Indications and limitations of chemotherapy and targeted agents in non-small cell lung cancer brain metastases.

Lung cancer is characterized by the highest incidence of solid tumor-related brain metastases, which are reported with a growing incidence during the last decade. Prognostic assessment may help to identify subgroups of patients that could benefit from more aggressive therapy of metastatic disease, in particular when central nervous system is involved. The recent sub-classification of non-small cell lung cancer (NSCLC) into molecularly-defined "oncogene-addicted" tumors, the emergence of effective targeted treatments in molecularly defined patient subsets, global improvement of advanced NSCLC survival as well as the availability of refined new radiotherapy techniques are likely to impact on outcomes of patients with brain dissemination. The present review focuses on key evidence and research strategies for systemic treatment of patients with central nervous system involvement in non-small cell lung cancer.

Maximising the duration of disease control in metastatic renal cell carcinoma with targeted agents: an expert agreement.

With six targeted agents approved (sorafenib, sunitinib, temsirolimus, bevacizumab [+interferon], everolimus and pazopanib), many patients with metastatic renal cell carcinoma (mRCC) will receive multiple therapies. However, the optimum sequencing approach has not been defined. A group of European experts reviewed available data and shared their clinical experience to compile an expert agreement on the sequential use of targeted agents in mRCC. To date, there are few prospective studies of sequential therapy. The mammalian target of rapamycin (mTOR) inhibitor everolimus was approved for use in patients who failed treatment with inhibitors of vascular endothelial growth factor (VEGF) and VEGF receptors (VEGFR) based on the results from a Phase III placebo-controlled study; however, until then, the only licensed agents across the spectrum of mRCC were VEGF(R) inhibitors (sorafenib, sunitinib and bevacizumab + interferon), and as such, a large body of evidence has accumulated regarding their use in sequence. Data show that sequential use of VEGF(R) inhibitors may be an effective treatment strategy to achieve prolonged clinical benefit. The optimal place of each targeted agent in the treatment sequence is still unclear, and data from large prospective studies are needed. The Phase III AXIS study of second-line sorafenib vs. axitinib (including post-VEGF(R) inhibitors) has completed, but the data are not yet published; other ongoing studies include the Phase III SWITCH study of sorafenib-sunitinib vs. sunitinib-sorafenib (NCT00732914); the Phase III 404 study of temsirolimus vs. sorafenib post-sunitinib (NCT00474786) and the Phase II RECORD 3 study of sunitinib-everolimus vs. everolimus-sunitinib (NCT00903175). Until additional data are available, consideration of patient response and tolerability to treatment may facilitate current decision-making regarding when to switch and which treatment to switch to in real-life clinical practice.

An Innovative Phase I Trial Design Allowing for the Identification of Multiple Potential Maximum Tolerated Doses with Combination Therapy of Targeted Agents

