Facts and Hopes on Biomarkers for Successful Early Clinical Immunotherapy Trials: Innovative Patient Enrichment Strategies.

Despite the clinical validation and unequivocal benefit to patients, the development of cancer immunotherapies is facing some key challenges and the attrition rate in early phases of development remains high. Identifying the appropriate patient population that would benefit most from the drug is on the critical path for successful clinical development. We believe that a systematic implementation of patient enrichment strategies early in the drug development process and trial design, is the basis for an innovative, more efficient, and leaner clinical development to achieve earlier a clear proof of concept or proof of failure. In this position article, we will describe and propose key considerations for the implementation of patient enrichment strategies as an opportunity to provide decision-enabling data earlier in the drug development process. We introduce an innovative multidimensional tool for immuno-oncology drug development that focuses on facilitating the identification and prioritization of enrichment-relevant biomarkers, based on the drug mechanism of action. To illustrate its utility, we discuss patient enrichment examples and use a case in the field of cancer immunotherapy, together with technical and regulatory considerations. Overall, we propose to implement fit for purpose enrichment strategies for all investigational drugs as early as possible in the development process. We believe that this will increase the success rate of immuno-oncology clinical trials, and eventually bring new and better medicines to patients faster.

Correlation Between Early Trends of a Prognostic Biomarker and Overall Survival in Non-Small-Cell Lung Cancer Clinical Trials.

PURPOSE: Overall survival (OS) is the primary end point in phase III oncology trials. Given low success rates, surrogate end points, such as progression-free survival or objective response rate, are used in early go/no-go decision making. Here, we investigate whether early trends of OS prognostic biomarkers, such as the ROPRO and DeepROPRO, can also be used for this purpose. METHODS: Using real-world data, we emulated a series of 12 advanced non-small-cell lung cancer (aNSCLC) clinical trials, originally conducted by six different sponsors and evaluated four different mechanisms, in a total of 19,920 individuals. We evaluated early trends (until 6 months) of the OS biomarker alongside early OS within the joint model (JM) framework. Study-level estimates of early OS and ROPRO trends were correlated against the actual final OS hazard ratios (HRs). RESULTS: We observed a strong correlation between the JM estimates and final OS HR at 3 months (adjusted R2 = 0.88) and at 6 months (adjusted R2 = 0.85). In the leave-one-out analysis, there was a low overall prediction error of the OS HR at both 3 months (root-mean-square error [RMSE] = 0.11) and 6 months (RMSE = 0.12). In addition, at 3 months, the absolute prediction error of the OS HR was lower than 0.05 for three trials. CONCLUSION: We describe a pipeline to predict trial OS HRs using emulated aNSCLC studies and their early OS and OS biomarker trends. The method has the potential to accelerate and improve decision making in drug development.

Anti-CSF-1R emactuzumab in combination with anti-PD-L1 atezolizumab in advanced solid tumor patients naïve or experienced for immune checkpoint blockade.

BACKGROUND: This phase 1b study (NCT02323191) evaluated the safety, antitumor activity, pharmacokinetics, and pharmacodynamics of colony-stimulating factor-1 receptor-blocking monoclonal antibody (mAb) emactuzumab in combination with the programmed cell death-1 ligand (PD-L1)-blocking mAb atezolizumab in patients with advanced solid tumors naïve or experienced for immune checkpoint blockers (ICBs). METHODS: Emactuzumab (500-1350 mg flat) and atezolizumab (1200 mg flat) were administered intravenously every 3 weeks. Dose escalation of emactuzumab was conducted using the 3+3 design up to the maximum tolerated dose (MTD) or optimal biological dose (OBD). Extension cohorts to evaluate pharmacodynamics and clinical activity were conducted in metastatic ICB-naive urothelial bladder cancer (UBC) and ICB-pretreated melanoma (MEL), non-small cell lung cancer (NSCLC) and UBC patients. RESULTS: Overall, 221 patients were treated. No MTD was reached and the OBD was determined at 1000 mg of emactuzumab in combination with 1200 mg of atezolizumab. Grade ≥3 treatment-related adverse events occurred in 25 (11.3%) patients of which fatigue and rash were the most common (14 patients (6.3%) each). The confirmed objective response rate (ORR) was 9.8% for ICB-naïve UBC, 12.5% for ICB-experienced NSCLC, 8.3% for ICB-experienced UBC and 5.6% for ICB-experienced MEL patients, respectively. Tumor biopsy analyses demonstrated increased activated CD8 +tumor infiltrating T lymphocytes (TILs) associated with clinical benefit in ICB-naïve UBC patients and less tumor-associated macrophage (TAM) reduction in ICB-experienced compared with ICB-naïve patients. CONCLUSION: Emactuzumab in combination with atezolizumab demonstrated a manageable safety profile with increased fatigue and skin rash over usual atezolizumab monotherapy. A considerable ORR was particularly seen in ICB-experienced NSCLC patients. Increase ofCD8 +TILs under therapy appeared to be associated with persistence of a TAM subpopulation.

