Current oncology practice consists of therapy targeted at specific biologic pathways, which has become an integral part of the armamentarium of how we treat tumors. These advances in oncology have come from a deeper understanding of specific pathways which promote tumor growth directly or indirectly through enhancement of tumor-associated blood vessels. It is therefore hard to read an ASCO abstract or a manuscript about a new drug without it being called a “novel” and “targeted” therapy. Indeed these advances have significant merits and they are no longer nonspecifically treating any proliferating cells, but rather are inhibiting specific proteins. Although many of these agents, especially small molecules, have unintended off-target effects, in large part they have provided a new dimension of benefit to patients.
What is more challenging, however, and is not yet adequately addressed with current agents and approaches is how to apply these targeted therapies at the right time for the right patient.
The first consideration when deciding upon therapy for patient is the timing of initiation. We have all been educated in an era of medicine when immediate treatment for metastatic cancer is considered largely imperative in solid tumor oncology. Borrowing from hematologic malignancy such as CLL, there can be a small subset of solid tumors with an indolent natural growth rate for which initial observation is an appropriate initial approach.
Recognizing that the best targeted therapies against solid tumors are largely non-curative, the issue of when to begin the application of these therapies takes on increased importance. This is coupled with ubiquitous and sometimes serious and life-altering side effects, which balance the risk-benefit ratio for these particular approaches.
In addition, there is emerging preclinical evidence to support increased metastatic potential, for instance, with the application of VEGF-targeted agents, providing a note of caution in the indiscriminate use of these drugs in all clinical settings.
More clinical and translational research is needed to understand indolent solid tumors to characterize the gene and protein expression so that patients with low-volume, slow-growing disease can be safely observed before the start of therapy.
The next consideration upon starting treatment is which agent to choose. Inevitably, when a viable therapeutic target is identified, a wave of agents inhibiting that target (sometimes via identical and sometimes with distinct mechanisms) enter clinical testing.
In some cases multiple agents are FDA-approved after comparison against placebo or some minimally effective standard of care. These agents show quite often just enough benefit for regulatory authority approval and may be of borderline clinical benefit.
As is widely recognized, application of such targeted therapy to an enriched subset of patients who could benefit would allow for a greater therapeutic ratio. However, the current state of knowledge is largely the empiric application of these agents, with the notable exception of EGFR mutations, for EGFR receptor inhibitors and K-ras mutations predicting against response to EGFR-directed therapy.
Large-scale clinical trials with registrational intent and in the post-marketing setting should have a significant and adequately powered biomarker component so that we may gain insight into targeting the right patient.
Educating the patient as to the risk and benefit involved in applying these targeted therapies is difficult, but I believe a requirement as we move forward in this in the current therapeutic environment.
Patients have a different evaluation of the benefit of a given drug, which may be quite different from an oncologist's perception. Patients also have very different perceptions of specific risks and how that might affect quality of life and lifestyle.
More research is needed in patient decision-making as well as in their understanding of the risks and benefits of a certain therapy. In addition, what is sorely needed and likely must be funded through agencies such as the NCI and NIH are comparative trials of similar agents. These trials may demonstrate increased benefit and/or reduce toxicity of one approach, and with proper translational correlates, validate predicted markers of either benefit or toxicity.
I believe that in the last several years the clinical development of targeted therapy has far outpaced our ability to truly understand the biology of response and resistance to these therapies. It is my hope that the next era of oncology management will be thoughtful and rational application of therapies targeted not only to a protein, but to a patient's tumor biology, to the patient's need to initiate therapy, and targeted to a patient's understanding and evaluation of the risks and benefits.