R Koornstra

Effective Clinical Responses in Metastatic Melanoma Patients after Vaccination with Primary Myeloid Dendritic Cells

Purpose: Thus far, dendritic cell (DC)-based immunotherapy of cancer was primarily based on in vitro–generated monocyte-derived DCs, which require extensive in vitro manipulation. Here, we report on a clinical study exploiting primary CD1c+ myeloid DCs, naturally circulating in the blood. Experimental Design: Fourteen stage IV melanoma patients, without previous systemic treatment for metastatic disease, received autologous CD1c+ myeloid DCs, activated by only brief (16 hours) ex vivo culture and loaded with tumor-associated antigens of tyrosinase and gp100. Results: Our results show that therapeutic vaccination against melanoma with small amounts (3–10 × 106) of myeloid DCs is feasible and without substantial toxicity. Four of 14 patients showed long-term progression-free survival (12–35 months), which directly correlated with the development of multifunctional CD8+ T-cell responses in three of these patients. In particular, high CD107a expression, indicative for cytolytic activity, and IFNγ as well as TNFα and CCL4 production was observed. Apparently, these T-cell responses are essential to induce tumor regression and promote long-term survival by stalling tumor growth. Conclusions: We show that vaccination of metastatic melanoma patients with primary myeloid DCs is feasible and safe and results in induction of effective antitumor immune responses that coincide with improved progression-free survival. Clin Cancer Res; 22(9); 2155–66. ©2015 AACR.

Management of fatigue in patients with cancer – A practical overview

Cancer-related fatigue (CRF) is a serious clinical problem and is one of the most common symptoms experienced by cancer patients. CRF has deleterious effects on many aspects of patient quality of life including their physical, psychological and social well-being. It can also limit their ability to function, socialise and participate in previously enjoyable activities. The aetiology of CRF is complex and multidimensional, involving many potentially contributing elements. These include tumour-related factors and comorbid medical/psychological conditions and also side effects associated with anti-cancer therapies or other medications. Barriers to the effective management of CRF exist both on the side of physicians and patients, and as a result CRF often remains unrecognised and undiscussed in clinical practice. A change of approach is required, where fatigue is treated as central to patient management during and after systemic anti-cancer treatment. In this review we summarise factors involved in the aetiology of CRF and the barriers to its effective management, as well as factors involved in the screening, diagnosis and treatment of cancer patients experiencing fatigue. Pharmacological and non-pharmacological approaches to its management are also reviewed. We suggest an algorithm for the process of managing CRF, guided by our experiences in The Netherlands, which we hope may provide a useful tool to healthcare professionals dealing with cancer patients in their daily practice. Although CRF is a serious and complex clinical problem, if it is worked through in a structured and comprehensive way, effective management has the potential to much improve patient quality of life.

Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma

Background The programmed death 1 (PD‐1) inhibitor pembrolizumab has been found to prolong progression‐free and overall survival among patients with advanced melanoma. We conducted a phase 3 double‐blind trial to evaluate pembrolizumab as adjuvant therapy in patients with resected, high‐risk stage III melanoma. Methods Patients with completely resected stage III melanoma were randomly assigned (with stratification according to cancer stage and geographic region) to receive 200 mg of pembrolizumab (514 patients) or placebo (505 patients) intravenously every 3 weeks for a total of 18 doses (approximately 1 year) or until disease recurrence or unacceptable toxic effects occurred. Recurrence‐free survival in the overall intention‐to‐treat population and in the subgroup of patients with cancer that was positive for the PD‐1 ligand (PD‐L1) were the primary end points. Safety was also evaluated. Results At a median follow‐up of 15 months, pembrolizumab was associated with significantly longer recurrence‐free survival than placebo in the overall intention‐to‐treat population (1‐year rate of recurrence‐free survival, 75.4% [95% confidence interval {CI}, 71.3 to 78.9] vs. 61.0% [95% CI, 56.5 to 65.1]; hazard ratio for recurrence or death, 0.57; 98.4% CI, 0.43 to 0.74; P<0.001) and in the subgroup of 853 patients with PD‐L1–positive tumors (1‐year rate of recurrence‐free survival, 77.1% [95% CI, 72.7 to 80.9] in the pembrolizumab group and 62.6% [95% CI, 57.7 to 67.0] in the placebo group; hazard ratio, 0.54; 95% CI, 0.42 to 0.69; P<0.001). Adverse events of grades 3 to 5 that were related to the trial regimen were reported in 14.7% of the patients in the pembrolizumab group and in 3.4% of patients in the placebo group. There was one treatment‐related death due to myositis in the pembrolizumab group. Conclusions As adjuvant therapy for high‐risk stage III melanoma, 200 mg of pembrolizumab administered every 3 weeks for up to 1 year resulted in significantly longer recurrence‐free survival than placebo, with no new toxic effects identified. (Funded by Merck; ClinicalTrials.gov number, NCT02362594; EudraCT number, 2014‐004944‐37.)