Treatment for cancer often involves combination therapies used both in medical practice and clinical trials. Korn and Simon listed three reasons for the utility of combinations: 1) biochemical synergism, 2) differential susceptibility of tumor cells to different agents, and 3) higher achievable dose intensity by exploiting non-overlapping toxicities to the host. Even if the toxicity profile of each agent of a given combination is known, the toxicity profile of the agents used in combination must be established. Thus, caution is required when designing and evaluating trials with combination therapies. Traditional clinical design is based on the consideration of a single drug. However, a trial of drugs in combination requires a dose-selection procedure that is vastly different than that needed for a single-drug trial. When two drugs are combined in a phase I trial, an important trial objective is to determine the maximum tolerated dose (MTD). The MTD is defined as the dose level below the dose at which two of six patients experience drug-related dose-limiting toxicity (DLT). In phase I trials that combine two agents, more than one MTD generally exists, although all are rarely determined. For example, there may be an MTD that includes high doses of drug A with lower doses of drug B, another one for high doses of drug B with lower doses of drug A, and yet another for intermediate doses of both drugs administered together. With classic phase I trial designs, only one MTD is identified. Our new trial design allows identification of more than one MTD efficiently, within the context of a single protocol. The two drugs combined in our phase I trial are temsirolimus and bevacizumab. Bevacizumab is a monoclonal antibody targeting the vascular endothelial growth factor (VEGF) pathway which is fundamental for tumor growth and metastasis. One mechanism of tumor resistance to antiangiogenic therapy is upregulation of hypoxia inducible factor 1α (HIF-1α) which mediates responses to hypoxic conditions. Temsirolimus has resulted in reduced levels of HIF-1α making this an ideal combination therapy. Dr. Donald Berry developed a trial design schema for evaluating low, intermediate and high dose levels of two drugs given in combination as illustrated in a recently published paper in Biometrics entitled “A Parallel Phase I/II Clinical Trial Design for Combination Therapies.” His trial design utilized cytotoxic chemotherapy. We adapted this design schema by incorporating greater numbers of dose levels for each drug. Additional dose levels are being examined because it has been the experience of phase I trials that targeted agents, when given in combination, are often effective at dosing levels lower than the FDA-approved dose of said drugs. A total of thirteen dose levels including representative high, intermediate and low dose levels of temsirolimus with representative high, intermediate, and low dose levels of bevacizumab will be evaluated. We hypothesize that our new trial design will facilitate identification of more than one MTD, if they exist, efficiently and within the context of a single protocol. Doses gleaned from this approach could potentially allow for a more personalized approach in dose selection from among the MTDs obtained that can be based upon a patient’s specific co-morbid conditions or anticipated toxicities.

A prospective study on the early evaluation of response to androgen receptor-targeted agents with 11C-Choline, 68Ga-PSMA and 18F-FACBC PET in metastatic castration-resistant prostate cancer: a single center experience.

Background: The early identification of responsive and resistant patients to androgen-receptor targeting agents (ARTA) in metastatic castration resistant-prostate cancer (CRPC) is not completely possible with PSA assessment and conventional imaging. Considering its ability to determine metabolic activity of lesions, PET assessment might be a promising tool. Materials and methods: We performed a monocentric prospective study in patients with metastatic CRPC under treatment with ARTA to evaluate the role of different PET radiotracers: 49 patients were randomized to receive 11C-Choline, 18F-FACBC or 68Ga-PSMA PET, one scan before therapy onset and one two months later. The primary aim was to investigate the performance of three different novel PET radiotracers for the early evaluation of response to ARTA in metastatic CRPC patients; with regards to this aim, the outcome evaluated was biochemical response (PSA reduction ≥50%). The secondary aim was to investigate the prognostic role of several semiquantitative PET parameters and their variations with the different radiotracers in terms of biochemical PFS (bPFS) and overall survival (OS). The study was promoted by the Italian Department of Health (code RF-2016-02364809). Results: With regards to the primary endpoint, at univariate analysis a statistically significant correlation was found between MTV_VARIATION% (p=0.018) and TLA_VARIATION% (p=0.025) with 68Ga-PSMA PET and biochemical response. As for the secondary endpoints, significant correlations with bPFS were found for 68Ga-PSMA PET MTV_TOT_PET1 (p=0.001), TLA_TOT_PET1 (p=0.025), MTV_VARIATION% (p=0.031). For OS, statistically significant correlations were found for: MAJ_SUV_MAX_PET1 with 11C-Choline PET (p=0.007); MTV_TOT_PET1 (p=0.004), MAJ_SUV_MAX_PET1 (p=0.029), SUVMAX_VARIATION% (p=0.04), MTV_VARIATION% (p=0.015), TLA_VARIATION% (p=0.03) with 68Ga-PSMA PET,; MTV_TOT_PET1 (p=0.011), TLA_TOT_PET1 (p=0.009), MAJ_SUV_MAX_PET1 (p=0.027), MTV_VARIATION% (p=0.048) with 18F-FACBC. Conclusions: Our prospective study highlighted that several 68Ga-PSMA and 18F-FACBC semiquantitative PET parameters and their variations present a prognostic value in terms of OS and bPFS and a correlation with biochemical response, that could help to assess response to ARTA.

Successes and limitations of targeted therapies in renal cell carcinoma.

