Advertisement
NeuroScientistNews
NeuroScientistNews

Cancer Clinical Trials of Tomorrow

Advances in genomics and cancer biology will alter the design of human cancer studies.

By | April 1, 2013

© A. FREEMAN PHOTOGRAPHY/GETTY IMAGESWe stand on the cusp of significant change in the fundamental structure of cancer clinical trials, as the emphasis begins to shift from large-scale studies of relatively unselected patients to smaller studies testing more narrowly targeted therapies in molecularly characterized populations.

The previous (and still current) generation of trials established the cancer treatment standards used today. Trials that demonstrated the value of combination chemotherapy in the adjuvant treatment of breast cancer are an excellent example. Meticulous development of treatment regimens through Phase 1 and Phase 2 trials, followed by large-scale comparisons of the new regimens to established treatment protocols, have defined the modern practice of oncology for the last 4 decades. Future cancer clinical trials will be very different from those of the past, adopting a more personalized, sometimes called “precision,” approach.

It is, of course, not entirely true that past clinical trials did not include efforts to target treatments to the right patients. Where possible, targeted therapies are already being implemented. Using the presence of endocrine receptors to guide endocrine therapy for breast cancer was one of the first forays into molecular selection of patients. Unfortunately, the ability to select subgroups of patients for study has been severely curtailed by a still-limited knowledge of human cancer biology.

This is rapidly changing, however, thanks to advances in genomics and comprehensive cancer biology research over the last decade. Large-scale efforts, such as The Cancer Genome Atlas, are comprehensively defining many of the crucial molecular characteristics of human malignancies by illuminating genetic alterations that are clinically and biologically important, and which, by virtue of their functional roles, are viable targets for cancer treatment. At the same time, the ability to design small-molecule inhibitors of specific cancer targets is rapidly accelerating. In 2011, two new agents exemplified the power of these trends: crizotinib was approved for the treatment of lung cancers that harbor a specific mutation in the ALK gene, and vemurafenib was approved for the treatment of melanomas with a specific BRAF mutation. In both cases, the drugs were approved along with companion diagnostic tests that identify patients with the target mutation, who are therefore likely to benefit from treatment.

Smaller, more precise trials ahead

Clinical trials are being transformed by these trends. It will not happen overnight, as the knowledge of cancer biology and the availability of targeted agents are uneven. Unselected populations of patients will still be studied, but it is inevitable that there will be a rise in the number of trials that incorporate molecular tumor testing prior to treatment, with treatment selection informed by the molecular features of each individual’s cancer. Such personalized trials have the potential to yield better outcomes by increasing the probability of response and to employ less toxic therapies by increasingly targeting cancer-specific functions, rather than normal proliferative functions.

To the extent that targeted therapies will prove more effective when given to selected patients, clinical trials should get dramatically smaller. Trial size is largely driven by how effective the treatment is expected to be, so fewer participants are needed when the therapeutic benefit is larger. But the promise of smaller trials will not to be universal; for example, when two targeted agents are compared to one another in the same molecularly selected population, the differences in efficacy may be small and larger trials will be required.

As approaches to cancer treatment advance, there will need to be continual engagement with patients and with cancer survivors.

Furthermore, smaller trials may not necessarily move faster or be easier to complete, as they will require the “right patients,” who may be hard to find. Many of the mutations that represent promising targets are present in a minority of tumors. Today, molecular characterization of tumors is often done as part of the screening process for each trial. Many, and sometimes most, of the patients prove ineligible, making this approach frustrating and difficult to carry out. A better avenue of attack would be to make comprehensive molecular characterization of tumors a routine part of establishing a patient’s eligibility for a range of therapies. With the plummeting cost of genomic analysis, one can envision a day in the near future when a complete cancer genome (and perhaps other molecular evaluations) becomes a standard component of an initial diagnostic evaluation. Patients will be armed with molecular information about their own tumors, and thus able to make more-informed decisions about standard and investigational therapies that match the mutations driving their cancer.

New challenges

The road to personalized and targeted treatment strategies will offer new challenges. For rare targets that are present in a minority of cases across many different types of cancers, one will have to consider clinical trials that include a number of different cancers. There are many design pitfalls to such trials, chiefly the additional clinical and molecular heterogeneity introduced by the inclusion of more than one cancer type. Despite these challenges, it will inevitably make sense in some settings to select patients who share a particular tumor biology, regardless of the tissue of origin.

Another major challenge is how to combine targeted therapies to improve clinical outcomes. To date, targeted therapies have not been able to cure advanced solid tumors. Clinical benefits, while sometimes quite impressive when compared to marginally effective treatments, still fall far short. It stands to reason that redundant survival and growth pathways enable tumors to overcome therapies that inhibit a single target. The simultaneous inhibition of relevant redundant pathways may yield dramatically better results, but will also dramatically increase the complexity of molecularly personalized clinical trials.

As approaches to cancer treatment advance, there will need to be continual engagement with patients and with cancer survivors. Fewer than 5 percent of adult cancer patients participate in a clinical trial. To carry out meaningful clinical trials in the future, that number must increase. This will be most important for treatments that target relatively rare mutations; a large number of potential volunteers will have to be screened to identify a sufficient number who harbor the relevant target. To succeed, we must partner with a much larger fraction of cancer patients.

Designing and executing future cancer clinical trials will not be easy, but physician-scientists are armed with a fast-growing body of omics-informed knowledge with which to surmount these hurdles. 

Tomasz M. Beer is deputy director of the Knight Cancer Institute and a professor of medicine at Oregon Health & Science University in Portland. He is the coauthor of Cancer Clinical Trials: A Commonsense Guide to Experimental Cancer Therapies and Clinical Trials. Written for people living with cancer, the book is accompanied by a blog (www.cancer-clinical-trials.com) that seeks to disseminate knowledge about clinical trials.

Advertisement

Add a Comment

Avatar of: You

You

Processing...
Processing...

Sign In with your LabX Media Group Passport to leave a comment

Not a member? Register Now!

LabX Media Group Passport Logo

Follow The Scientist

icon-facebook icon-linkedin icon-twitter icon-vimeo icon-youtube
Advertisement

Stay Connected with The Scientist

  • icon-facebook The Scientist Magazine
  • icon-facebook The Scientist Careers
  • icon-facebook Neuroscience Research Techniques
  • icon-facebook Genetic Research Techniques
  • icon-facebook Cell Culture Techniques
  • icon-facebook Microbiology and Immunology
  • icon-facebook Cancer Research and Technology
  • icon-facebook Stem Cell and Regenerative Science
Advertisement
Advertisement
Life Technologies