Vaccine Fix

As research continues to uncover additional mechanisms to promote tumor cell death, vaccines are emerging as a new weapon—not only to prevent cancer but to combat it as well. The most well-known breakthrough in this area is the use of vaccines to prevent certain strains of the human papilloma virus (HPV), which have been associated with cervical cancer. Most recently, vaccines are being investigated for their potential to treat active cancer. As with all cancer vaccines, the aim is to generate an immune reaction against a specific molecular target that is greater than the tumor's immunosuppressive mechanisms. The first therapeutic cancer vaccine in the US to be approved was sipuleucel-T in 2010. This autologous vaccine demonstrated an increase in median overall survival from 21.7 months to 25.8 months in patients with metastatic castration-resistant prostate cancer. However, the extra 4.1 months of survival does not come without an extravagant preparation process and costs. Physicians also struggle with determining when continuation of therapy is worthwhile.

Immunotherapy and vaccine research continues to progress with ongoing Phase III trials in the areas of NSCLC and non-Hodgkin's lymphoma (NHL) as well as further explorations of combination therapy with vaccines as well as cytotoxic agents.

An ethical debate that will impact the future climate for cancer research is whether new oncologic agents should undergo accelerated approval prior to adequate, well-controlled studies, or if these agents should only be available on a compassionate-use basis. The average time for a drug to gain regular FDA approval is seven years from the start of human trials, and approval is usually based on survival advantages for the new agent. Accelerated approval was created in 1992 as a method for patients to gain earlier access to promising drugs for diseases with limited treatment options. Accelerated approval can be obtained by demonstrating improvements in surrogate endpoints, such as tumor progression, progression-free survival, response rates, or symptom relief in Phase II or Phase III trials.

Adequate, well-controlled trials must then be conducted, and if a survival benefit is demonstrated, the agent can be converted to regular FDA approval. The problem is that it is increasingly apparent that accelerated approval is no longer a carte blanche—regulators are getting tougher in demanding that efficacy and safety be certified through real-time clinical use to obtain permanent licensing rights. More restrictive labeling is another consequence of the emphasis on survival benefits. All told, the trend adds to the risk inherent in the registration process, which means that the market access hurdle for cancer drugs will rise higher. At present, an anti-cancer drug entering Phase I testing has only a 3 percent chance of entering the market, compared to the 10 percent average for drugs overall.

Between 1992 and 2010, 35 oncology drugs with 47 new indications were granted accelerated approval. Of these, 28 indications have been converted to regular approval. The first FDA-proposed withdrawal of an accelerated approval indication was made in late 2010 for bevacizumab in metastatic breast cancer. This decision was made after required confirmatory trials failed to substantiate the improvements in progression-free survival seen with earlier studies. Roche, as sponsor, is expected to undergo a hearing with the FDA in June to determine the future of this indication.

Twenty-one accelerated approval oncology indications have not been converted to regular approval, as confirmatory trials have not yet been completed. The FDA Amendments Act of 2007 allows the FDA to fine companies up to $10 million for not completing confirmatory trials in a timely manner.

One challenge in confirmatory trials after accelerated approval is patient accrual. Patients are reluctant to risk randomization to standard therapy after hearing reports of promising therapeutic alternatives and having off-study access to such agents. To overcome this obstacle, the FDA has recommended sponsors submit interim Phase III trial data for accelerated approval with continued followup of current patients for confirmatory studies. The FDA is also encouraging open discussion of the timeline and plans for confirmatory studies.

Themes for the Future

Pharmacogenomics, the study of the role of inherited and acquired genetic variation in drug response, is in the forefront of personalized medicine for cancer. It facilitates the identification of biomarkers that can help optimize drug selection, dosage, treatment duration, and avert adverse drug reactions.

However, just where pharmacogenomics fits into clinical practice is still evolving. Although the technology holds promise for the future, the ability to fulfill that potential will depend on the characterization of tissue and blood samples, collected from well-differentiated and uniformly treated patient populations, using validated and standardized assays. As new technology requires smaller amounts of tissue for diagnosis, it will be a challenge to maintain tissue banks, which can be utilized for future areas of investigation. And the clinical value of these gene sets must ultimately be validated in prospective clinical trials. In contrast to earlier data where the currently studied biomarkers are being validated retrospectively with bevacizumab in breast cancer (VEGF) and cetuximab in colon cancer (Kras), enrollment in studies for current promising breakthroughs such as crizotinib requires upfront biomarker tests for mutations (EML4-ALK).

The landscape of cancer treatment is changing rapidly as more underlying molecular abnormalities, which play a role in prognosis as well as response to various therapies, become apparent. While anatomical staging of tumors will always be a treatment mainstay, further classification based on the genetic makeup of tumors will hopefully carry more prognostic weight and influence clinical decisions. It is likely we will see more FDA-mandated pharmacogenomic information in package inserts as we further identify genetic variations that affect medications' efficacy and toxicity. Although payers may drag their heels initially, reimbursement for pharmacogenomic testing will be a requirement that precedes reimbursement for these medications. Through all of these changes, the utility of a pharmacist will be essential, as drug dosing will not only be based on body measurements but on molecular profiles as well.

This wealth of growing knowledge will further enable development of personalized cancer therapy based on a tumor's molecular profile. Outcomes can be improved and side effects avoided by utilizing individual genetic information to determine the optimal anti-neoplastic therapy for patients. This genetic information can further aid the development of novel targeted therapies and should enhance our search for understanding mechanisms of resistance and predictive biomarkers. Cancer is where the future of personalized medicine will play out. It will be a strong focus of research and has the potential to pilot new breakthroughs.

Natalie Dickmeyer, PharmD, is a researcher at the Indiana University Simon Cancer Center. She can be reached at ndickmey@gmail.com
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Lindsay Rosenbeck, PharmD, is a researcher at Indiana University Health. She can be reached at lrosenb1@iuhealth.org
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