Addressing the dichotomy between individual and societal approaches to personalised medicine in oncology.

Academic, industry, regulatory leaders and patient advocates in cancer clinical research met in November 2018 at the Innovation and Biomarkers in Cancer Drug Development meeting in Brussels to address the existing dichotomy between increasing calls for personalised oncology approaches based on individual molecular profiles and the need to make resource and regulatory decisions at the societal level in differing health-care delivery systems around the globe. Novel clinical trial designs, the utility and limitations of real-world evidence (RWE) and emerging technologies for profiling patient tumours and tumour-derived DNA in plasma were discussed. While randomised clinical trials remain the gold standard approach to defining clinical utility of local and systemic therapeutic interventions, the broader adoption of comprehensive tumour profiling and novel trial designs coupled with RWE may allow patient and physician autonomy to be appropriately balanced with broader assessments of safety and overall societal benefit.

Global Development of Anticancer Therapies for Rare Cancers, Pediatric Cancers, and Molecular Subtypes of Common Cancers.

Advances in genetic sequencing and other diagnostic technologies have enabled the use of precision medicine in clinical cancer care, as well as the development of novel therapies that are targeted to specific molecular drivers of cancer. Developing these new agents and making them accessible to patients requires global clinical studies and regulatory review and approval by different national regulatory agencies. Whereas these global trials present challenges for drug developers who conduct them and regulatory agencies who oversee them, they also raise practical issues about patients with low-frequency cancers who need these therapies. A lack of uniform standards in both regulatory approval for marketing and reimbursement for approved agents across countries may make the newly developed agent either unavailable or inaccessible to patients in certain countries or regions, even if patients from those countries or regions participated in the clinical research that established the safety and efficacy of the agent. In an effort to further understand and address this need, we convened an international workshop in 2017 in North Bethesda, MD. After presentations of the individual regulatory pathways for marketing approval and reimbursement for individual nations, participants discussed expedited pathways and specific challenges for uncommon cancers. As a matter of justice, agents being developed for rare cancers, pediatric cancers, or uncommon molecular subsets of common cancers need a pragmatic, science-based regulatory policy framework to clearly specify the type and quantity of evidence needed to demonstrate efficacy from these trials and evidence to support accessibility.

The development of immunomodulatory monoclonal antibodies as a new therapeutic modality for cancer: the Bristol-Myers Squibb experience.

The discovery and increased understanding of the complex interactions regulating the immune system have contributed to the pharmacologic activation of antitumor immunity. The activity of effector cells, such as T and NK cells, is regulated by an array of activating and attenuating receptors and ligands. Agents that target these molecules can modulate immune responses by exerting antagonistic or agonistic effects. Several T- or NK-cell modulators have entered clinical trials, and two have been approved for use. Ipilimumab (Yervoy®, Bristol-Myers Squibb) and nivolumab (OPDIVO, Ono Pharmaceutical Co., Ltd./Bristol-Myers Squibb) were approved for the treatment of metastatic melanoma, in March 2011 in the United States, and in July 2014 in Japan, respectively. The clinical activity of these two antibodies has not been limited to tumor types considered sensitive to immunotherapy, and promising activity has been reported in other solid and hematologic tumors. Clinical development of ipilimumab and nivolumab has presented unique challenges in terms of safety and efficacy, requiring the establishment of new evaluation criteria for adverse events and antitumor effects. Guidelines intended to help oncologists properly manage treatment in view of these non-traditional features have been implemented. The introduction of this new modality of cancer treatment, which is meant to integrate with or replace the current standards of care, requires additional efforts in terms of optimization of treatment administration, identification of biomarkers and application of new clinical trial designs. The availability of immune modulators with different mechanisms of action offers the opportunity to establish immunological combinations as new standards of care.

Expanding public-private collaborations to enhance cancer drug development: a report of the Institute of Medicine's workshop series, "Implementing a National Cancer Clinical Trials System for the 21st Century".

Since their inception in the 1950s, the National Cancer Institute-funded cancer cooperative groups have been important contributors to cancer clinical and translational research. In 2010, a committee appointed by the Institute of Medicine (IOM) of the National Academy of Sciences completed a consensus review on the status of the U.S. publicly funded cancer clinical trials system. This report identified a need to reinvigorate the cooperative groups and provided recommendations for improving their effectiveness. Follow-up workshops to monitor progress were conducted by the IOM's National Cancer Policy Forum and the American Society of Clinical Oncology (ASCO) in 2011 and 2013. One of the key recommendations of the IOM report was a call for greater collaboration among stakeholders in cancer research. In particular, more active engagement and better alignment of incentives among the cooperative groups, the National Cancer Institute, the U.S. Food and Drug Administration, and the biopharmaceutical industry were identified as essential to achieving the promise of oncology drug development. This review, based on presentations and discussion during the IOM-ASCO workshops, outlines the progress and remaining challenges of these collaborations.

