Preclinical models to understand the biology and to discover new targets in brain metastases.

PURPOSE OF REVIEW: Incidence of brain metastases increases overtime therefore it is important to rapidly progress in the discovery of new strategies of treatment for these patients. In consequence, more and more preclinical models of brain metastases (BM) are established to study new treatments for melanoma, lung, and breast cancer BM. Here, we reviewed the most recent findings of new drugs assessed in BM mouse preclinical models. RECENT FINDINGS: BM are a common metastatic site of several types of solid cancers and can be difficult to treat due to the unique environment of the brain and the blood-brain barrier. Currently, several preclinical models of BM have been demonstrated that new molecular targeted therapies, small metabolic inhibitors, immunotherapies or a combination of these drugs with radiotherapy lead to a reduction of BM growth and an improvement of mouse survival. SUMMARY: The use of preclinical models of BM is crucial to discover new treatment strategies for patients with BM. In the last years, some new drugs have been highlighted in preclinical models and are now tested in clinical trials including patients with brain metastases.

Molecular oncology: what is needed to speed access to innovative therapies in clinical research?

PURPOSE OF REVIEW: A better understanding of the biology of cancer cells has led in the past 20 years to more and more molecular and immunological driven treatment strategies impacting both clinical trials and day-to-day practice. The aim of this review is to describe new approaches to conduct clinical trials in this area to speed up drug development and increase access to innovation for cancer patients. RECENT FINDINGS: The design of an early phase trial has an impact on its clinical benefit. Trials deriving from a specific biomarker or histologic characteristic (also known as enrichment design) are more likely to demonstrate benefit than trials based on a more conventional design. However, the increase of low incidence cancer molecular subtypes poses a major hurdle in the clinical management and drug development research for cancer patients. SUMMARY: With the identification of news targets and the subsequent introduction of precision medicine, new strategies and tools are needed to provide access to biomarker identification and target-oriented clinical trials to all cancer patients. We propose to set up a new patient-centered model to conduct clinical trials allowing simply to 'bring the trial to the patient'.

Analyses of the Rationale and Implementation of Research Biopsies in Oncology Clinical Trials at a Tertiary Cancer Center.

BACKGROUND: Biomarkers in clinical trials have led to massive incorporation of research biopsies, with potentially risks and no direct benefit for patients. In 2018, the American Society of Clinical Oncology (ASCO) released an ethical framework to provide guidance on incorporating research biopsies in cancer clinical trials. MATERIALS AND METHODS: We collected biopsy requirements of cancer clinical trials conducted at Institut Jules Bordet (IJB) between 2015 and 2019 to examine adherence with the ASCO Ethical Framework. We used logistic regression models to test the association between the request for biopsy, the request for tissue, and the adherence to the ASCO framework as well as some trial characteristics. RESULTS: Between January 2015 and December 2019, 178 oncological studies were conducted at IJB. Of these, 138 (78%) were sponsored by industry, 132 (74%) were phase II and III studies, and 141 (79%) concerned metastatic disease. Tissue was required for inclusion for 119 (67%) studies, among which 59 required at least one new biopsy. Adherence to ASCO's Ethical Framework was 67% for studies requiring tissue and went down to 39% for studies requiring at least one new biopsy. In multivariate analysis, requests for tissue or new biopsies increased in early-phase studies (p < .001, p < .001, respectively) and in studies investigating innovative treatments (immunotherapy or targeted therapies; p < .01, p = .02). Compliance to the ASCO framework significantly decreased with time (p < .001) and in early-phase studies (p < .001). CONCLUSION: Numerous studies required tissue or new biopsies for exploratory objectives of unknown clinical utility. Requests for tissue increased over the years, whereas compliance to ASCO's Ethical Framework decreased. IMPLICATIONS FOR PRACTICE: In 2019, the American Society of Clinical Oncology (ASCO) developed an ethical framework to provide guidance on incorporating research biopsies in clinical trials. This study underlines the growing request for tissue in clinical trials with potentially no impact on drug development and no benefit to actual or future patients. Adherence to ASCO's Ethical Framework decreases through time. These results highlight the importance of improving the ethics of research biopsies. ASCO's Ethical Framework offers an opportunity to improve quality of care in clinical research by maximizing scientific utility and allowing for clinically meaningful correlative science and safe access to innovative treatments for a maximum number of patients.