Preclinical Characterization of a Next-Generation Brain Permeable, Paradox Breaker BRAF Inhibitor.

PURPOSE: Disease progression in BRAF V600E/K positive melanomas to approved BRAF/MEK inhibitor therapies is associated with the development of resistance mediated by RAF dimer inducing mechanisms. Moreover, progressing disease after BRAFi/MEKi frequently involves brain metastasis. Here we present the development of a novel BRAF inhibitor (Compound Ia) designed to address the limitations of available BRAFi/MEKi. EXPERIMENTAL DESIGN: The novel, brain penetrant, paradox breaker BRAFi is comprehensively characterized in vitro, ex vivo, and in several preclinical in vivo models of melanoma mimicking peripheral disease, brain metastatic disease, and acquired resistance to first-generation BRAFi. RESULTS: Compound Ia manifested elevated potency and selectivity, which triggered cytotoxic activity restricted to BRAF-mutated models and did not induce RAF paradoxical activation. In comparison to approved BRAFi at clinical relevant doses, this novel agent showed a substantially improved activity in a number of diverse BRAF V600E models. In addition, as a single agent, it outperformed a currently approved BRAFi/MEKi combination in a model of acquired resistance to clinically available BRAFi. Compound Ia presents high central nervous system (CNS) penetration and triggered evident superiority over approved BRAFi in a macro-metastatic and in a disseminated micro-metastatic brain model. Potent inhibition of MAPK by Compound Ia was also demonstrated in patient-derived tumor samples. CONCLUSIONS: The novel BRAFi demonstrates preclinically the potential to outperform available targeted therapies for the treatment of BRAF-mutant tumors, thus supporting its clinical investigation.

Phase 1b study of the BET protein inhibitor RO6870810 with venetoclax and rituximab in patients with diffuse large B-cell lymphoma.

Bromodomain and extraterminal (BET) proteins are transcriptional activators for multiple oncogenic processes in diffuse large B-cell lymphoma (DLBCL), including MYC, BCL2, E2F, and toll-like receptor signaling. We report results of a phase 1b dose-escalation study of the novel, subcutaneous BET inhibitor RO6870810 (RO) combined with the BCL-2 inhibitor venetoclax, and rituximab, in recurrent/refractory DLBCL. RO was delivered for 14 days of a 21-day cycle, whereas venetoclax was delivered continuously. A 3 + 3 escalation design was used to determine the safety of the RO+venetoclax doublet; rituximab was added in later cohorts. Thirty-nine patients were treated with a median of 2.8 cycles (range, 1-11). Dose-limiting toxicities included grade 3 febrile neutropenia, grade 4 diarrhea, and hypomagnesemia for the doublet; and grade 3 hyperbilirubinemia and grade 4 diarrhea when rituximab was added. The doublet maximum tolerated dose (MTD) was determined to be 0.65 mg/kg RO+600 mg venetoclax; for RO+venetoclax+rituximab, the MTDs were 0.45 mg/kg, 600 mg, and 375 mg/m2, respectively. The most frequent grade 3 and 4 adverse events were neutropenia (28%) and anemia and thrombocytopenia (23% each). Responses were seen in all cohorts and molecular subtypes. Sustained decreases in CD11b on monocytes indicated pharmacodynamic activity of RO. Overall response rate according to modified Lugano criteria was 38.5%; 48% of responses lasted for ≥180 days. Complete response was observed in 8 patients (20.5%). Optimization of the treatment schedule and a better understanding of predictors of response would be needed to support broader clinical use. This trial is registered on www.clinicaltrials.gov as NCT03255096.