Anti-PD1 treatment in metastatic uveal melanoma in the Netherlands

M. K. van der Kooij, A. Joosse, F. M. Speetjens, G. A. P. Hospers, C. Bisschop, J. W. B. de Groot, R. Koornstra, C. U. Blank and E. Kapiteijn Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands; Department of Medical Oncology, University Medical Center Groningen, Groningen, The Netherlands; Department of Medical Oncology, Isala, Zwolle, The Netherlands; Department of Medical Oncology, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Medical Oncology, Netherlands Cancer Institute (NKI-AVL), Amsterdam, The Netherlands

Dutch Melanoma Treatment Registry: Quality assurance in the care of patients with metastatic melanoma in the Netherlands

BACKGROUND In recent years, the treatment of metastatic melanoma has changed dramatically due to the development of immune checkpoint and mitogen-activated protein (MAP) kinase inhibitors. A population-based registry, the Dutch Melanoma Treatment Registry (DMTR), was set up in July 2013 to assure the safety and quality of melanoma care in the Netherlands. This article describes the design and objectives of the DMTR and presents some results of the first 2 years of registration. METHODS The DMTR documents detailed information on all Dutch patients with unresectable stage IIIc or IV melanoma. This includes tumour and patient characteristics, treatment patterns, clinical outcomes, quality of life, healthcare utilisation, informal care and productivity losses. These data are used for clinical auditing, increasing the transparency of melanoma care, providing insights into real-world cost-effectiveness and creating a platform for research. RESULTS Within 1 year, all melanoma centres were participating in the DMTR. The quality performance indicators demonstrated that the BRAF inhibitors and ipilimumab have been safely introduced in the Netherlands with toxicity rates that were consistent with the phase III trials conducted. The median overall survival of patients treated with systemic therapy was 10.1 months (95% confidence interval [CI] 9.1-11.1) in the first registration year and 12.7 months (95% CI 11.6-13.7) in the second year. CONCLUSION The DMTR is the first comprehensive multipurpose nationwide registry and its collaboration with all stakeholders involved in melanoma care reflects an integrative view of cancer management. In future, the DMTR will provide insights into challenging questions regarding the definition of possible subsets of patients who benefit most from the new drugs.

Immune-related Adverse Events of Dendritic Cell Vaccination Correlate With Immunologic and Clinical Outcome in Stage III and IV Melanoma Patients.

The purpose of this study was to determine the toxicity profile of dendritic cell (DC) vaccination in stage III and IV melanoma patients, and to evaluate whether there is a correlation between side effects and immunologic and clinical outcome. This is a retrospective analysis of 82 stage III and 137 stage IV melanoma patients, vaccinated with monocyte-derived or naturally circulating autologous DCs loaded with tumor-associated antigens gp100 and tyrosinase. Median follow-up time was 54.3 months in stage III patients and 12.9 months in stage IV patients. Treatment-related adverse events occurred in 84% of patients; grade 3 toxicity was present in 3% of patients. Most common adverse events were flu-like symptoms (67%) and injection site reactions (50%), and both correlated with the presence of tetramer-positive CD8+ T cells (both P<0.001). In stage III melanoma patients experiencing flu-like symptoms, median overall survival (OS) was not reached versus 32.3 months in patients without flu-like symptoms (P=0.009); median OS in patients with an injection site reaction was not reached versus 53.7 months in patients without an injection site reaction (P<0.05). In stage IV melanoma patients (primary uveal and mucosal melanomas excluded), median OS in patients with or without flu-like symptoms was 13.1 versus 8.9 months, respectively (P=0.03); median OS in patients with an injection site reaction was 15.7 months versus 9.8 months in patients without an injection site reaction (P=0.003). In conclusion, DC vaccination is safe and tolerable and the occurrence of the immune-related side effects, such as flu-like symptoms and injection site reactions, correlates with immunologic and clinical outcome.

