Publications by authors named "Leslie A Fecher"

31 Publications

The Role of Systemic Therapy in Advanced Cutaneous Melanoma of the Head and Neck.

Otolaryngol Clin North Am 2021 Apr 15;54(2):329-342. Epub 2021 Feb 15.

University of Michigan, Rogel Cancer Center, C343 MIB, 1500 East Medical Center Drive, SPC 5848, Ann Arbor, MI 48109-5848, USA. Electronic address:

The treatment of advanced melanoma has changed dramatically over the last decade. With the discovery of activating BRAF mutations and the development of targeted therapies and checkpoint inhibitors, the overall survival of patients with advanced melanoma has improved. This article provides an overview of systemic therapies, including the pivotal agents that have led to these advances.
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http://dx.doi.org/10.1016/j.otc.2020.11.006DOI Listing
April 2021

The impact of BRAF mutation status on clinical outcomes with anti-PD-1 monotherapy versus combination ipilimumab/nivolumab in treatment-naïve advanced stage melanoma.

Pigment Cell Melanoma Res 2021 May 22;34(3):629-640. Epub 2020 Nov 22.

Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.

Nearly half of all metastatic melanoma patients possess the BRAF V600 mutation. Several therapies are approved for advanced stage melanoma, but it is unclear if there is a differential outcome to various immunotherapy regimens based on BRAF mutation status. We retrospectively analyzed a cohort of metastatic or unresectable melanoma patients who were treated with combination ipilimumab/nivolumab (ipi/nivo) or anti-PD-1 monotherapy, nivolumab, or pembrolizumab, as first-line treatment. 235 previously untreated patients were identified in our study. Our univariate analysis showed no statistical difference in progression-free survival (PFS) or overall survival (OS) with ipi/nivo versus anti-PD-1 monotherapy in the BRAF V600 mutant cohort, but there was improved PFS [HR: 0.48, 95% CI, 0.28-0.80] and OS [HR: 0.50, 95% CI, 0.26-0.96] with ipi/nivo compared to anti-PD-1 monotherapy in the BRAF WT group. After adjusting for known prognostic variables in our multivariable analysis, the BRAF WT cohort continued to show PFS and OS benefit with ipi/nivo compared to anti-PD-1 monotherapy. Our single-institution analysis suggests ipi/nivo should be considered over anti-PD-1 monotherapy as the initial immunotherapy regimen for metastatic melanoma patients regardless of BRAF mutation status, but possibly with greater benefit in BRAF WT.
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http://dx.doi.org/10.1111/pcmr.12944DOI Listing
May 2021

Efficacy and Outcome of Tofacitinib in Immune checkpoint Inhibitor Colitis.

Gastroenterology 2021 Feb 21;160(3):932-934.e3. Epub 2020 Oct 21.

Division of Gastroenterology, Department of Medicine, University of Michigan, Ann Arbor, Michigan.

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http://dx.doi.org/10.1053/j.gastro.2020.10.029DOI Listing
February 2021

Adjuvant nivolumab versus ipilimumab in resected stage IIIB-C and stage IV melanoma (CheckMate 238): 4-year results from a multicentre, double-blind, randomised, controlled, phase 3 trial.

Lancet Oncol 2020 11 19;21(11):1465-1477. Epub 2020 Sep 19.

Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA.

Background: Previously, findings from CheckMate 238, a double-blind, phase 3 adjuvant trial in patients with resected stage IIIB-C or stage IV melanoma, showed significant improvements in recurrence-free survival and distant metastasis-free survival with nivolumab versus ipilimumab. This report provides updated 4-year efficacy, initial overall survival, and late-emergent safety results.

Methods: This multicentre, double-blind, randomised, controlled, phase 3 trial was done in 130 academic centres, community hospitals, and cancer centres across 25 countries. Patients aged 15 years or older with resected stage IIIB-C or IV melanoma and an Eastern Cooperative Oncology Group performance status of 0 or 1 were randomly assigned (1:1) to receive nivolumab or ipilimumab via an interactive voice response system and stratified according to disease stage and baseline PD-L1 status of tumour cells. Patients received intravenous nivolumab 3 mg/kg every 2 weeks or intravenous ipilimumab 10 mg/kg every 3 weeks for four doses, and then every 12 weeks until 1 year of treatment, disease recurrence, unacceptable toxicity, or withdrawal of consent. The primary endpoint was recurrence-free survival by investigator assessment, and overall survival was a key secondary endpoint. Efficacy analyses were done in the intention-to-treat population (all randomly assigned patients). All patients who received at least one dose of study treatment were included in the safety analysis. The results presented in this report reflect the 4-year update of the ongoing study with a database lock date of Jan 30, 2020. This study is registered with ClinicalTrials.gov, NCT02388906.