Deep Learning-based Propensity Scores for Confounding Control in Comparative Effectiveness Research: A Large-scale, Real-world Data Study.

BACKGROUND: Due to the non-randomized nature of real-world data, prognostic factors need to be balanced, which is often done by propensity scores (PSs). This study aimed to investigate whether autoencoders, which are unsupervised deep learning architectures, might be leveraged to compute PS. METHODS: We selected patient-level data of 128,368 first-line treated cancer patients from the Flatiron Health EHR-derived de-identified database. We trained an autoencoder architecture to learn a lower-dimensional patient representation, which we used to compute PS. To compare the performance of an autoencoder-based PS with established methods, we performed a simulation study. We assessed the balancing and adjustment performance using standardized mean differences, root mean square errors (RMSE), percent bias, and confidence interval coverage. To illustrate the application of the autoencoder-based PS, we emulated the PRONOUNCE trial by applying the trial's protocol elements within an observational database setting, comparing two chemotherapy regimens. RESULTS: All methods but the manual variable selection approach led to well-balanced cohorts with average standardized mean differences <0.1. LASSO yielded on average the lowest deviation of resulting estimates (RMSE 0.0205) followed by the autoencoder approach (RMSE 0.0248). Altering the hyperparameter setup in sensitivity analysis, the autoencoder approach led to similar results as LASSO (RMSE 0.0203 and 0.0205, respectively). In the case study, all methods provided a similar conclusion with point estimates clustered around the null (e.g., HRautoencoder 1.01 [95% confidence interval = 0.80, 1.27] vs. HRPRONOUNCE 1.07 [0.83, 1.36]). CONCLUSIONS: Autoencoder-based PS computation was a feasible approach to control for confounding but did not perform better than some established approaches like LASSO.

Long-term clinical activity, safety and patient-reported quality of life for emactuzumab-treated patients with diffuse-type tenosynovial giant-cell tumour.

OBJECTIVES: This study investigated the safety, clinical activity and patient-reported outcomes of patients with diffuse-type tenosynovial giant-cell tumour (dTGCT) of the soft tissue who were treated with emactuzumab, a humanised anti-colony stimulating factor 1 receptor (CSF1R) monoclonal antibody and were followed up for up to 2 years after the start of treatment. METHODS: In this open-label phase 1 study (ClinicalTrials.govNCT01494688), patients received intravenous (IV) emactuzumab from 900 to 2000 mg every two weeks in the dose-escalation phase and at the optimal biological dose of 1000 mg with different schedules in the dose-expansion phase. Adverse event (AE) rates and biomarker assessments from tumour biopsies were analysed. Quality of life was assessed using a standard questionnaire (EuroQol-5D-3L) and the WOMAC® 3.1 Osteoarthritis Index. Tumour responses were determined with magnetic resonance imaging. RESULTS: Altogether, 63 patients were enrolled into the study. The most frequently reported AEs were pruritus, asthenia and oedema. In 36 patients for whom biopsy tissue was available a substantial decrease of CSF1R-positive and CD68/CD163-positive macrophages was detected. The independently reviewed best overall objective response rate (ORR) (Response Evaluation Criteria in Solid Tumors version 1.1) was 71%. Responses were durable, and an ORR of 70% and 64% was determined after one or two years after enrolment into the study. Clinical activity was accompanied by an improvement in EuroQol-5D-3L and particularly the joint disorder-specific WOMAC score. CONCLUSIONS: Systemic therapy of dTGCT patients with emactuzumab resulted in pronounced and durable responses associated with symptomatic improvement and a manageable safety profile.