Until recently, the standard treatment for metastatic renal cell carcinoma (RCC) was nonspecific immunotherapy based on interleukin-2 or interferon-α. This was associated with a modest survival benefit and with significant clinical toxicities. The understanding of numerous molecular pathways in RCC, including HIF, VEGF, mTOR, and the consecutive use of targeted therapies since the beginning of 2005 have significantly improved outcomes for patients with metastatic RCC with an overall survival greater than 2 years. At present, at least 7 targeted agents are approved for first and consecutive lines of treatment of clear cell metastatic RCC. Long-term benefit and extended survival may be achieved through the optimal use of targeted therapies: optimal dosing, adverse event management and treatment duration and compliance. Advances in the finding of prognostic factors highlight the potential for personalizing treatment for patients with metastatic RCC. Data regarding the best sequencing of targeted therapies, predictive biomarkers, best timing of surgery, patient risk profiles, understanding of resistance mechanisms and safety of targeted therapies are growing and will provide a further step ahead in the management of advanced RCC. In parallel, a new class of therapeutics is emerging in RCC: immunotherapy; in particular check-point blockade antibodies are showing very promising results.

Efficacy of PI3K pathway inhibitors as single agents in metastatic breast cancer

L’objectiu del cribatge molecular és seleccionar pacients que es beneficiïn especialment de teràpies dirigides. S’analitza l’activitat en monoteràpia de fàrmacs inhibidors de la via de PI3K/AKT/mTOR (PI3Ki) en pacients amb càncer de mama metastàtic (CMM) i s’exploren potencials predictors de benefici clínic. La mitjana de temps a la progressió és de 2.6 mesos en 38 pacients incloses. No existeix correlació entre alteracions de la via i l’eficàcia, excepte en pacients amb mutació de PIK3CA que van millor al tractar-se amb un PI3Ki alfa-especific. Aquests resultats emfatitzen la necessitat d’un adequat cribatge molecular previ al tractament amb teràpies dirigides en CMM

Advances in targeted therapies for hepatocellular carcinoma in the genomic era

Mortality owing to liver cancer has increased in the past 20 years, and the latest estimates indicate that the global health burden of this disease will continue to grow. Most patients with hepatocellular carcinoma (HCC) are still diagnosed at intermediate or advanced disease stages, where curative approaches are often not feasible. Among the treatment options available, the molecular targeted agent sorafenib is able to significantly increase overall survival in these patients. Thereafter, up to seven large, randomized phase III clinical trials investigating other molecular therapies in the first-line and second-line settings have failed to improve on the results observed with this agent. Potential reasons for this include intertumour heterogeneity, issues with trial design and a lack of predictive biomarkers of response. During the past 5 years, substantial advances in our knowledge of the human genome have provided a comprehensive picture of commonly mutated genes in patients with HCC. This knowledge has not yet influenced clinical decision-making or current clinical practice guidelines. In this Review the authors summarize the molecular concepts of progression, discuss the potential reasons for clinical trial failure and propose new concepts of drug development, which might lead to clinical implementation of emerging targeted agents.

Predictive Value Of Phase I Trials For Safety In Later Trials And Final Approved Dose: Analysis Of 61 Approved Cancer Drugs.

Phase I trials use a small number of patients to define a maximum tolerated dose (MTD) and the safety of new agents. We compared data from phase I and registration trials to determine whether early trials predicted later safety and final dose. We searched the U.S. Food and Drug Administration (FDA) website for drugs approved in nonpediatric cancers (January 1990-October 2012). The recommended phase II dose (R2PD) and toxicities from phase I were compared with doses and safety in later trials. In 62 of 85 (73%) matched trials, the dose from the later trial was within 20% of the RP2D. In a multivariable analysis, phase I trials of targeted agents were less predictive of the final approved dose (OR, 0.2 for adopting ± 20% of the RP2D for targeted vs. other classes; P = 0.025). Of the 530 clinically relevant toxicities in later trials, 70% (n = 374) were described in phase I. A significant relationship (P = 0.0032) between increasing the number of patients in phase I (up to 60) and the ability to describe future clinically relevant toxicities was observed. Among 28,505 patients in later trials, the death rate that was related to drug was 1.41%. In conclusion, dosing based on phase I trials was associated with a low toxicity-related death rate in later trials. The ability to predict relevant toxicities correlates with the number of patients on the initial phase I trial. The final dose approved was within 20% of the RP2D in 73% of assessed trials.