Development of other microtubule-stabilizer families: the epothilones and their derivatives.

Chemotherapy is the mainstay of treatment for numerous cancer types, but resistance to chemotherapy remains a major clinical issue and is one of the driving influences underlying the development of new anticancer medications. One of the most important classes of chemotherapy agents is the taxanes, which target the cytoskeleton and spindle apparatus of tumor cells by binding to the microtubules, thereby disrupting key cellular mechanisms, including mitosis. Taxane resistance, however, limits treatment options and creates a major challenge for clinicians. Ongoing research has identified several newer classes of microtubule-targeting chemotherapies that may retain activity despite clinical resistance to taxanes. Among these classes, the epothilones have been studied most extensively in the clinical setting. Like taxanes, epothilones stabilize microtubulin turnover, and they have properties favoring their development as anticancer agents. The most clinically advanced epothilone analog is ixabepilone, which is currently the only approved epothilone derivative. Ixabepilone is indicated for the treatment of metastatic or locally advanced breast cancer in combination with capecitabine after failure of an anthracycline and a taxane, or as monotherapy after failure of an anthracycline, a taxane, and capecitabine. In phase II and III trials, ixabepilone showed efficacy in several patient subgroups and in various stages of breast cancer. Common adverse reactions include peripheral sensory neuropathy and asthenia. This paper will discuss the preclinical and clinical development of epothilones and their derivatives across a variety of cancer types.

An audit strategy for time-to-event outcomes measured with error: application to five randomized controlled trials in oncology.

BACKGROUND: Measurement error in time-to-event end points complicates interpretation of treatment effects in clinical trials. Non-differential measurement error is unlikely to produce large bias [1]. When error depends on treatment arm, bias is of greater concern. Blinded-independent central review (BICR) of all images from a trial is commonly undertaken to mitigate differential measurement-error bias that may be present in hazard ratios (HRs) based on local evaluations. Similar BICR and local evaluation HRs may provide reassurance about the treatment effect, but BICR adds considerable time and expense to trials. METHODS: We describe a BICR audit strategy [2] and apply it to five randomized controlled trials to evaluate its use and to provide practical guidelines. The strategy requires BICR on a subset of study subjects, rather than a complete-case BICR, and makes use of an auxiliary-variable estimator. RESULTS: When the effect size is relatively large, the method provides a substantial reduction in the size of the BICRs. In a trial with 722 participants and a HR of 0.48, an average audit of 28% of the data was needed and always confirmed the treatment effect as assessed by local evaluations. More moderate effect sizes and/or smaller trial sizes required larger proportions of audited images, ranging from 57% to 100% for HRs ranging from 0.55 to 0.77 and sample sizes between 209 and 737. LIMITATIONS: The method is developed for a simple random sample of study subjects. In studies with low event rates, more efficient estimation may result from sampling individuals with events at a higher rate. CONCLUSION: The proposed strategy can greatly decrease the costs and time associated with BICR, by reducing the number of images undergoing review. The savings will depend on the underlying treatment effect and trial size, with larger treatment effects and larger trials requiring smaller proportions of audited data.

Accelerating cancer therapy development: the importance of combination strategies and collaboration. Summary of an Institute of Medicine workshop.

Cancer cells contain multiple genetic changes in cell signaling pathways that drive abnormal cell survival, proliferation, invasion, and metastasis. Unfortunately, patients treated with single agents inhibiting only one of these pathways--even if showing an initial response--often develop resistance with subsequent relapse or progression of their cancer, typically via the activation of an alternative uninhibited pathway. Combination therapies offer the potential for inhibiting multiple targets and pathways simultaneously to more effectively kill cancer cells and prevent or delay the emergence of drug resistance. However, there are many unique challenges to developing combination therapies, including devising and applying appropriate preclinical tests and clinical trial designs, prioritizing which combination therapies to test, avoiding overlapping toxicity of multiple agents, and overcoming legal, cultural, and regulatory barriers that impede collaboration among multiple companies, organizations, and/or institutions. More effective strategies to efficiently develop combination cancer therapies are urgently needed. Thus, the Institute of Medicine's National Cancer Policy Forum recently convened a workshop with the goal of identifying barriers that may be impeding the development of combination investigational cancer therapies, as well as potential solutions to overcome those barriers, improve collaboration, and ultimately accelerate the development of promising combinations of investigational cancer therapies.