Phase Ib study of anti-CSF-1R antibody emactuzumab in combination with CD40 agonist selicrelumab in advanced solid tumor patients.

BACKGROUND: This phase Ib study evaluated the safety, clinical activity, pharmacokinetics, and pharmacodynamics (PD) of emactuzumab (anti-colony stimulating factor 1 receptor monoclonal antibody (mAb)) in combination with selicrelumab (agonistic cluster of differentiation 40 mAb) in patients with advanced solid tumors. METHODS: Both emactuzumab and selicrelumab were administered intravenously every 3 weeks and doses were concomitantly escalated (emactuzumab: 500 to 1000 mg flat; selicrelumab: 2 to 16 mg flat). Dose escalation was conducted using the product of independent beta probabilities dose-escalation design. PD analyzes were performed on peripheral blood samples and tumor/skin biopsies at baseline and on treatment. Clinical activity was evaluated using investigator-based and Response Evaluation Criteria In Solid Tumors V.1.1-based tumor assessments. RESULTS: Three dose-limiting toxicities (all infusion-related reactions (IRRs)) were observed at 8, 12 and 16 mg of selicrelumab together with 1000 mg of emactuzumab. The maximum tolerated dose was not reached at the predefined top doses of emactuzumab (1000 mg) and selicrelumab (16 mg). The most common adverse events were IRRs (75.7%), fatigue (54.1%), facial edema (37.8%), and increase in aspartate aminotransferase and creatinine phosphokinase (35.1% both). PD analyzes demonstrated an increase of Ki67+-activated CD8+ T cells accompanied by a decrease of B cells and the reduction of CD14Dim CD16bright monocytes in peripheral blood. The best objective clinical response was stable disease in 40.5% of patients. CONCLUSION: Emactuzumab in combination with selicrelumab demonstrated a manageable safety profile and evidence of PD activity but did not translate into objective clinical responses. TRIALREGISTRATION NUMBER: NCT02760797.

PK/PD Mediated Dose Optimization of Emactuzumab, a CSF1R Inhibitor, in Patients With Advanced Solid Tumors and Diffuse-Type Tenosynovial Giant Cell Tumor.

Targeted biological therapies may achieve maximal therapeutic efficacy at doses below the maximum tolerated dose (MTD); therefore, the search for the MTD in clinical studies may not be ideal for these agents. Emactuzumab is an investigational monoclonal antibody that binds to and inhibits the activation of the cell surface colony-stimulating factor-1 receptor. Here, we show how modeling target-mediated drug disposition coupled with pharmacodynamic end points was used to optimize the dose of emactuzumab without defining an MTD. The model could be used to recommend doses across different disease indications. The approach recommended an optimal biological dose of emactuzumab for dosing every 2 weeks (q2w) ≥ 900 mg, approximately three-fold lower than the highest dose tested clinically. The model predicted that emactuzumab doses ≥ 900 mg q2w would achieve target saturation in excess of 90% over the entire dosing cycle. Subsequently, a dose of 1,000 mg q2w was used in the extension phase of a phase I study of emactuzumab in patients with advanced solid tumors or diffuse-type tenosynovial giant cell tumor. Clinical data from this study were consistent with model predictions. The model was also used to predict the optimum dose of emactuzumab for use with dosing every 3 weeks, enabling dosing flexibility with respect to comedications. In summary, this work demonstrates the value of quantitative clinical pharmacology approaches to dose selection in oncology as opposed to traditional MTD methods.

The PET-Tracer 89Zr-Df-IAB22M2C Enables Monitoring of Intratumoral CD8 T-cell Infiltrates in Tumor-Bearing Humanized Mice after T-cell Bispecific Antibody Treatment.