New horizons in early drugs development in solid cancers.

PURPOSE OF REVIEW: Drug development is the process of bringing new anticancer agents into clinical practice. From the basic research to clinical research each step is essential and intimately linked. The aim of this review is to describe emerging preclinical models and to provide an overview of selected drugs recently developed in oncology. RECENT FINDINGS: Preclinical models reproducing human immune-tumor interactions, 3D cell cultures and microfluidic platforms are of great interest for the development of immunotherapies and combination therapies and offer the opportunity to better understand the interplay between cancer and stromal cells.Following a better biological understanding of cancer and advances in precision oncology, new exciting drugs (e.g. antibodies-drugs conjugates [ADCs], immunotherapeutic strategies, molecular-targeted therapies) have entered the field of clinical research and even clinical practice. SUMMARY: Recent improvements in preclinical models will allow an accurate selection of drug candidates for clinical research. Innovative drugs are currently being developed from early to later phases of development. An important remaining challenge in drug development is to set up a new model of patient-centered clinical research to facilitate quick access to innovation and target-oriented trials.

A Phase 1 dose-escalation study to evaluate safety, pharmacokinetics and pharmacodynamics of AsiDNA, a first-in-class DNA repair inhibitor, administered intravenously in patients with advanced solid tumours.

BACKGROUND: AsiDNA, a first-in-class oligonucleotide-mimicking double-stranded DNA breaks, acts as a decoy agonist to DNA damage response in tumour cells. It also activates DNA-dependent protein kinase and poly (adenosine diphosphate [ADP]-ribose) polymerase enzymes that induce phosphorylation of H2AX and protein PARylation. METHODS: The aim of this Phase 1 study was to determine dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), safety and pharmacokinetics/pharmacodynamics of AsiDNA administered daily for 3 days in the first week then weekly thereafter. Twenty-two patients with advanced solid tumours were enrolled in 5 dose levels: 200, 400, 600, 900, and 1300 mg, using a 3 + 3 design. RESULTS: The MTD was not reached. IV AsiDNA was safe. Two DLTs (grade 4 and grade 3 hepatic enzymes increased at 900 and 1300 mg), and two related SAE at 900 mg (grade 3 hypotension and grade 4 hepatic enzymes increased) were reported. AsiDNA PK increased proportionally with dose. A robust activation of DNA-PK by a significant posttreatment increase of γH2AX was evidenced in tumour biopsies. CONCLUSION: The dose of 600 mg was identified as the optimal dose for further clinical development. CLINICAL TRIAL REGISTRATION: Clinical trial registration (NCT number): NCT03579628.

Targeting molecular subtypes in solid cancers: successes and failures.

PURPOSE OF REVIEW: We herein review some of the major patterns of resistance and lessons learned from the use of earlier targeted therapies in two genotype-driven solid tumors. RECENT FINDINGS: Targeted agents have rapidly expanded in the field of oncology over the past 2 decades. The breakthroughs achieved by these agents have been, however, hindered by the inevitable development of drug resistance. Intrinsic or acquired mechanisms of resistance eventually lead to treatment tolerance and tumoral plasticity with phenotypic switch and evasion of the original targeted pathway. Failures in such therapies also result from poor selectivity of the target, drug delivery, and unaffordable costs. SUMMARY: Based on above findings, collaborative efforts are advancing at the molecular level to design better drugs or combinatorial strategies and to develop more sensitive assays to monitor responses and the emergence of resistance.

Checkpoints inhibitors in the (neo)adjuvant setting of solid tumors: lessons learnt and perspectives.

PURPOSE OF REVIEW: The aim of this review is to provide an overview of the current development of immuno-oncology in the (neo)adjuvant setting. RECENT FINDINGS: Several checkpoint inhibitors (CPis) have been approved for the treatment of advanced solid cancers, mostly for unresectable metastatic setting. Thus, the next logical step is to explore the potential of CPi in earlier stages of the disease. SUMMARY: There are currently many ongoing trials investigating immunotherapy agents in the early setting in various tumor types, involving various CPis and other innovative immunotherapies, as well as combinations with either chemotherapy or radiotherapy. So far, reported results in melanoma, nonsmall-cell lung cancer, and nonmuscle-invasive bladder cancer among others are promising. The neoadjuvant setting offers a high potential for translational research and identification of biomarkers with clinical utility.

