolutionary advancement in immunotherapy, treatment resistance remains a challenge leading to decreased response rate in a significant proportion of patients. As such, there has recently been an evolving focus to enhance efficacy, durability, and toxicity profiles of immunotherapy. Although immune checkpoint inhibitors have revolutionized cancer treatment with many already-approved antibodies and several others in the pipeline, bispecific antibodies build on their success in an attempt to deliver an even more potent immune response against tumor cells. On the other hand, vaccines comprise the oldest and most versatile form of immunotherapy. Peptide and nucleic acid vaccines are relatively simple to manufacture compared with oncolytic virus-based vaccines, whereas the dendritic cell vaccines are the most complex, requiring autologous cell culture. Nevertheless, a crucial question in the development of cancer vaccines is the choice of antigen whereby shared and patient-private antigen approaches are currently being pursued. There is hope that cancer vaccines will join the repertoire of successful novel immunotherapeutics in the market. Better insights into the impact of immunotherapy on effector T cells and other immune cell populations in the TME shall be a major priority across the immune-oncology discipline and can help identify predictive biomarkers to evaluate response to treatment and identify patients who would most likely benefit from immunotherapy.

Current and emerging options for patients with melanoma brain metastases.

Melanoma is the most aggressive skin cancer, with a high incidence of metastatic spread and a predilection for metastases to the brain. It represents the third most common origin of brain metastases after breast and lung cancer. With the advent of targeted therapy and immunotherapy in melanoma, along with improved local therapy options such as stereotactic radiosurgery (SRS), the treatment of melanoma brain metastases (MBM) has led to significant improvements in outcome. In this review, we provide an overview of management options for patients with MBM while highlighting emerging treatment options. Surgery may be considered for patients with symptomatic MBM, whereas SRS is considered standard for patients with 1 to 4 brain lesions. Combination immunotherapy has led to durable intracranial responses and improved long-term outcomes for patients with asymptomatic MBM. The data available to date have shown that patients with MBM can have a durable response and overall response that are similar to those of patients without brain metastases, and additional trials are ongoing. Mounting evidence suggests that patients with MBM should be considered for inclusion in clinical trials, which range from early-phase trials to phase 3 studies, to accelerate much-needed drug development in this population.

Practice and Impact of Multidisciplinary Tumor Boards on Patient Management: A Prospective Study.

PURPOSE: Multidisciplinary tumor boards (MTBs) have become commonplace. The use, attendance, and function of MTBs need continued assessment and improvement. METHODS: We prospectively recorded and assessed all cases presented at MTBs between October 2013 and December 2014. Data were collected before and during each MTB. Data were analyzed using SPSS for Windows version 23 (SPSS, Chicago, IL). RESULTS: Five hundred three cases were presented: 234 cases (46%) at GI cancer MTBs, 149 cases (29.6%) at breast cancer MTBs, 69 cases (13.7%) at thoracic/head and neck cancer MTBs, and 51 cases (10.7%) at neuro-oncology MTBs. A total of 86.7% of MTB cases were presented to make plans for management. Plans for upfront management were made in 67% of the breast cancer cases, 63% of GI cases, 59% of thoracic/head and neck cases, and 49% of neuro-oncology cases. Three hundred ninety-four cases (78.3%) were presented by medical oncologists, whereas only 74 cases (14.7%) were presented by surgeons, and 10 cases (2%) were presented by radiation oncologists. The majority of MTBs, with the exception of the neurosurgery MTBs, were led by medical oncologists. Surgeons presented the least number of cases but attended the most, and their contributions to discussions and decision making were essential. CONCLUSION: MTBs enhance the multidisciplinary management of patients with cancer. Upfront multidisciplinary decision making should be considered as an indicator of benefit from MTBs, in addition to changes in management plans made at MTBs. Increasing the contributions of surgeons to MTBs should include bringing more of their own cases for discussion.

Overview, prevention and management of chemotherapy extravasation.