CD8-expressing T cells are the main effector cells in cancer immunotherapy. Treatment-induced changes in intratumoral CD8+ T cells may represent a biomarker to identify patients responding to cancer immunotherapy. Here, we have used a 89Zr-radiolabeled human CD8-specific minibody (89Zr-Df-IAB22M2C) to monitor CD8+ T-cell tumor infiltrates by PET. The ability of this tracer to quantify CD8+ T-cell tumor infiltrates was evaluated in preclinical studies following single-agent treatment with FOLR1-T-cell bispecific (TCB) antibody and combination therapy of CEA-TCB (RG7802) and CEA-targeted 4-1BB agonist CEA-4-1BBL. In vitro cytotoxicity assays with peripheral blood mononuclear cells and CEA-expressing MKN-45 gastric or FOLR1-expressing HeLa cervical cancer cells confirmed noninterference of the anti-CD8-PET-tracer with the mode of action of CEA-TCB/CEA-4-1BBL and FOLR1-TCB at relevant doses. In vivo, the extent of tumor regression induced by combination treatment with CEA-TCB/CEA-4-1BBL in MKN-45 tumor-bearing humanized mice correlated with intratumoral CD8+ T-cell infiltration. This was detectable by 89Zr-IAB22M2C-PET and γ-counting. Similarly, single-agent treatment with FOLR1-TCB induced strong CD8+ T-cell infiltration in HeLa tumors, where 89Zr-Df-IAB22M2C again was able to detect CD8 tumor infiltrates. CD8-IHC confirmed the PET imaging results. Taken together, the anti-CD8-minibody 89Zr-Df-IAB22M2C revealed a high sensitivity for the detection of intratumoral CD8+ T-cell infiltrates upon either single or combination treatment with TCB antibody-based fusion proteins. These results provide further evidence that the anti-CD8 tracer, which is currently in clinical phase II, is a promising monitoring tool for intratumoral CD8+ T cells in patients treated with cancer immunotherapy. SIGNIFICANCE: Monitoring the pharmacodynamic activity of cancer immunotherapy with novel molecular imaging tools such as 89Zr-Df-IAB22M2C for PET imaging is of prime importance to identify patients responding early to cancer immunotherapy.

Therapeutic targeting of macrophages enhances chemotherapy efficacy by unleashing type I interferon response.

Recent studies have revealed a role for macrophages and neutrophils in limiting chemotherapy efficacy; however, the mechanisms underlying the therapeutic benefit of myeloid-targeting agents in combination with chemotherapy are incompletely understood. Here, we show that targeting tumour-associated macrophages by colony-stimulating factor-1 receptor (CSF-1R) blockade in the K14cre;Cdh1F/F;Trp53F/F transgenic mouse model for breast cancer stimulates intratumoural type I interferon (IFN) signalling, which enhances the anticancer efficacy of platinum-based chemotherapeutics. Notably, anti-CSF-1R treatment also increased intratumoural expression of type I IFN-stimulated genes in patients with cancer, confirming that CSF-1R blockade is a powerful strategy to trigger an intratumoural type I IFN response. By inducing an inflamed, type I IFN-enriched tumour microenvironment and by further targeting immunosuppressive neutrophils during cisplatin therapy, antitumour immunity was activated in this poorly immunogenic breast cancer mouse model. These data illustrate the importance of breaching multiple layers of immunosuppression during cytotoxic therapy to successfully engage antitumour immunity in breast cancer.

Addressing current challenges and future directions in immuno-oncology: expert perspectives from the 2017 NIBIT Foundation Think Tank, Siena, Italy.

A collaborative think tank involving panellists from immuno-oncology networks, clinical/translational investigators and the pharmaceutical industry was held in Siena, Italy, in October 2017 to discuss the evolving immune-oncology landscape, identify selected key challenges, and provide a perspective on the next steps required in the translation of current research and knowledge to clinical reality. While there is a trend of combining new agents (e.g., co-stimulator agonists) with a PD-1/PD-L1 treatment backbone, use of alternative combination therapy approaches should also be considered. While the rapid evolution in systems biology provides a deeper understanding of tumor and tumor microenvironment heterogeneity, there remains the need to identify and define genuinely predictive biomarkers to guide treatment and patient selection. Cross-specialty and cross-sector collaboration, along with a broader collective data-sharing approach are key to optimizing immuno-oncology therapy in clinical practice. Continued support of younger research-clinicians is essential for future success in clinical, translational and basic science investigations.