Metastatic melanoma mimicking solitary fibrous tumor: report of two cases

Malignant melanomas are known for their remarkable morphological variation and aberrant immunophenotype with loss of lineage-specific markers, especially in recurrences and metastases. Hot spot mutations in BRAF, NRAS, GNAQ, and GNA11 and mutations in KIT are oncogenic events in melanomas. Therefore, genotyping can be a useful ancillary diagnostic tool. We present one case each of recurrent and metastatic melanoma, both showing histological and immunohistochemical features of solitary fibrous tumor (SFT). Mutational analysis detected BRAF and NRAS mutations in the primary and secondary lesions, respectively. This result confirmed the diagnosis of recurrent/metastastic melanoma.

Ipilimumab administered to metastatic melanoma patients who progressed after dendritic cell vaccination

ABSTRACT Background: Ipilimumab has proven to be effective in metastatic melanoma patients. The purpose of this study was to determine the efficacy of ipilimumab in advanced melanoma patients who showed progressive disease upon experimental dendritic cell (DC) vaccination. Methods: Retrospective analysis of 48 stage IV melanoma patients treated with ipilimumab after progression upon DC vaccination earlier in their treatment. DC vaccination was given either as adjuvant treatment for stage III disease (n = 18) or for stage IV disease (n = 30). Ipilimumab (3 mg/kg) was administered every 3 weeks for up to 4 cycles. Results: Median time between progression upon DC vaccination and first gift of ipilimumab was 5.4 mo. Progression-free survival (PFS) rates for patients that received ipilimumab after adjuvant DC vaccination, and patients that received DC vaccination for stage IV melanoma, were 35% and 7% at 1 y and 35% and 3% at 2 y, while the median PFS was 2.9 mo and 3.1 mo, respectively. Median overall survival of patients pre-treated with adjuvant DC vaccination for stage III melanoma was not reached versus 8.0 mo (95% CI, 5.2–10.9) in the group pre-treated with DC vaccination for stage IV disease (HR of death, 0.36; p = 0.017). Grade 3 immune-related adverse events occurred in 19% of patients and one death (2%) was related to ipilimumab. Conclusions: Clinical responses to ipilimumab were found in a considerable number of advanced melanoma patients with progression after adjuvant DC vaccination for stage III disease, while the effect was very limited in patients who showed progression after DC vaccination for stage IV disease.

Panitumumab monotherapy as a second-line treatment in metastasised colorectal cancer: a single centre experience.