Findings: Between March 30 and Nov 30, 2015, 906 patients were assigned to nivolumab (n=453) or ipilimumab (n=453). Median follow-up was 51·1 months (IQR 41·6-52·7) with nivolumab and 50·9 months (36·2-52·3) with ipilimumab; 4-year recurrence-free survival was 51·7% (95% CI 46·8-56·3) in the nivolumab group and 41·2% (36·4-45·9) in the ipilimumab group (hazard ratio [HR] 0·71 [95% CI 0·60-0·86]; p=0·0003). With 211 (100 [22%] of 453 patients in the nivolumab group and 111 [25%] of 453 patients in the ipilimumab group) of 302 anticipated deaths observed (about 73% of the originally planned 88% power needed for significance), 4-year overall survival was 77·9% (95% CI 73·7-81·5) with nivolumab and 76·6% (72·2-80·3) with ipilimumab (HR 0·87 [95% CI 0·66-1·14]; p=0·31). Late-emergent grade 3-4 treatment-related adverse events were reported in three (1%) of 452 and seven (2%) of 453 patients. The most common late-emergent treatment-related grade 3 or 4 adverse events reported were diarrhoea, diabetic ketoacidosis, and pneumonitis (one patient each) in the nivolumab group, and colitis (two patients) in the ipilimumab group. Two previously reported treatment-related deaths in the ipilimumab group were attributed to study drug toxicity (marrow aplasia in one patient and colitis in one patient); no further treatment-related deaths were reported.

Interpretation: At a minimum of 4 years' follow-up, nivolumab demonstrated sustained recurrence-free survival benefit versus ipilimumab in resected stage IIIB-C or IV melanoma indicating a long-term treatment benefit with nivolumab. With fewer deaths than anticipated, overall survival was similar in both groups. Nivolumab remains an efficacious adjuvant treatment for patients with resected high-risk melanoma, with a safety profile that is more tolerable than that of ipilimumab.

Funding: Bristol Myers Squibb and Ono Pharmaceutical.
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http://dx.doi.org/10.1016/S1470-2045(20)30494-0DOI Listing
November 2020

Utilization of COVID-19 Treatments and Clinical Outcomes among Patients with Cancer: A COVID-19 and Cancer Consortium (CCC19) Cohort Study.

Cancer Discov 2020 10 22;10(10):1514-1527. Epub 2020 Jul 22.

Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.

Among 2,186 U.S. adults with invasive cancer and laboratory-confirmed SARS-CoV-2 infection, we examined the association of COVID-19 treatments with 30-day all-cause mortality and factors associated with treatment. Logistic regression with multiple adjustments (e.g., comorbidities, cancer status, baseline COVID-19 severity) was performed. Hydroxychloroquine with any other drug was associated with increased mortality versus treatment with any COVID-19 treatment other than hydroxychloroquine or untreated controls; this association was not present with hydroxychloroquine alone. Remdesivir had numerically reduced mortality versus untreated controls that did not reach statistical significance. Baseline COVID-19 severity was strongly associated with receipt of any treatment. Black patients were approximately half as likely to receive remdesivir as white patients. Although observational studies can be limited by potential unmeasured confounding, our findings add to the emerging understanding of patterns of care for patients with cancer and COVID-19 and support evaluation of emerging treatments through inclusive prospective controlled trials. SIGNIFICANCE: Evaluating the potential role of COVID-19 treatments in patients with cancer in a large observational study, there was no statistically significant 30-day all-cause mortality benefit with hydroxychloroquine or high-dose corticosteroids alone or in combination; remdesivir showed potential benefit. Treatment receipt reflects clinical decision-making and suggests disparities in medication access..
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http://dx.doi.org/10.1158/2159-8290.CD-20-0941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541683PMC
October 2020

An adolescent with uveal melanoma and tumor predisposition syndrome.

JAAD Case Rep 2020 Jun 25;6(6):563-566. Epub 2020 Apr 25.

Department of Dermatology, Michigan Medicine, Ann Arbor, Michigan.

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http://dx.doi.org/10.1016/j.jdcr.2020.04.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7265053PMC
June 2020

Neoadjuvant systemic therapy in melanoma: recommendations of the International Neoadjuvant Melanoma Consortium.

Lancet Oncol 2019 07;20(7):e378-e389

Department of Pathology, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, Netherlands.

Advances in the treatment of metastatic melanoma have improved responses and survival. However, many patients continue to experience resistance or toxicity to treatment, highlighting a crucial need to identify biomarkers and understand mechanisms of response and toxicity. Neoadjuvant therapy for regional metastases might improve operability and clinical outcomes over upfront surgery and adjuvant therapy, and has become an established role for drug development and biomarker discovery in other cancers (including locally advanced breast cancer, head and neck squamous cell carcinomas, gastroesophageal cancer, and anal cancer). Patients with clinically detectable stage III melanoma are ideal candidates for neoadjuvant therapy, because they represent a high-risk patient population with poor outcomes when treated with upfront surgery alone. Neoadjuvant therapy is now an active area of research for melanoma with numerous completed and ongoing trials (since 2014) with disparate designs, endpoints, and analyses under investigation. We have, therefore, established the International Neoadjuvant Melanoma Consortium with experts in medical oncology, surgical oncology, pathology, radiation oncology, radiology, and translational research to develop recommendations for investigating neoadjuvant therapy in melanoma to align future trial designs and correlative analyses. Alignment and consistency of neoadjuvant trials will facilitate optimal data organisation for future regulatory review and strengthen translational research across the melanoma disease continuum.
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http://dx.doi.org/10.1016/S1470-2045(19)30332-8DOI Listing
July 2019

Liver Toxicity with Cancer Checkpoint Inhibitor Therapy.