Rapid activation of tumor-associated macrophages boosts preexisting tumor immunity.

Depletion of immunosuppressive tumor-associated macrophages (TAMs) or reprogramming toward a proinflammatory activation state represent different strategies to therapeutically target this abundant myeloid population. In this study, we report that inhibition of colony-stimulating factor-1 receptor (CSF-1R) signaling sensitizes TAMs to profound and rapid reprogramming in the presence of a CD40 agonist before their depletion. Despite the short-lived nature of macrophage hyperactivation, combined CSF-1R+CD40 stimulation of macrophages is sufficient to create a proinflammatory tumor milieu that reinvigorates an effective T cell response in transplanted tumors that are either responsive or insensitive to immune checkpoint blockade. The central role of macrophages in regulating preexisting immunity is substantiated by depletion experiments, transcriptome analysis of ex vivo sorted TAMs, and gene expression profiling of whole tumor lysates at an early treatment time point. This approach enabled the identification of specific combination-induced changes among the pleiotropic activation spectrum of the CD40 agonist. In patients, CD40 expression on human TAMs was detected in mesothelioma and colorectal adenocarcinoma.

Colony-stimulating factor 1 receptor (CSF1R) inhibitors in cancer therapy.

The tumor-permissive and immunosuppressive characteristics of tumor-associated macrophages (TAM) have fueled interest in therapeutically targeting these cells. In this context, the colony-stimulating factor 1 (CSF1)/colony-stimulating factor 1 receptor (CSF1R) axis has gained the most attention, and various approaches targeting either the ligands or the receptor are currently in clinical development. Emerging data on the tolerability of CSF1/CSF1R-targeting agents suggest a favorable safety profile, making them attractive combination partners for both standard treatment modalities and immunotherapeutic agents. The specificity of these agents and their potent blocking activity has been substantiated by impressive response rates in diffuse-type tenosynovial giant cell tumors, a benign connective tissue disorder driven by CSF1 in an autocrine fashion. In the malignant disease setting, data on the clinical activity of immunotherapy combinations with CSF1/CSF1R-targeting agents are pending. As our knowledge of macrophage biology expands, it becomes apparent that the complex phenotypic and functional properties of macrophages are heavily influenced by a continuum of survival, differentiation, recruitment, and polarization signals within their specific tissue environment. Thus, the role of macrophages in regulating tumorigenesis and the impact of depleting and/or reprogramming TAM as therapeutic approaches for cancer patients may vary greatly depending on organ-specific characteristics of these cells. We review the currently available clinical safety and efficacy data with CSF1/CSF1R-targeting agents and provide a comprehensive overview of ongoing clinical studies. Furthermore, we discuss the local tissue macrophage and tumor-type specificities and their potential impact on CSF1/CSF1R-targeting treatment strategies for the future.

Macrophage Susceptibility to Emactuzumab (RG7155) Treatment.