AIMS To report our clinical experience of panitumumab monotherapy as a second-line treatment for patients with metastatic colorectal cancer (mCRC). MATERIALS AND METHODS This retrospective, descriptive study included a series of consecutive patients receiving panitumumab monotherapy (6 mg/kg 2 weekly) at a single centre in the Netherlands between June 2009 and November 2011. All patients had wild-type KRAS tumours, had progressed during first-line fluoropyrimidine-based therapy and were not candidates for, or refused, standard second-line therapy (usually irinotecan in the Netherlands). Prophylactic medication was given for epidermal growth factor receptor inhibitor-associated skin toxicities. RESULTS Thirty-one patients were treated during this period. The most commonly administered first-line mCRC regimen was capecitabine/oxaliplatin/bevacizumab (18/31 patients; 58.1%). Patients received a mean of 7.9 (range 1-18) panitumumab cycles. The median progression-free survival was 3.4 (95% confidence interval 2.4, 4.4) months. The median overall survival estimates were 11.4 (95% confidence interval 1.2, 21.6) months from the initiation of panitumumab monotherapy. Ten patients experienced partial responses according to Response Evaluation Criteria In Solid Tumors (RECIST; objective response rate: 32.3%); disease was controlled (objective response or stable disease) in 15 patients (48.4%). Carcinoembryonic antigen (CEA) responses (two consecutive ≥10% decreases from baseline) occurred in 11/29 patients (37.9%); all of whom had >50% decreases in CEA levels. All patients with an objective response at week 12 had CEA reductions at weeks 6 and 12. The only adverse events were grade 1/2 skin toxicities (61.3%) and gastrointestinal complaints (6.5%); three other patients (9.7%) experienced both skin and gastrointestinal complaints. CONCLUSION Panitumumab monotherapy seems to be a safe and active second-line treatment for patients with wild-type KRAS mCRC, with activity in line with that seen for irinotecan monotherapy, but with less toxicity. CEA may provide a useful early indicator of response to panitumumab.

Abstract A38: Effects on epigenomic, transcriptomic, and genomic landscape of neoadjuvant tamoxifen in estrogen receptor alpha breast cancer

Background: The Anastrozole, Fulvestrant or Tamoxifen Exposure—Response in molecular profile (AFTER study, NCT00738777) aims to investigate the molecular basis of therapy response to neoadjuvant treatment in Estrogen Receptor alpha (ERα) breast cancer patients. ERα breast cancer makes up the majority of breast cancer diagnosed in the world each year. In these patients, tumor cell proliferation is driven by transcriptional activation through ERα binding DNA at specific genomic locations. To block this proliferation, endocrine therapies such as tamoxifen have been developed. While endocrine therapy is considered a successful targeted treatment, resistance is common. Patients who recur are typically given a different type of endocrine therapy and frequently respond well, suggesting ERα breast cancer is a heterogeneous disease made up of subtypes responsive to different treatments. We hypothesize drug exposure induces molecular changes in the tumor and the basis for these alterations may provide insight into the phenomenon of therapy resistance. Study Design and Methods: In the AFTER study ERα breast cancer patients are randomized for treatment arm in a multi-institutional study. Male and pre-menopausal patients receive tamoxifen. The primary endpoint is decreased tumor cell proliferation assessed by Ki67 gene expression. Tumor samples are taken at the time of diagnosis (biopsy) and surgery (primary tumor) for molecular and clinical assays. Treatment occurs during the pre-operative window after diagnosis. All data are collected at both timepoints. Molecular data collected include gene expression and ERα/DNA binding patterns and DNA copy number profiles. Clinical data comprise ERα/PR/HER2 and Ki67 immunohistochemical staining (IHC) and lymphnode status. Results: 67 patients are currently enrolled in the study. We examined the subset of tamoxifen treated patients (n=28). All tumors were HER2-negative. ERα/PR showed no significant difference between pre- and post-treatment levels. Tumor cell proliferation was significantly lower in post-treatment samples (Ki67 gene expression P Conclusions: Substantial synchronization in ERα/DNA binding and gene expression pattern was observed after treatment, while DNA copy number patterns remained stable. Our results indicate neoadjuvant tamoxifen induces molecular changes in a heterogeneous group of breast cancers associated with change in proliferation and ERα/DNA binding landscape. Importantly, while most tumors show these changes, some do not. Follow-up data will demonstrate whether taking samples after treatment exposure may be a powerful tool to help understand response to treatment. Citation Format: Tesa M. Severson, Ekaterina Nevedomskaya, Justine Peeters, Annelot van Rossum, Thomas Kuilman, Oscar Krijgsman, Rutger Koornstra, Daniel Peeper, Jelle Wesseling, Iris M. Simon, Lodewyk Wessels, Wilbert Zwart, Sabine C. Linn. Effects on epigenomic, transcriptomic, and genomic landscape of neoadjuvant tamoxifen in estrogen receptor alpha breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr A38.