Semin Liver Dis 2018 Nov 24;38(4):366-378. Epub 2018 Oct 24.

Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.

Immune checkpoint inhibition targeted against cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) has shown clinically significant survival benefit when used to treat multiple types of advanced cancer. These drugs have gained approval by the US Food and Drug Administration and their indications continue to increase. Checkpoint inhibitor therapy is associated with a unique side-effect profile characterized as immune-related adverse events (irAEs), which can result in significant morbidity and rarely mortality. Hepatotoxicity from checkpoint inhibitors is a less common irAE and often mild, while its incidence and severity vary based on the class and dose of checkpoint inhibitor, monotherapy versus combination therapy, and the type of cancer. Histological assessment of suspected irAEs is nonspecific and can show a variety of features. Hepatic irAEs can require discontinuation of checkpoint inhibitor therapy and treatment with immunosuppressive agents.
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http://dx.doi.org/10.1055/s-0038-1667358DOI Listing
November 2018

Metastatic melanoma with diffuse melanosis histologically after stable response to talimogene laherparepvec therapy.

JAAD Case Rep 2018 May 4;4(4):379-381. Epub 2018 Apr 4.

Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan.

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http://dx.doi.org/10.1016/j.jdcr.2018.01.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5911974PMC
May 2018

Host expression of PD-L1 determines efficacy of PD-L1 pathway blockade-mediated tumor regression.

J Clin Invest 2018 02 16;128(2):805-815. Epub 2018 Jan 16.

Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.

Programmed death-1 receptor (PD-L1, B7-H1) and programmed cell death protein 1 (PD-1) pathway blockade is a promising therapy for treating cancer. However, the mechanistic contribution of host and tumor PD-L1 and PD-1 signaling to the therapeutic efficacy of PD-L1 and PD-1 blockade remains elusive. Here, we evaluated 3 tumor-bearing mouse models that differ in their sensitivity to PD-L1 blockade and demonstrated a loss of therapeutic efficacy of PD-L1 blockade in immunodeficient mice and in PD-L1- and PD-1-deficient mice. In contrast, neither knockout nor overexpression of PD-L1 in tumor cells had an effect on PD-L1 blockade efficacy. Human and murine studies showed high levels of functional PD-L1 expression in dendritic cells and macrophages in the tumor microenvironments and draining lymph nodes. Additionally, expression of PD-L1 on dendritic cells and macrophages in ovarian cancer and melanoma patients correlated with the efficacy of treatment with either anti-PD-1 alone or in combination with anti-CTLA-4. Thus, PD-L1-expressing dendritic cells and macrophages may mechanistically shape and therapeutically predict clinical efficacy of PD-L1/PD-1 blockade.
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http://dx.doi.org/10.1172/JCI96113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5785251PMC
February 2018

Erratum to: Metastatic Merkel cell carcinoma response to nivolumab.

J Immunother Cancer 2017 6;5:27. Epub 2017 Mar 6.

Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan, C451 Med Inn, 1500 East Medical Center Drive, Ann Arbor, MI 48109 USA.

[This corrects the article DOI: 10.1186/s40425-016-0186-1.].
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http://dx.doi.org/10.1186/s40425-017-0221-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5340072PMC
March 2017

Metastatic Merkel cell carcinoma response to nivolumab.

J Immunother Cancer 2016 15;4:79. Epub 2016 Nov 15.

Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan, C451 Med Inn, 1500 East Medical Center Drive, Ann Arbor, MI 48109 USA.

Background: Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine malignancy with limited treatment options. Several lines of evidence support the programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) axis as a likely contributor to immune evasion in MCC.

Case Presentation: We report a case of a patient with metastatic MCC with a significant and durable response to nivolumab, a humanized IgG4 monoclonal anti-PD-1 antibody.

Conclusion: Immunotherapy with PD-1/PD-L1 inhibitors has become a rational and promising treatment option for MCC in the advanced or metastatic disease. Clinical trials are currently in progress to further evaluate these novel therapeutic agents.
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http://dx.doi.org/10.1186/s40425-016-0186-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5109712PMC
February 2018

Acute visual loss after ipilimumab treatment for metastatic melanoma.

J Immunother Cancer 2016 18;4:66. Epub 2016 Oct 18.

Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA USA ; Present address: Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan, C366 MIB 1500 E. Medical Center Drive, SPC5848, Ann Arbor, MI 48109 USA.

Background: Ipilimumab, a humanized CLTA-4 antibody is a standard therapy in the treatment of advanced melanoma. While ipilimumab provides an overall survival benefit to patients, it can be associated with immune related adverse events (IrAEs).

Case Presentation: Here we describe a patient treated with ipilimumab who experienced known IrAEs, including hypophysitis, as well as a profound vision loss due to optic neuritis. There are rare reports of optic neuritis occurring as an adverse event associated with ipilimumab treatment. Furthermore, the patient experienced multiple complications from high dose steroids used to manage his IrAEs.