Systematic identification of genomic markers of drug sensitivity in cancer cells.

Clinical responses to anticancer therapies are often restricted to a subset of patients. In some cases, mutated cancer genes are potent biomarkers for responses to targeted agents. Here, to uncover new biomarkers of sensitivity and resistance to cancer therapeutics, we screened a panel of several hundred cancer cell lines--which represent much of the tissue-type and genetic diversity of human cancers--with 130 drugs under clinical and preclinical investigation. In aggregate, we found that mutated cancer genes were associated with cellular response to most currently available cancer drugs. Classic oncogene addiction paradigms were modified by additional tissue-specific or expression biomarkers, and some frequently mutated genes were associated with sensitivity to a broad range of therapeutic agents. Unexpected relationships were revealed, including the marked sensitivity of Ewing's sarcoma cells harbouring the EWS (also known as EWSR1)-FLI1 gene translocation to poly(ADP-ribose) polymerase (PARP) inhibitors. By linking drug activity to the functional complexity of cancer genomes, systematic pharmacogenomic profiling in cancer cell lines provides a powerful biomarker discovery platform to guide rational cancer therapeutic strategies.

MET: a promising anticancer therapeutic target.

The MET pathway is dysregulated in many human cancers and promotes tumour growth, invasion and dissemination. Abnormalities in MET signalling have been reported to correlate with poor clinical outcomes and drug resistance in patients with cancer. Thus, MET has emerged as an attractive target for cancer therapy. Several MET inhibitors have been introduced into the clinic, and are currently in all phases of clinical trials. In general, initial results from these studies indicate only a modest benefit in unselected populations. In this Review, we discuss current challenges in developing MET inhibitors--including identification of predictive biomarkers--as well as the most-efficient ways to combine these drugs with other targeted agents or with classic chemotherapy or radiotherapy.

Molecular neuro-oncology in clinical practice: a new horizon.

Primary brain tumours are heterogeneous in histology, genetics, and outcome. Although WHO's classification of tumours of the CNS has greatly helped to standardise diagnostic criteria worldwide, it does not consider the substantial progress that has been made in the molecular classification of many brain tumours. Recent practice-changing clinical trials have defined a role for routine assessment of MGMT promoter methylation in glioblastomas in elderly people, and 1p and 19q codeletions in anaplastic oligodendroglial tumours. Moreover, large-scale molecular profiling approaches have identified new mutations in gliomas, affecting IDH1, IDH2, H3F3, ATRX, and CIC, which has allowed subclassification of gliomas into distinct molecular subgroups with characteristic features of age, localisation, and outcome. However, these molecular approaches cannot yet predict patients' benefit from therapeutic interventions. Similarly, transcriptome-based classification of medulloblastoma has delineated four variants that might now be candidate diseases in which to explore novel targeted agents.

Optimising translational oncology in clinical practice: Strategies to accelerate progress in drug development.

Despite intense efforts, the socioeconomic burden of cancer remains unacceptably high and treatment advances for many common cancers have been limited, suggesting a need for a new approach to drug development. One issue central to this lack of progress is the heterogeneity and genetic complexity of many tumours. This results in considerable variability in therapeutic response and requires knowledge of the molecular profile of the tumour to guide appropriate treatment selection for individual patients. While recent advances in the molecular characterisation of different cancer types have the potential to transform cancer treatment through precision medicine, such an approach presents a major economic challenge for drug development, since novel targeted agents may only be suitable for a small cohort of patients. Identifying the patients who would benefit from individual therapies and recruiting sufficient numbers of patients with particular cancer subtypes into clinical trials is challenging, and will require collaborative efforts from research groups and industry in order to accelerate progress. A number of molecular screening platforms have already been initiated across Europe, and it is hoped that these networks, along with future collaborations, will benefit not only patients but also society through cost reductions as a result of more efficient use of resources. This review discusses how current developments in translational oncology may be applied in clinical practice in the future, assesses current programmes for the molecular characterisation of cancer and describes possible collaborative approaches designed to maximise the benefits of translational science for patients with cancer.