How to assimilate the tsunami of immune checkpoints inhibitors data into clinical practice?

PURPOSE OF REVIEW: Immune checkpoint inhibitors (ICIs) are rapidly changing practice across different tumor settings. With this article, we reflect on how to assimilate the tsunami of ICIs data into clinical practice. RECENT FINDINGS: A tremendous increase on approvals, number of publications, and clinical trials ongoing with ICIs on many different tumor types. SUMMARY: ICIs are innovative treatments that are showing a significant benefit on different tumors. More approvals and an explosive increase of knowledge around the usage of ICI are to be expected in the near future, bringing new challenges on how to integrate this fast-growing evidence with ICI into clinical practice. To be updated, oncologists could follow approved guidelines from relevant societies and complement it with an appropriate search from publication databases. There are also some available courses, conferences and online material that are useful to improve knowledge in this so rapidly changing environment. In the future, we believe the integration of artificial intelligence and learning machines will play an important role to facilitate best clinical practices in different fields of medicine but particularly for oncology.

How to emerge from the conservatism in clinical research methodology?

PURPOSE OF REVIEW: Despite recent changes in clinical research methodology, many challenges remain in drug development methodology. RECENT FINDINGS: Advances in molecular biology and cancer treatments have changed the clinical research landscape. Thus, we moved from empirical clinical oncology to molecular and immunological therapeutic approaches. Along with this move, adapted dose-limiting toxicities definitions, endpoints, and dose escalation methods have been proposed. Moreover, the classical frontier between phase I, phase II, and phase III has become unclear in particular for immunological approaches. So, investigators are facing major challenges in drug development methodology. SUMMARY: We propose to individualize clinical research using innovative approaches to significantly improve patient outcomes and targeting what is considered unmet need. Integrating high level of translational research and performing well designed biomarker studies with great potential for clinical practice are of utmost importance. This could be performed within new models of clinical research networks and by building a strong collaboration between academic, cooperative groups, on-site investigators, and pharma.

Inappropriate dose of multitargeted tyrosine kinase inhibitors: the original sin.

PURPOSE OF REVIEW: The use of antiangiogenic tyrosine kinase inhibitors (TKIs) is challenging and often requires dose adaptation and transient or definitive treatment interruption. We believe that the inappropriate recommended dose of TKI is related to no optimal study designs in the early development of the drug. RECENT FINDINGS: As an example of this, we described herein some pitfalls made in the successive development of sunitinib, sorafenib, regorafenib, and pazopanib, but there are several other examples of early drugs development illustrating this issue. SUMMARY: Regarding the antiangiogenic TKI mechanism of action, we strongly feel that innovative approaches are needed such as extended dose-limiting toxicity period or a better definition of the induced toxicity. Furthermore, before classic phase II/III trials, an intermediate step may be needed to better define the recommended phase II dose, such as a randomized phase I/II trial with several expansion cohorts.

First-Line Chemotherapy for Metastatic Esophageal Squamous Cell Carcinoma: Clinico-Biological Predictors of Disease Control.

OBJECTIVE: This study aimed to identify predictors of tumor control (TC) in metastatic esophageal squamous cell carcinoma patients receiving first-line chemotherapy. METHODS: A development cohort of 68 patients from a prospective multicenter trial (NCT01248299) was used to identify predictors of TC at first radiological tumor assessment and to generate a predictive score for TC. That score was applied in an independent retrospective single-center validation cohort of 60 consecutive patients. RESULTS: Multivariate analysis identified three predictors of TC: body mass index ≥18.5 (OR 4.5, 95% CI 0.91-22.5), absence of bone metastasis (OR 4.6, 95% CI 0.91-23.2) and albumin ≥35 g/l (OR 3.5, 95% CI 1.0-12.1). Based on the presence or absence of these three independent prognosticators, we built a predictive model using a score from 0 to 3. In the development cohort, the TC rates were 14.3 and 78.0% and in the validation cohort 12.5 and 44.2%, for scores of 0-1 and 2-3, respectively. With negative predictive values of 85 and 88% in the development and validation cohorts, respectively, we were able to identify patients with a very low probability of TC. CONCLUSION: We have developed and validated a score that can be easily determined at the bedside to predict TC in metastatic esophageal squamous cell carcinoma patients.