Development of ipilimumab: contribution to a new paradigm for cancer immunotherapy.

Identification of cytotoxic T-lymphocyte antigen-4 (CTLA-4) as a key negative regulator of T-cell activity led to development of the fully human, monoclonal antibody ipilimumab to block CTLA-4 and potentiate antitumor T-cell responses. Animal studies first provided insight into the ability of an anti-CTLA-4 antibody to cause tumor regression, particularly in combination regimens. Early clinical studies defined ipilimumab pharmacokinetics and possibilities for combinability. Phase II trials of ipilimumab in advanced melanoma showed objective responses, but a greater number of patients had disease stabilization. In a phase III trial, ipilimumab was the first agent to demonstrate an improvement in overall survival in patients with previously treated, advanced melanoma. The adverse event profile associated with ipilimumab was primarily immune-related. Adverse events can be severe and life-threatening, but most were reversible using treatment guidelines. Ipilimumab monotherapy exhibits conventional and new patterns of activity in advanced melanoma, with a delayed separation of Kaplan-Meier survival curves. The observation of some new response patterns with ipilimumab, which are not captured by standard response criteria, led to novel criteria for the evaluation of immunotherapy in solid tumors. Overall, lessons from the development of ipilimumab contributed to a new clinical paradigm for cancer immunotherapy evolved by the Cancer Immunotherapy Consortium.

Selection of response criteria for clinical trials of sarcoma treatment.

Soft tissue sarcomas are a heterogeneous group of malignancies arising from mesenchymal tissues. A large number of new therapies are being evaluated in patients with sarcomas, and consensus criteria defining treatment responses are essential for comparison of results from studies completed by different research groups. The 1979 World Health Organization (WHO) handbook set forth operationally defined criteria for response evaluation in solid tumors that were updated in 2000 with the publication of the Response Evaluation Criteria in Solid Tumors (RECIST). There have been significant advances in tumor imaging, however, that are not reflected in the RECIST. For example, computed tomography (CT) slice thickness has been reduced from 10 mm to < or =2.5 mm, allowing for more reproducible and accurate measurement of smaller lesions. Combination of imaging techniques, such as positron emission tomography with fluorine-18-fluorodeoxyglucose (18FDG-PET) and CT can provide investigators and clinicians with both anatomical and functional information regarding tumors, and there is now a large body of evidence demonstrating the effectiveness of PET/CT and other newer imaging methods for the detection and staging of tumors as well as early determination of responses to therapy. The application of newer imaging methods has the potential to decrease both the sample sizes required for, and duration of, clinical trials by providing an early indication of therapeutic response that is well correlated with clinical outcomes, such as time to tumor progression or overall survival. The results summarized in this review support the conclusion that the RECIST and the WHO criteria for evaluation of response in solid tumors need to be modernized. In addition, there is a current need for prospective trials to compare new response criteria with established endpoints and to validate imaging-based response rates as surrogate endpoints for clinical trials of new agents for sarcoma and other solid tumors.

Apoptotic pathways of epothilone BMS 310705.

OBJECTIVE: BMS 310705 is a novel water-soluble analog of epothilone B currently in phase I clinical evaluation in the treatment of malignancies such as ovarian, renal, bladder, and lung carcinoma. Using an early passage cell culture model derived from the ascites of a patient clinically refractory to platinum/paclitaxel therapy, we evaluated the pathway of caspase-mediated apoptosis. METHODS: Cells were treated for 1 h and subsequently evaluated for apoptosis, survival, and caspase activity. Apoptosis was determined by fluorescent microscopy. Caspase-3, -8, and -9 activities were determined by fluorometry using target tetrapeptide substrates. Mitochondrial release of cytochrome c was determined by immunoblot analysis. RESULTS: After treatment with BMS 310705, apoptosis was confirmed in >25% of cells at 24 h. Survival was significantly lower (P < 0.02) in cells treated with 0.05 micro M BMS 310705 vs paclitaxel. Analysis revealed an increase of caspase-9 and -3 activity; no caspase -8 activity was observed. Release of cytochrome c was detected at 12 h following treatment. SN-38 and topotecan failed to induce apoptosis. CONCLUSIONS: BMS 310705 induces significant apoptosis, decreases survival, and utilizes the mitochondrial-mediated pathway for apoptosis in this model.