Chemotherapy for castration-resistant prostate cancer

The development and use of chemotherapy for patients with prostate cancer was slow and modest in comparison with other solid tumor sites. While many cytotoxic agents and multiple drug combinations were tested during the 1980, the first recognized drug for men with metastatic castration-resistant prostate cancer (mCRPC) was mitoxantrone combined with prednisone in 1996. Mitoxantrone showed an improvement in quality of life and pain compared to men treated with prednisone alone. In 2004, two randomized controlled trials found docetaxel superior to mitoxantrone in PSA response and survival. Despite the somewhat higher side effect rate, quality of life and pain were also improved with docetaxel. Unfortunately only about every second man benefits from this treatment and there are no approved criteria to select patients with better chances of response. It takes about 3 months of treatment to identify non-responders and all patients will ultimately progress and most of them will die of prostate cancer. Many men with mCRPC were treated with mitoxantrone after progression on docetaxel without a strong evidence for such a choice. More recently, the benefit of a second-line chemotherapy was addressed within a randomized controlled trial. A new taxane, cabazitaxel, was found superior to mitoxantrone in terms of overall survival despite the previous treatment with docetaxel and therefore recently approved in this indication. The most important challenges and opportunities for future studies will be the combination of chemotherapy with hormonal or non-hormonal targeted agents, the establishment of treatment algorithms to best sequence docetaxel and cabazitaxel and non-cytotoxic agents. Patient selection criteria as well as early biomarkers of response or resistance would also be important for patients and clinicians. Toxicity and quality of life are particular important aspects of drug development in current and future studies which aim to improve treatment options in this frequently elderly patient population.

Strategies for improving outcomes in NSCLC: a look to the future.

Advances in the management of non-small cell lung cancer (NSCLC) over the past 30 years have led to small increases in 5-year survival rates across Europe, though further improvements may require new treatment strategies. In order to improve efficiency and reduce the cost of development, future trials for new targeted agents in NSCLC should aim to recruit patients on the basis of tumour biology rather than clinical characteristics. However, identification of predictive biomarkers is required to maximise the benefits of new approaches and expedite the drug development process. Nevertheless, the NSCLC landscape is changing rapidly, and recent improvements in our understanding of the molecular biology of the disease will help in the identification of novel targeted agents as well as assisting in the development of personalised strategies for the numerous small subsets of defined NSCLC. Progress in imaging and treatment delivery is also likely to improve outcomes for patients with the disease. This article outlines recent progress in the treatment of NSCLC, identifies current challenges and describes proposals for improving the future management of the disease. It is hoped that implementation of some of these strategies will go some way to improving the outlook for patients with NSCLC.

Brain metastasis: opportunity for drug development?

PURPOSE OF REVIEW: Brain metastases are a common clinical problem, and only limited treatment options exist. We review recent advances in medical brain metastasis research with a focus on the most common tumor types associated with secondary brain colonization: melanoma, breast cancer and lung cancer. We speculate on opportunities for drug development in patients with brain metastases, both as a treatment of established disease and as an adjuvant and prophylactic strategy. RECENT FINDINGS: BRAF inhibitors and the immunomodulatory anticytotoxic T-lymphocyte-associated antigen 4 antibody ipilimumab have shown clinically meaningful activity in melanoma patients with brain metastases. In breast cancer, current studies on drug treatment of brain metastases are mainly focusing on human epidermal growth factor receptor 2 targeting agents such as lapatinib. Emerging data seem to implicate a potential role of targeted agents including antiangiogenic compounds, pazopanib, and epithelial growth factor receptor inhibitors for prevention of brain metastasis formation in breast cancer or nonsmall cell lung cancer. SUMMARY: Novel drugs are beginning to enter clinical practice for selected patients with brain metastases. The promising findings from recent studies may fuel more research on brain metastases and their optimal drug treatment.