Conclusions: This case highlights the need for recognition of atypical immune mediated processes associated with newer checkpoint inhibitor therapies including ipilimumab.
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http://dx.doi.org/10.1186/s40425-016-0170-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5067900PMC
February 2018

Advanced basal cell carcinoma, the hedgehog pathway, and treatment options - role of smoothened inhibitors.

Biologics 2015 6;9:129-40. Epub 2015 Nov 6.

The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.

Cutaneous basal cell carcinoma (BCC) is the most common human cancer and its incidence is rising worldwide. Ultraviolet radiation exposure, including tanning bed use, as well as host factors play a role in its development. The majority of cases are treated and cured with local therapies including surgery. Yet, the health care costs of diagnosis and treatment of BCCs in the US is substantial. In the United States, the cost of nonmelanoma skin cancer care in the Medicare population is estimated to be US$426 million per year. While rare, locally advanced BCCs that can no longer be controlled with surgery and/or radiation, and metastatic BCCs do occur and can be associated with significant morbidity and mortality. Vismodegib (GDC-0449), a smoothened inhibitor targeted at the hedgehog pathway, is the first US Food and Drug Association (FDA)-approved agent in the treatment of locally advanced, unresectable, and metastatic BCCs. This class of agents appears to be changing the survival rates in advanced BCC patients, but appropriate patient selection and monitoring are important. Multidisciplinary assessments are essential for the optimal care and management of these patients. For some patients with locally advanced BCC, treatment with a hedgehog inhibitor may eliminate the need for an excessively disfiguring or morbid surgery.
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http://dx.doi.org/10.2147/BTT.S54179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4642804PMC
November 2015

Discordancy in BRAF mutations among primary and metastatic melanoma lesions: clinical implications for targeted therapy.

Mod Pathol 2015 Apr 7;28(4):480-6. Epub 2014 Nov 7.

Department of Pathology, Indiana University School of Medicine, Indianapolis, IN, USA.

Systemic targeted molecular therapy, in the form of a selective BRAF inhibitor with or without a MEK inhibitor, is a standard treatment for patients with BRAF V600 mutation-positive melanoma with unresectable stage III and IV disease. Patients with BRAF mutation-negative primary tumors may manifest BRAF mutation-positive metastatic disease. It is unclear whether all metastatic lesions carry the same BRAF mutation status found in the primary tumor and if discordancy exists, in what frequency it occurs. Primary and matched metastatic lesions in 25 melanoma patients were tested for the BRAF V600E/Ec, V600K, V600D, and V600R mutations using a BRAF RGQ PCR kit (Qiagen). Four patients (16%) had discrepancies between their primary and metastatic melanoma BRAF status. Of these patients, 2 (8%) had BRAF mutation-positive primary melanomas with BRAF mutation-negative metastatic lesions and 2 (8%) patient had BRAF mutation-negative melanoma with a BRAF mutation-positive metastatic lesion. In summary, discordancy of BRAF mutation status is not an infrequent finding between primary and metastatic melanoma. It may be prudent in previously negative patients to determine BRAF mutation status of new metastatic tumors for proper allocation of BRAF inhibitor therapy. Discordant BRAF status may have a role in the varying patterns of response and inevitable resistance seen with BRAF inhibitor therapies.
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http://dx.doi.org/10.1038/modpathol.2014.136DOI Listing
April 2015

Phase I trial of hydroxychloroquine with dose-intense temozolomide in patients with advanced solid tumors and melanoma.

Autophagy 2014 Aug 20;10(8):1369-79. Epub 2014 May 20.

Department of Medicine and Abramson Cancer Center; University of Pennsylvania; Philadelphia, PA USA.

Blocking autophagy with hydroxychloroquine (HCQ) augments cell death associated with alkylating chemotherapy in preclinical models. This phase I study evaluated the maximum tolerated dose (MTD), safety, preliminary activity, pharmacokinetics, and pharmacodynamics of HCQ in combination with dose-intense temozolomide (TMZ) in patients with advanced solid malignancies. Forty patients (73% metastatic melanoma) were treated with oral HCQ 200 to 1200 mg daily with dose-intense oral TMZ 150 mg/m (2) daily for 7/14 d. This combination was well tolerated with no recurrent dose-limiting toxicities observed. An MTD was not reached for HCQ and the recommended phase II dose was HCQ 600 mg twice daily combined with dose-intense TMZ. Common toxicities included grade 2 fatigue (55%), anorexia (28%), nausea (48%), constipation (20%), and diarrhea (20%). Partial responses and stable disease were observed in 3/22 (14%) and 6/22 (27%) patients with metastatic melanoma. In the final dose cohort 2/6 patients with refractory BRAF wild-type melanoma had a near complete response, and prolonged stable disease, respectively. A significant accumulation in autophagic vacuoles (AV) in peripheral blood mononuclear cells was observed in response to combined therapy. Population pharmacokinetics (PK) modeling, individual PK simulations, and PK-pharmacodynamics (PD) analysis identified a threshold HCQ peak concentration that predicts therapy-associated AV accumulation. This study indicates that the combination of high-dose HCQ and dose-intense TMZ is safe and tolerable, and is associated with autophagy modulation in patients. Prolonged stable disease and responses suggest antitumor activity in melanoma patients, warranting further studies of this combination, or combinations of more potent autophagy inhibitors and chemotherapy in melanoma.
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http://dx.doi.org/10.4161/auto.29118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4203514PMC
August 2014

Combined MTOR and autophagy inhibition: phase I trial of hydroxychloroquine and temsirolimus in patients with advanced solid tumors and melanoma.