Blockade of colony-stimulating factor-1 receptor (CSF-1R) enables the therapeutic targeting of tumor-associated macrophages (TAM) in cancer patients. Various CSF-1R inhibitors, mAbs, and tyrosine kinase inhibitors are currently evaluated in early clinical trials. Presence of an alternative survival signal, such as GM-CSF, rescues human monocyte-derived macrophages from CSF-1R inhibitor-induced apoptosis. In this study, we sought to identify additional factors that mediate resistance to CSF-1R-blocking antibody RG7155 (emactuzumab). We investigated the impact of hypoxia, macrophage-polarizing cytokines IL4 and IL10, and genetic alterations within the CSF1R locus and mitochondrial DNA. Among all investigated factors, only IL4 completely rescued viability of RG7155-treated macrophages in vitro This RG7155-resistant population was characterized by a substantially increased mannose receptor-1 (CD206) expression. Analysis of CD206 and the hemoglobin scavenger receptor CD163 expression on normal tissue allowed for discrimination of distinct macrophage populations according to localization and frequency. In emactuzumab-treated cancer patients, we found a significant reduction of CSF-1R, CD204, and CD163 mRNA levels in contrast to a less pronounced decrease of CD206 expression by transcriptome analysis of tumor biopsies. However, we detected in normal skin tissue, which shows lower IL4 mRNA expression compared with melanoma tissue, significant reduction of CD206+ dermal macrophages in RG7155-treated skin biopsies. These results suggest that in cancers where the cytokines IL4 and GM-CSF are sufficiently expressed to induce very high CD206 expression on macrophages, CSF-1R inhibition may not deplete CD206hi TAM. This observation can help to identify those patients most likely to benefit from CSF-1R-targeting agents. Mol Cancer Ther; 15(12); 3077-86. ©2016 AACR.

First-in-human phase I clinical trial of RG7356, an anti-CD44 humanized antibody, in patients with advanced, CD44-expressing solid tumors.

Transmembrane glycoprotein CD44 is overexpressed in various malignancies. Interactions between CD44 and hyaluronic acid are associated with poor prognosis, making CD44 an attractive therapeutic target. We report results from a first-in-human phase I trial of RG7356, a recombinant anti-CD44 immunoglobulin G1 humanized monoclonal antibody, in patients with advanced CD44-expressing solid malignancies.Sixty-five heavily pretreated patients not amenable to standard therapy were enrolled and received RG7356 intravenously biweekly (q2w) or weekly (qw) in escalating doses from 100 mg to 2,250 mg. RG7356 was well tolerated. Most frequent adverse events were fever, headache and fatigue. Dose-limiting toxicities included headache (1,500 mg q2w and 1,350 mg qw) and febrile neutropenia (2,250 mg q2w). The maximum tolerated dose with q2w dosing was 1,500 mg, but was not defined for qw dosing due to early study termination. Clinical efficacy was modest; 13/61 patients (21%) experienced disease stabilization lasting a median of 12 (range, 6-35) weeks. No apparent dose- or dose schedule-dependent changes in biological activity were reported from blood or tissue analyses. Tumor-targeting by positron emission tomography (PET) using 89Zr-labeled RG7356 was observed for doses ≥200 mg (q2w) warranting further investigation of this agent in combination regimens.

CSF1R inhibition with emactuzumab in locally advanced diffuse-type tenosynovial giant cell tumours of the soft tissue: a dose-escalation and dose-expansion phase 1 study.