Metabolic disorders associated with the use of targeted cancer therapies.

PURPOSE OF REVIEW: The everyday use of targeted therapies, whose mechanisms of action differ from the conventional cytotoxic agents, also causes the emergence of new toxicities as metabolic disorders about which little is known. We propose a systematic literature review of the incidence and physiopathology of targeted therapies-induced metabolic disorders and provide some management guidance. RECENT FINDINGS: In recent decades, significant breakthroughs in molecular oncology and immunology have been made. The administration of targeted therapies and immunotherapy has been associated with metabolic toxicities such as endocrine disorders, dyslipidemia, induced diabetes, and electrolytic disorders. Current data show that metabolic disorders are becoming increasingly common, but rarely life threatening and often reversible with prompt therapeutic intervention. SUMMARY: In the era of targeted therapies, medical oncologists should know the symptoms, carefully monitor patients for potential metabolic disorders, and manage these emerging side-effects with the help of endocrinologists and other medical specialists.

Transient TNF regulates the self-renewing capacity of stem-like label-retaining cells in sphere and skin equivalent models of melanoma.

BACKGROUND: It is well established that inflammation promotes cancer, including melanoma, although the exact mechanisms involved are less known. In this study, we tested the hypothesis that inflammatory factors affect the cancer stem cell (CSC) compartment responsible for tumor development and relapse. RESULTS: Using an inducible histone 2B-GFP fusion protein as a tracer of cell divisional history, we determined that tumor necrosis factor (TNF), which is a classical pro-inflammatory cytokine, enlarged the CSC pool of GFP-positive label-retaining cells (LRCs) in tumor-like melanospheres. Although these cells acquired melanoma stem cell markers, including ABCB5 and CD271, and self-renewal ability, they lost their capacity to differentiate, as evidenced by the diminished MelanA expression in melanosphere cells and the loss of pigmentation in a skin equivalent model of human melanoma. The undifferentiated cell phenotype could be reversed by LY294002, which is an inhibitor of the PI3K/AKT signaling pathway, and this reversal was accompanied by a significant reduction in CSC phenotypic markers and functional properties. Importantly, the changes induced by a transient exposure to TNF were long-lasting and observed for many generations after TNF withdrawal. CONCLUSIONS: We conclude that pro-inflammatory TNF targets the quiescent/slow-cycling melanoma SC compartment and promotes PI3K/AKT-driven expansion of melanoma SCs most likely by preventing their asymmetrical self-renewal. This TNF effect is maintained and transferred to descendants of LRC CSCs and is manifested in the absence of TNF, suggesting that a transient exposure to inflammatory factors imprints long-lasting molecular and/or cellular changes with functional consequences long after inflammatory signal suppression. Clinically, these results may translate into an inflammation-triggered accumulation of quiescent/slow-cycling CSCs and a post-inflammatory onset of an aggressive tumor.

First-In-Human Effects of PPT1 Inhibition Using the Oral Treatment with GNS561/Ezurpimtrostat in Patients with Primary and Secondary Liver Cancers.