Autophagy 2014 Aug 20;10(8):1391-402. Epub 2014 May 20.

Department of Medicine and the Abramson Cancer Center; Perelman School of Medicine; University of Pennsylvania; Philadelphia, PA USA.

The combination of temsirolimus (TEM), an MTOR inhibitor, and hydroxychloroquine (HCQ), an autophagy inhibitor, augments cell death in preclinical models. This phase 1 dose-escalation study evaluated the maximum tolerated dose (MTD), safety, preliminary activity, pharmacokinetics, and pharmacodynamics of HCQ in combination with TEM in cancer patients. In the dose escalation portion, 27 patients with advanced solid malignancies were enrolled, followed by a cohort expansion at the top dose level in 12 patients with metastatic melanoma. The combination of HCQ and TEM was well tolerated, and grade 3 or 4 toxicity was limited to anorexia (7%), fatigue (7%), and nausea (7%). An MTD was not reached for HCQ, and the recommended phase II dose was HCQ 600 mg twice daily in combination with TEM 25 mg weekly. Other common grade 1 or 2 toxicities included fatigue, anorexia, nausea, stomatitis, rash, and weight loss. No responses were observed; however, 14/21 (67%) patients in the dose escalation and 14/19 (74%) patients with melanoma achieved stable disease. The median progression-free survival in 13 melanoma patients treated with HCQ 1200mg/d in combination with TEM was 3.5 mo. Novel 18-fluorodeoxyglucose positron emission tomography (FDG-PET) measurements predicted clinical outcome and provided further evidence that the addition of HCQ to TEM produced metabolic stress on tumors in patients that experienced clinical benefit. Pharmacodynamic evidence of autophagy inhibition was evident in serial PBMC and tumor biopsies only in patients treated with 1200 mg daily HCQ. This study indicates that TEM and HCQ is safe and tolerable, modulates autophagy in patients, and has significant antitumor activity. Further studies combining MTOR and autophagy inhibitors in cancer patients are warranted.
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http://dx.doi.org/10.4161/auto.29119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4203516PMC
August 2014

Detection of circulating tumor DNA in early- and late-stage human malignancies.

Sci Transl Med 2014 Feb;6(224):224ra24

Ludwig Center for Cancer Genetics and Therapeutics, Howard Hughes Medical Institute and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA.

The development of noninvasive methods to detect and monitor tumors continues to be a major challenge in oncology. We used digital polymerase chain reaction-based technologies to evaluate the ability of circulating tumor DNA (ctDNA) to detect tumors in 640 patients with various cancer types. We found that ctDNA was detectable in >75% of patients with advanced pancreatic, ovarian, colorectal, bladder, gastroesophageal, breast, melanoma, hepatocellular, and head and neck cancers, but in less than 50% of primary brain, renal, prostate, or thyroid cancers. In patients with localized tumors, ctDNA was detected in 73, 57, 48, and 50% of patients with colorectal cancer, gastroesophageal cancer, pancreatic cancer, and breast adenocarcinoma, respectively. ctDNA was often present in patients without detectable circulating tumor cells, suggesting that these two biomarkers are distinct entities. In a separate panel of 206 patients with metastatic colorectal cancers, we showed that the sensitivity of ctDNA for detection of clinically relevant KRAS gene mutations was 87.2% and its specificity was 99.2%. Finally, we assessed whether ctDNA could provide clues into the mechanisms underlying resistance to epidermal growth factor receptor blockade in 24 patients who objectively responded to therapy but subsequently relapsed. Twenty-three (96%) of these patients developed one or more mutations in genes involved in the mitogen-activated protein kinase pathway. Together, these data suggest that ctDNA is a broadly applicable, sensitive, and specific biomarker that can be used for a variety of clinical and research purposes in patients with multiple different types of cancer.
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http://dx.doi.org/10.1126/scitranslmed.3007094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4017867PMC
February 2014

Ipilimumab and its toxicities: a multidisciplinary approach.

Oncologist 2013 Jun 17;18(6):733-43. Epub 2013 Jun 17.

University of Pennsylvania Abramson Cancer Center, Philadelphia, Pennsylvania, USA.

The treatment for metastatic melanoma has evolved significantly in the past few years. Ipilimumab, an immunotherapy, is now in mainstream oncology practice given that it has shown improved overall survival in randomized clinical trials. Other immune modulating agents, such as programmed death receptor-1 and programmed death receptor ligand-1 antibodies, are showing promise in early clinical trials. This manuscript will review ipilimumab and its most common side effects. Immune-related adverse events (irAEs) are important to recognize early, and their presentation, timing of onset, and general recommendations for workup and management will be reviewed. Assembling a multidisciplinary team, as well as thorough education of the patient, is recommended to optimize patient care.
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http://dx.doi.org/10.1634/theoncologist.2012-0483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4063401PMC
June 2013

Systemic therapy for inoperable and metastatic basal cell cancer.

