Abstract and Introduction
Abstract
It is becoming increasingly evident that cancers are dependent on a number of altered molecular pathways and can develop diverse mechanisms of resistance to therapy with single agents. Therefore, combination regimens may provide the best hope for effective therapies with durable effects. Despite preclinical data to support this notion, there are many challenges to the development of targeted combinations including scientific, economic, legal, and regulatory barriers. A discussion of these challenges and identification of models and best practices are presented with intent of aiding the research community in addressing real and perceived barriers to the development of combination therapies for cancer.
Introduction
Cancers are dependent on many altered molecular pathways and use multiple mechanisms of immune resistance such that single-agent therapies alone may not provide long-lasting benefit for most patients. Even dramatic objective responses to single agents are commonly short-lived as evolving mutations in the agent's primary target or changes in a downstream effector lead to drug resistance and cancer progression. For example, the median duration of response to vemurafenib (RO5185426, RG7204, or PLX4032), a highly selective mutant BRAF inhibitor under development for BRAF mutant metastatic melanoma, is approximately 7 months despite an initial response rate of 81%. Although it has been reported that some patients in this first cohort are still responding more than 2 years after initial treatment, the majority of responses are temporary and incomplete. In addition, analyses of tissues from relapsed patients and laboratory studies with cell lines are identifying several mechanisms of resistance to highly selective BRAF inhibition. These studies and other reports support the hypothesis that drug combinations will be necessary to provide long-term tumor control for most patients. These considerations recapitulate infectious disease paradigms in which combination therapies for disorders such as HIV/AIDS and tuberculosis are the rule rather than the exception. Potential combinations of anticancer agents include a variety of permutations of experimental agents and/or standards of care (eg, chemotherapy, targeted agents, and immunomodulators). Evidence from animal tumor models indicates that the therapeutic effects of certain drug combinations may exceed those of monotherapies. Before phase II or phase III studies of combination therapies can be initiated, rational preclinical models should guide clinical trial design and may illuminate issues such as dosing regimens (administering two drugs concomitantly or sequentially), drug interactions affecting pharmacokinetics, and interactive toxic effects. In addition, new approaches to phase I studies of combination therapies should be considered to improve efficiency and increase our understanding of how best to test agents in combination.
Despite evidence of the potential for improved benefit when two anticancer agents are combined, the majority of cancer drugs follow development pathways as single agents, resulting in substantial failure rates. Roughly, 90% of the oncology drugs that entered clinical testing between 1993 and 2002 ultimately did not receive US Food and Drug Administration (FDA) approval. Oncology therapeutic strategies that incorporate rationally designed drug combinations at earlier stages of development have the potential to substantially improve this disappointing track record. Numerous challenges exist in developing research approaches for combination therapy, particularly for agents developed by multiple institutions, both academic and pharmaceutical based. For example, in addition to the scientific challenges inherent in optimizing drug combinations, productive collaborations can be challenged by economic considerations, issues related to contract terms including intellectual property, and a range of logistical obstacles. Mechanisms are needed to efficiently identify the potential therapeutic advantage in the combination of select anticancer drugs, drive decision making about the prioritization of rational combination trials, and then implement the clinical development of high-priority combinations efficiently. Clinical trial design for combination therapies is complex, and there is no one-size-fits-all approach; however, new and more flexible development models described here and in previous reports may simplify the process. Regulatory and safety considerations, such as concerns about unexpected toxic effects, are barriers to clinical development and approval. Some of these barriers are perceived rather than real, but perception can (and has) become reality. Overcoming these barriers will take cooperation among the regulatory bodies, the academic community, and the private sector.
The economic environment for the commercial development of combination therapies is an overarching challenge. Drug development is primarily funded by the private sector; thus, business considerations play a role. Efficacy must outweigh the increased cost and development complexity of a combination product. Importantly, partnerships between companies (risk sharing and profit sharing business models) as well as between sectors (academia, industry, and government) can leverage resources and mitigate risk and have become more common for these reasons. Other solutions include improved preclinical research, innovative trial design, rational intellectual property and legal approaches, and more frequent interactions with regulatory agencies.
The need for new more effective cancer treatments has never been greater. Cancer is the second-most common cause of death in the United States; in 2010, it was estimated that more than half a million Americans died of cancer, or more than 1500 people per day. Given the opportunities and challenges for combination therapies for cancer, the Melanoma Research Alliance hosted the session, "Developing Experimental Drug Combinations: Opportunities and Challenges" as part of the Melanoma Research Alliance Annual Scientific Retreat held February 24–26, 2010, in Las Vegas, NV. Whereas the potential value of combinatorial therapies applies to all cancer types, the incidence of melanoma has risen faster than any other cancer during the last three decades, and is particularly relevant because of the recent monotherapies that statistically significantly slow disease progression and improve overall survival but infrequently produce long-term remission in patients. These monotherapies include kinase inhibitors such as vemurafenib and immunotherapies such as ipilimumab (anti-cytotoxic T-lymphocyte antigen-4). Precedent for the development of combinatorial therapies of cancer comes from the cure of most childhood leukemias with combinations of agents, which displayed only transient anticancer effects on their own. Thus, a discussion of the opportunities and challenges to developing combination therapies for melanoma in particular, and cancer in general, was held among representatives from academia, industry, and government with the goal of accelerating the delivery of new tools and treatments to patients. The discussion prepared the Melanoma Research Alliance for a continuing dialog on these issues, the summary of which is presented here.