Introduction: GNS561/Ezurpimtrostat is a first-in-class, orally bioavailable, small molecule that blocks cancer cell proliferation by inhibiting late-stage autophagy and dose-dependent build-up of enlarged lysosomes by interacting with the palmitoyl-protein thioesterase 1 (PPT1). Methods: This phase I, open-label, dose-escalation trial (3 + 3 design) explored two GNS561 dosing schedules: one single oral intake 3 times a week (Q3W) and twice daily (BID) continuous oral administration in patients with advanced hepatocellular carcinoma, cholangiocarcinoma, and pancreatic adenocarcinoma or colorectal adenocarcinomas with liver metastasis. The primary objective was to determine GNS561 recommended phase II dose (RP2D) and schedule. Secondary objectives included evaluation of the safety/tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of GNS561. Results: Dose escalation ranged from 50 to 400 mg Q3W to 200-300 mg BID. Among 26 evaluable patients for safety, 20 were evaluable for efficacy and no dose-limiting toxicity was observed. Adverse events (AEs) included gastrointestinal grade 1-2 events, primarily nausea and vomiting occurred in 13 (50%) and 14 (54%) patients, respectively, and diarrhea in 11 (42%) patients. Seven grade 3 AEs were reported (diarrhea, decreased appetite, fatigue, alanine aminotransferase, and aspartate aminotransferase increased). Q3W administration was associated with limited exposure and the BID schedule was preferred. At 200 mg BID GNS561, plasma and liver concentrations were comparable to active doses in animal models. Liver trough concentrations were much higher than in plasma a median time of 28 days of administration with a mean liver to plasma ratio of 9,559 (Min 149-Max 25,759), which is in accordance with rat preclinical data observed after repeated administration. PPT1 expression in cancer tissues in the liver was reduced upon GNS561 exposure. There was no complete or partial response. Five patients experienced tumor stable diseases (25%), including one minor response (-23%). Conclusion: Based on a favorable safety profile, exposure, and preliminary signal of activity, oral GNS561 RP2D was set at 200 mg BID. Studies to evaluate the antitumor activity of GNS561 in hepatocarcinoma cells and intrahepatic cholangiocarcinoma are to follow NCT03316222.

Complications related to the placement of an intraventricular chemotherapy device.

Leptomeningeal meningitis occurs in 4-15% of patients with solid tumors. It is a severe disease which seriously affects patients' neurological status and quality of life. Intrathecal chemotherapy increases survival and improves quality of life. Administration of drugs by lumbar puncture causes pain and discomfort, reducing therapeutic compliance. Implantation of an intraventricular catheter fixed to a subcutaneous reservoir overcomes these drawbacks. To evaluate complications compared with implantation of an intraventricular chemotherapy device, between June 2006 and December 2009, 50 patients with a solid tumor underwent implantation of a catheter to treat leptomeningeal metastases. Clinical evaluation of all patients was performed every two weeks and magnetic resonance imaging at one month then every three months. Surgical data (operative time, blood loss) and all clinical and radiological complications were prospectively monitored. All patients underwent surgery with local anesthesia. The mean operative time was 15 min, with no complication during surgery. We report five complications (10%) during the follow-up; three required the removal of the device and another was lethal. There was no case of misplacement or obstruction of the catheter. Intraventricular chemotherapy is an effective treatment procedure which improves therapeutic compliance with acceptable morbidity.

High Prevalence of 5T4/Trophoblast Glycoprotein in Soft Tissue Sarcomas.

The expression of 5T4/trophoblast glycoprotein was evaluated in several histological subtypes of soft tissue sarcoma (STS) to determine whether the prevalence and level of expression of this membrane-associated glycoprotein is sufficient for use in targeted therapies. Tumor tissue microarrays containing cores from different histological subtypes of STS were stained using a standardized immunohistochemical staining method to detect 5T4; the level of staining was assessed using a semi-quantitative scoring method. No 5T4 staining was seen in the angiosarcomas and liposarcomas investigated in this study. 5T4 staining in the other STS subtypes was seen in more than 50% of cases, warranting further investigation into whether this antigen could evoke an anti-tumor immune response or can be used as target for the delivery of more potent toxins through antibody drug conjugates.

Clinical Implications of Body Mass Index in Metastatic Breast Cancer Patients Treated With Abemaciclib and Endocrine Therapy.