Authors:
Leslie A Fecher

Curr Treat Options Oncol 2013 Jun;14(2):237-48

Hematology-Oncology, Indiana University Health Simon Cancer Center, 535 Barnhill Drive, RT-473, Indianapolis, IN 46202, USA.

Cutaneous basal cell carcinoma (BCC) is the most common human malignancy. The majority of cases are cured with local therapies and advanced disease is quite rare. However, locally advanced (inoperable) and metastatic basal cell carcinoma may occur more often than previously thought. Surgery, and other local therapies, is the primary treatment for BCC. However, some resections can be extensive and carry significant morbidity or disfigurement. The prognosis for locally advanced and metastatic BCC is quite poor, and cytotoxic chemotherapies offer limited benefit. Aberrations in the sonic hedgehog (HH) signaling pathway are common in BCC. Novel molecular therapies targeted against this pathway, such as vismodegib (GDC-0449), have shown dramatic activity in advanced basal cell carcinoma. The role of these in nevoid basal cell carcinoma syndrome (Gorlin) syndrome is still under investigation. However, systemic therapies are not curative and require long-term treatment and should not be used in place of curative procedures. Evaluation by experienced physicians and/or by a multidisciplinary tumor board for possible curative/definitive surgery with or without radiation is recommended before initiation of systemic therapy. Clinical trial enrollment also is recommended. Comorbid conditions as well as social circumstances may be factors when deciding on an optimal therapy, in particular with oral agents. Patients treated with HH pathway inhibitors require regular physician monitoring to assess for side effects, benefit, and compliance. Patients of child-bearing potential must be strongly counseled regarding the risk of birth defects and need for birth control. Primary and secondary resistance to HH pathway inhibitors is only beginning to be described.
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http://dx.doi.org/10.1007/s11864-013-0233-9DOI Listing
June 2013

Phase II study of the MEK1/MEK2 inhibitor Trametinib in patients with metastatic BRAF-mutant cutaneous melanoma previously treated with or without a BRAF inhibitor.

J Clin Oncol 2013 Feb 17;31(4):482-9. Epub 2012 Dec 17.

Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Purpose: BRAF mutations promote melanoma cell proliferation and survival primarily through activation of MEK. The purpose of this study was to determine the response rate (RR) for the selective, allosteric MEK1/MEK2 inhibitor trametinib (GSK1120212), in patients with metastatic BRAF-mutant melanoma.

Patients And Methods: This was an open-label, two-stage, phase II study with two cohorts. Patients with metastatic BRAF-mutant melanoma previously treated with a BRAF inhibitor (cohort A) or treated with chemotherapy and/or immunotherapy (BRAF-inhibitor naive; cohort B) were enrolled. Patients received 2 mg of trametinib orally once daily.

Results: In cohort A (n = 40), there were no confirmed objective responses and 11 patients (28%) with stable disease (SD); the median progression-free survival (PFS) was 1.8 months. In cohort B (n = 57), there was one (2%) complete response, 13 (23%) partial responses (PRs), and 29 patients (51%) with SD (confirmed RR, 25%); the median PFS was 4.0 months. One patient each with BRAF K601E and BRAF V600R had prolonged PR. The most frequent treatment-related adverse events for all patients were skin-related toxicity, nausea, peripheral edema, diarrhea, pruritis, and fatigue. No cutaneous squamous cell carcinoma was observed.

Conclusion: Trametinib was well tolerated. Significant clinical activity was observed in BRAF-inhibitor-naive patients previously treated with chemotherapy and/or immunotherapy. Minimal clinical activity was observed as sequential therapy in patients previously treated with a BRAF inhibitor. Together, these data suggest that BRAF-inhibitor resistance mechanisms likely confer resistance to MEK-inhibitor monotherapy. These data support further evaluation of trametinib in BRAF-inhibitor-naive BRAF-mutant melanoma, including rarer forms of BRAF-mutant melanoma.
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http://dx.doi.org/10.1200/JCO.2012.43.5966DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878037PMC
February 2013

Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: a phase 1 dose-escalation trial.

Lancet Oncol 2012 Aug 16;13(8):782-9. Epub 2012 Jul 16.

Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Background: MEK is a member of the MAPK signalling cascade that is commonly activated in melanoma. Direct inhibition of MEK blocks cell proliferation and induces apoptosis. We aimed to analyse safety, efficacy, and genotyping data for the oral, small-molecule MEK inhibitor trametinib in patients with melanoma.

Methods: We undertook a multicentre, phase 1 three-part study (dose escalation, cohort expansion, and pharmacodynamic assessment). The main results of this study are reported elsewhere; here we present data relating to patients with melanoma. We obtained tumour samples to assess BRAF mutational status, and available tissues underwent exploratory genotyping analysis. Disease response was measured by Response Evaluation Criteria in Solid Tumors, and adverse events were defined by common toxicity criteria. This study is registered with ClinicalTrials.gov, number NCT00687622.