BACKGROUND: Diffuse-type tenosynovial giant cell tumour (dt-GCT) of the soft tissue (alternatively known as pigmented villonodular synovitis), an orphan disease with unmet medical need, is characterised by an overexpression of colony-stimulating factor 1 (CSF1), and is usually caused by a chromosomal translocation involving CSF1. CSF1 receptor (CSF1R) activation leads to the recruitment of CSF1R-expressing cells of the mononuclear phagocyte lineage that constitute the tumor mass in dt-GCT. Emactuzumab (RG7155) is a novel monoclonal antibody that inhibits CSF1R activation. We have assessed the safety, tolerability and activity of emactuzumab in patients with Dt-GCT of the soft tissue. METHODS: In this phase 1, first-in-human dose-escalation and dose-expansion study, eligible patients were aged 18 years or older with dt-GCT of the soft tissue with locally advanced disease or resectable tumours requiring extensive surgery, an Eastern Cooperative Oncology Group performance status of 1 or less, measurable disease according to Response Evaluation Criteria In Solid Tumors version 1.1, and adequate end-organ function. Patients with GCT of the bone were not eligible. Patients received intravenous emactuzumab at 900 mg, 1350 mg, or 2000 mg every 2 weeks in the dose-escalation phase and at the optimal biological dose in a dose-expansion phase. The primary objective was to evaluate the safety and tolerability of emactuzumab, and to determine the maximum tolerated dose or optimal biological dose. All treated patients were included in the analyses. Expansion cohorts are currently ongoing. This study is registered with ClinicalTrials.gov, number NCT01494688. FINDINGS: Between July 26, 2012, and Oct 21, 2013, 12 patients were enrolled in the dose-escalation phase. No dose-limiting toxicities were noted in the dose-escalation cohort; on the basis of pharmacokinetic, pharmacodynamic, and safety information, we chose a dose of 1000 mg every 2 week for the dose-expansion cohort, into which 17 patients were enrolled. Owing to different cutoff dates for safety and efficacy readouts, the safety population comprised 25 patients. Common adverse events after emactuzumab treatment were facial oedema (16 [64%] of 25 patients), asthenia (14 [56%]), and pruritus (14 [56%]). Five serious adverse events (periorbital oedema, lupus erythematosus [occurring twice], erythema, and dermohypodermitis all experienced by one [4%] patient each) were reported in five patients. Three of the five serious adverse events-periorbital oedema (one [4%]), lupus erythematosus (one [4%]), and dermohypodermitis (one [4%])-were assessed as grade 3. Two other grade 3 events were reported: mucositis (one [4%]) and fatigue (one [4%]). 24 (86%) of 28 patients achieved an objective response; two (7%) patients achieved a complete response. INTERPRETATION: Further study of dt-GCT is warranted and different possibilities, such as an international collaboration with cooperative groups to assure appropriate recruitment in this rare disease, are currently being assessed. FUNDING: F Hoffmann-La Roche.

CSF-1/CSF-1R targeting agents in clinical development for cancer therapy.

Macrophage infiltration has been identified as an independent poor prognostic factor for several cancer entities. In mouse tumor models macrophages orchestrate various tumor-promoting processes. This observation sparked an interest to therapeutically target these plastic innate immune cells. To date, blockade of colony stimulating factor-1 or its receptor represents the only truly selective approach to manipulate macrophages in cancer patients. Here, we discuss the currently available information on efficacy and safety of various CSF-1/CSF-1R inhibitors in cancer patients and highlight potential combination partners emerging from preclinical studies while considering the differences between mouse and human macrophage biology.

Targeting tumor-associated macrophages with anti-CSF-1R antibody reveals a strategy for cancer therapy.

Macrophage infiltration has been identified as an independent poor prognostic factor in several cancer types. The major survival factor for these macrophages is macrophage colony-stimulating factor 1 (CSF-1). We generated a monoclonal antibody (RG7155) that inhibits CSF-1 receptor (CSF-1R) activation. In vitro RG7155 treatment results in cell death of CSF-1-differentiated macrophages. In animal models, CSF-1R inhibition strongly reduces F4/80(+) tumor-associated macrophages accompanied by an increase of the CD8(+)/CD4(+) T cell ratio. Administration of RG7155 to patients led to striking reductions of CSF-1R(+)CD163(+) macrophages in tumor tissues, which translated into clinical objective responses in diffuse-type giant cell tumor (Dt-GCT) patients.

Future of cancer vaccines.

Extensive research in the area of active-specific immunotherapy has led to the approval of the first therapeutic cancer vaccine sipuleucel-T (Provenge™) in 2010. Even though a major milestone for the field of cancer immunotherapy, many obstacles towards successful integration of vaccination strategies into the oncologists' armamentarium remain. This chapter discusses possible future perspectives for cancer vaccines as a treatment modality in oncology with special focus on biomarkers (response prediction and patient selection), requirements for clinical trial design, and combination therapies (standard of care and new molecular entities).Extensive research in the area of active-specific immunotherapy has led to the approval of the first therapeutic cancer vaccine sipuleucel-T (Provenge™) in 2010. Even though a major milestone for the field of cancer immunotherapy, many obstacles towards successful integration of vaccination strategies into the oncologists' armamentarium remain. This chapter discusses possible future perspectives for cancer vaccines as a treatment modality in oncology with special focus on biomarkers (response prediction and patient selection), requirements for clinical trial design, and combination therapies (standard of care and new molecular entities).