BACKGROUND: There are limited data regarding the impact of body mass index (BMI) on outcomes in advanced breast cancer, especially in patients treated with endocrine therapy (ET) + cyclin-dependent kinase 4/6 inhibitors. METHODS: A pooled analysis of individual patient-level data from MONARCH 2 and 3 trials was performed. Patients were classified according to baseline BMI into underweight (<18.5 kg/m2), normal (18.5-24.9 kg/m2), overweight (25-29.9 kg/m2), and obese (≥30 kg/m2) and divided into 2 treatment groups: abemaciclib + ET vs placebo + ET. The primary endpoint was progression-free survival (PFS) according to BMI in each treatment group. Secondary endpoints were response rate, adverse events according to BMI, and loss of weight (≥5% from baseline) during treatment. RESULTS: This analysis included 1138 patients (757 received abemaciclib + ET and 381 placebo + ET). There was no difference in PFS between BMI categories in either group, although normal-weight patients presented a numerically higher benefit with abemaciclib + ET (Pinteraction = .07). Normal and/or underweight patients presented higher overall response rate in the abemaciclib + ET group compared with overweight and/or obese patients (49.4% vs 41.6%, odds ratio = 0.73, 95% confidence interval = 0.54 to 0.99) as well as higher neutropenia frequency (51.0% vs 40.4%, P = .004). Weight loss was more frequent in the abemaciclib + ET group (odds ratio = 3.23, 95% confidence interval = 2.09 to 5.01). CONCLUSIONS: Adding abemaciclib to ET prolongs PFS regardless of BMI, showing that overweight or obese patients also benefit from this regimen. Our results elicit the possibility of a better effect of abemaciclib in normal and/or underweight patients compared with overweight and/or obese patients. More studies analyzing body composition parameters in patients under treatment with cyclin-dependent kinase 4/6 inhibitors may further clarify this hypothesis.

A Phase I Study of an IDO-1 Inhibitor (LY3381916) as Monotherapy and in Combination With an Anti-PD-L1 Antibody (LY3300054) in Patients With Advanced Cancer.

LY3381916 is an orally available, highly selective, potent inhibitor of indoleamine 2,3-dioxygenase 1. This study explored the safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of LY3381916 monotherapy and in combination with a programmed death-ligand 1 (PD-L1) inhibitor (LY3300054) in patients with advanced solid tumors. During dose escalation, patients received escalating doses of LY3381916 at 60-600 mg once daily (qd) and 240 mg twice daily in monotherapy (n=21) and in combination with PD-L1 inhibitor at 700 mg every 2 weeks (n=21). A modified toxicity probability interval method was used to guide dose escalation. Dose-limiting toxicities occurred in 3 patients; 1 at LY3381916 240 mg twice daily (alanine aminotransferase/aspartate aminotransferase increase and systemic inflammatory response syndrome) and 2 at LY3381916 240 mg qd in combination with PD-L1 inhibitor (fatigue and immune-related hepatitis). LY3381916, at the recommended phase II dose, 240 mg qd, in combination with PD-L1 inhibitor, produced maximal inhibition of indoleamine 2,3-dioxygenase 1 activity in plasma and tumor tissue, and led to an increase of CD8 T cells in tumor tissue. In the combination dose expansion cohorts, 14 triple-negative breast cancer and 4 non-small cell lung cancer patients were enrolled. Treatment-related liver toxicity (grade ≥2 alanine aminotransferase/aspartate aminotransferase increase or immune-related hepatitis) was the most prominent adverse event in triple-negative breast cancer patients (n=5, 35.7%). Best response was stable disease. These preliminary data suggest an alternative dose level of LY3381916 is needed for the combination with PD-L1 inhibitor. The combination clinical activity was limited in this study.

Brain Metastasis and Renal Cell Carcinoma: Prognostic Scores Assessment in the Era of Targeted Therapies.

AIM: This study aimed at exploring several brain metastatic prognostic scores in patients with renal cell carcinoma. PATIENTS AND METHODS: We retrospectively analyzed data of 93 metastatic renal cell carcinoma patients who were diagnosed with brain metastases between October 2005 and July 2016 who received targeted therapy. Potential prognostic factors (RTOG RPA, BS-BM, and a newly developed score CERENAL) were analyzed. RESULTS: A total of 75 patients received targeted therapy. All scores showed prognostic value in progression-free survival after first-line treatment with CERENAL being the sole independent prognostic factor associated with improved duration of first-line treatment. Both RTOG RPA and CERENAL were potential prognosticators for overall survival, whereas only the CERENAL score was associated with prolonged disease-specific survival. CONCLUSION: Several prognostic scores can be useful to predict survival of patients with brain metastases from renal cancer, especially the newly developed CERENAL score.