Findings: 97 patients with melanoma were enrolled, including 81 with cutaneous or unknown primary melanoma (36 BRAF mutant, 39 BRAF wild-type, six BRAF status unknown), and 16 with uveal melanoma. The most common treatment-related adverse events were rash or dermatitis acneiform (n=80; 82%) and diarrhoea (44; 45%), most of which were grade 2 or lower. No cutaneous squamous-cell carcinomas were recorded. Of 36 patients with BRAF mutations, 30 had not received a BRAF inhibitor before; two complete responses (both confirmed) and ten partial responses (eight confirmed) were noted in this subgroup (confirmed response rate, 33%). Median progression-free survival of this subgroup was 5·7 months (95% CI 4·0-7·4). Of the six patients who had received previous BRAF inhibition, one unconfirmed partial response was recorded. Of 39 patients with BRAF wild-type melanoma, four partial responses were confirmed (confirmed response rate, 10%).

Interpretation: Our data show substantial clinical activity of trametinib in melanoma and suggest that MEK is a valid therapeutic target. Differences in response rates according to mutations indicate the importance of mutational analyses in the future.

Funding: GlaxoSmithKline.
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http://dx.doi.org/10.1016/S1470-2045(12)70269-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4109286PMC
August 2012

Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial.

Lancet Oncol 2012 Aug 16;13(8):773-81. Epub 2012 Jul 16.

Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN, USA.

Background: Inhibition of MEK stops cell proliferation and induces apoptosis; therefore, this enzyme is a key anticancer target. Trametinib is a selective, orally administered MEK1/MEK2 inhibitor. We aimed to define the maximum tolerated dose and recommended phase 2 dose of trametinib and to assess its safety, pharmacokinetics, pharmacodynamics, and response rate in individuals with advanced solid tumours.

Methods: We undertook a multicentre phase 1 study in patients with advanced solid tumours and adequate organ function. The study was in three parts: dose escalation to define the maximum tolerated dose; identification of the recommended phase 2 dose; and assessment of pharmacodynamic changes. Intermittent and continuous dosing regimens were analysed. Blood samples and tumour biopsy specimens were taken to assess pharmacokinetic and pharmacodynamic changes. Adverse events were defined with common toxicity criteria, and tumour response was measured by Response Evaluation Criteria In Solid Tumors. This study is registered with ClinicalTrials.gov, number NCT00687622.

Findings: We enrolled 206 patients (median age 58·5 years, range 19-92). Dose-limiting toxic effects included rash (n=2), diarrhoea (n=1), and central serous retinopathy (n=2). The most common treatment-related adverse events were rash or dermatitis acneiform (n=165; 80%) and diarrhoea (87; 42%), most of which were grade 1 and 2. The maximum tolerated dose was 3 mg once daily and the recommended phase 2 dose was 2 mg a day. The effective half-life of trametinib was about 4 days. At the recommended phase 2 dose, the exposure profile of the drug showed low interpatient variability and a small peak:trough ratio of 1·81. Furthermore, mean concentrations in plasma were greater than the preclinical target concentration throughout the dosing interval. Pathway inhibition and clinical activity were seen, with 21 (10%) objective responses recorded.

Interpretation: The recommended phase 2 dose of 2 mg trametinib once a day is tolerable, with manageable side-effects. Trametinib's inhibition of the expected target and clinical activity warrants its further development as a monotherapy and in combination.

Funding: GlaxoSmithKline.
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http://dx.doi.org/10.1016/S1470-2045(12)70270-XDOI Listing
August 2012

Diverse cutaneous side effects associated with BRAF inhibitor therapy: a clinicopathologic study.

J Am Acad Dermatol 2012 Dec 18;67(6):1265-72. Epub 2012 May 18.

Department of Dermatology, Hospital of University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.

Background: Vemurafenib, a novel selective small molecule inhibitor of BRAF, has recently been shown to be effective in the treatment of melanomas harboring the BRAF V600E mutation. Similar to the broad-spectrum RAF inhibitor sorafenib, vemurafenib induces development of squamous cell carcinomas and keratoacanthomas as a side effect of therapy.

Objective: We sought to detail additional cutaneous adverse effects of vemurafenib and a similar BRAF inhibitor, dabrafenib.

Methods: We evaluated the clinical and histologic feature of skin side effects developing on vemurafenib or dabrafenib therapy in 14 patients.

Results: Eight patients developed one or more squamous cell carcinomas, and 11 patients formed benign verrucous keratoses. Eight patients developed single lesions and/or widespread eruptions with histopathologic findings of acantholytic dyskeratosis, consistent with warty dyskeratomas and Darier- or Grover-like rashes, respectively. One patient developed palmoplantar hyperkeratosis, and darkening of existing nevi and new nevi within 2 months of starting vemurafenib. Side effects presented as early as 1 week after beginning therapy, with a mean time of onset of 12.6 weeks in our cohort.

Limitations: This study was limited by the small number of cases, all from a single institution.

Conclusion: Selective BRAF inhibitor therapy is associated with the development of malignant and benign growths, including keratoacanthoma-like squamous cell carcinomas, warty dyskeratomas, and verrucous keratoses, along with widespread eruptions with histologic features of acantholytic dyskeratosis. Given the potential for malignant lesions to develop on treatment, awareness of potential adverse effects of these agents is necessary, and a low threshold for biopsy of new growths is recommended.
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http://dx.doi.org/10.1016/j.jaad.2012.04.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4838029PMC
December 2012

Collapse of the CD27+ B-cell compartment associated with systemic plasmacytosis in patients with advanced melanoma and other cancers.