Chemotherapy extravasation remains an accidental complication of chemotherapy administration and may result in serious damage to patients. We review in this article the clinical aspects of chemotherapy extravasation and latest advances in definitions, classification, prevention, management and guidelines. We review the grading of extravasation and tissue damage according to various chemotherapeutic drugs and present an update on treatment and new antidotes including dexrazoxane for anthracyclines extravasation. We highlight the importance of education and training of the oncology team for prevention and prompt pharmacological and non-pharmacological management and stress the availability of new antidotes like dexrazoxane wherever anthracyclines are being infused.

BRCA1 and BRCA2 mutations in ethnic Lebanese Arab women with high hereditary risk breast cancer.

PURPOSE: Breast cancer is the most common malignancy among women in Lebanon and in Arab countries, with 50% of cases presenting before the age of 50 years. METHODS: Between 2009 and 2012, 250 Lebanese women with breast cancer who were considered to be at high risk of carrying BRCA1 or BRCA2 mutations because of presentation at young age and/or positive family history (FH) of breast or ovarian cancer were recruited. Clinical data were analyzed statistically. Coding exons and intron-exon boundaries of BRCA1 and BRCA2 were sequenced from peripheral blood DNA. All patients were tested for BRCA1 rearrangements using multiplex ligation-dependent probe amplification (MLPA). BRCA2 MLPA was done in selected cases. RESULTS: Overall, 14 of 250 patients (5.6%) carried a deleterious BRCA mutation (7 BRCA1, 7 BRCA2) and 31 (12.4%) carried a variant of uncertain significance. Eight of 74 patients (10.8%) aged ≤40 years with positive FH and only 1 of 74 patients (1.4%) aged ≤40 years without FH had a mutated BRCA. Four of 75 patients (5.3%) aged 41-50 years with FH had a deleterious mutation. Only 1 of 27 patients aged >50 years at diagnosis had a BRCA mutation. All seven patients with BRCA1 mutations had grade 3 infiltrating ductal carcinoma and triple-negative breast cancer. Nine BRCA1 and 17 BRCA2 common haplotypes were observed. CONCLUSION: Prevalence of deleterious BRCA mutations is lower than expected and does not support the hypothesis that BRCA mutations alone cause the observed high percentage of breast cancer in young women of Lebanese and Arab descent. Studies to search for other genetic mutations are recommended.

Global Practice and Efficiency of Multidisciplinary Tumor Boards: Results of an American Society of Clinical Oncology International Survey.

PURPOSE: Multidisciplinary tumor boards (MDTBs) are universally recommended, but recent literature has challenged their efficiency. METHODS: The American Society of Clinical Oncology (ASCO) conducted a survey of a randomly selected cohort of international ASCO members. The survey was built on SurveyMonkey and was sent via e-mail to a sample of 5,357 members. RESULTS: In all, 501 ASCO members practicing outside the United States responded, and 86% of them participated in MDTBs at their own institutions. Those who attended represented a variety of disciplines in 70% to 86% of all MDTBs. The majority of MDTBs held weekly specialty and/or general meetings. Eighty-nine percent of 409 respondents attended for advice on treatment decisions. Survey respondents reported changes of 1% to 25% in treatment plans for 44% to 49% of patients with breast cancer and in 47% to 50% of patients with colorectal cancer. They reported 25% to 50% changes in surgery type and/or treatment plans for 14% to 21% of patients with breast cancer and 12% to 18% of patients with colorectal cancer. Of the 430 respondents 96% said overall benefit to patients was worth the time and effort spent at MDTBs, and 96% said that MDTBs have teaching value. Mini tumor boards held with whatever types of specialists were available were considered valid. In all, 94.8% (425 of 448) said that MDTBs should be required in institutions in which patients with cancer are treated. CONCLUSION: MDTBs are commonplace worldwide. A majority of respondents attend them to obtain recommendations, and they report changes in patient management. Change occurred more frequently with nonmedical oncologists and with physicians who had less than 15 years in practice. MDTBs helped practitioners make management decisions. Mini tumor boards may improve time efficiency and are favored when the full team is not available. Suggestions for improving MDTBs included making them more efficient, better selection and preparation of cases, choosing an effective team leader, and improving how time is used, but more research is needed on ways to improve the efficiency of MDTBs.