Clin Cancer Res 2009 Jul 23;15(13):4277-87. Epub 2009 Jun 23.

Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.

Purpose: Disturbed peripheral blood B-cell homeostasis complicates certain infections and autoimmune diseases, such as HIV and systemic lupus erythematosus, but has not been reported in cancer. This study aimed to investigate whether B-cell physiology was altered in the presence of melanoma and other cancers.

Experimental Design: Flow cytometry was used to identify phenotypic differences in B cells from patients with melanoma and normal donors. In vitro stimulated B cells were assessed for responsiveness and also used as stimulators of allogeneic T cells in mixed lymphocyte reactions.

Results: We show B-cell dysregulation in patients with advanced melanoma (n = 26) and other solid tumors (n = 13), marked by a relative and absolute loss of CD27+ (memory) B cells and associated with an aberrant systemic plasmacytosis. Functionally, B cells from patients with melanoma inefficiently up-regulated immunoregulatory molecules and weakly secreted cytokines in response to CD40 and toll-like receptor 9 agonists. Stimulated B cells from patients induced proliferation of alloreactive CD4+ T cells, but these T cells poorly secreted IFNgamma and interleukin-2. These effects were recapitulated by using purified normal donor CD27(neg) B cells in these same assays, linking the predominance of CD27(neg) B cells in patients with the observed functional hyporesponsiveness. Indeed, B-cell dysfunction in patients strongly correlated with the extent of loss of CD27+ B cells in peripheral blood.

Conclusions: Disturbed B-cell homeostasis is a previously unrecognized feature of patients with advanced melanoma and other cancers and may represent an unanticipated mechanism of immune incompetence in cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-09-0537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2896505PMC
July 2009

Drug targeting of oncogenic pathways in melanoma.

Hematol Oncol Clin North Am 2009 Jun;23(3):599-618, x

Department of Medicine, Division of Hematology and Oncology, Abramson Cancer Center, University of Pennsylvania, 3400 Spruce Street, 16 Penn Tower, Philadelphia, PA 19104, USA.

Melanoma continues to be one of the most aggressive and morbid malignancies once metastatic. Overall survival for advanced unresectable melanoma has not changed over the past several decades. However, the presence of some long-term survivors of metastatic melanoma highlights the heterogeneity of this disease and the potential for improved outcomes. Current research is uncovering the molecular and genetic scaffolding of normal and aberrant cell function. The known oncogenic pathways in melanoma and the attempts to develop therapy for them are discussed. The targeting of certain cellular processes, downstream of the common genetic alterations, for which the issues of target and drug validation are somewhat distinct, are also highlighted.
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http://dx.doi.org/10.1016/j.hoc.2009.03.004DOI Listing
June 2009

Where are we with adjuvant therapy of stage III and IV melanoma in 2009?

J Natl Compr Canc Netw 2009 Mar;7(3):295-304

Abramson Cancer Center of the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Adjuvant therapy options for advanced melanoma in 2009 remain active observation, high-dose interferon, or clinical trial participation. Close observation is currently the only required adjuvant management, with the purpose of detecting the emergence of regional or metastatic disease early, when surgical management may still be possible. The National Comprehensive Cancer Network guidelines for the workup and follow-up of all stages of melanoma must be tailored to specific patients by the treating physician. This article explores the factors to consider when individualizing care within the scope of these guidelines.
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http://dx.doi.org/10.6004/jnccn.2009.0022DOI Listing
March 2009

The MAPK pathway in melanoma.

Curr Opin Oncol 2008 Mar;20(2):183-9

University of Pennsylvania, Division of Hematology and Oncology, Department of Medicine, The Abramson Cancer Center, Philadelphia, Pennsylvania 19104, USA.

Purpose Of Review: As understanding of molecular and genetic processes in cancer evolves, so does appreciation of tumor heterogeneity. Tumor profiling has expanded knowledge of relevant pathways, and their interplay. Similar to the revolution in breast cancer with the discovery and successful therapeutic targeting of HER2/neu, the melanoma field is rapidly evolving. The MAPK pathway is dysregulated in most melanomas. Several therapeutic agents directed against this pathway are in development. This review summarizes current understanding of the MAPK pathway in melanoma biology and therapeutic strategies.

Recent Findings: Recent data support the concept of distinct groups of molecular and genetic abnormalities in melanomas, related to type of sun exposure and body site. MAPK abnormalities, specifically BRAF or NRAS mutations, are most prevalent. The efficacy of sorafenib, a multitargeted kinase inhibitor, in melanoma is still under evaluation. While ineffective as a single agent, efficacy in combination with chemotherapy or targeted agents is being assessed. More specific inhibitors of BRAF, or other MAPK members, may prove more effective.

Summary: Tumor profiling has led to exciting advances. The MAPK pathway is one of several potentially targetable pathways in melanoma. Ultimately, combinatorial therapeutics against relevant disrupted pathways in specific tumors likely will prove most successful.
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http://dx.doi.org/10.1097/CCO.0b013e3282f5271cDOI Listing
March 2008