Phase II Studies of Modern Drugs Directed Against New Targets: If You Are Fazed, Too, Then Resist RECIST
Authors: Mark J. Ratain, S. Gail Eckhardt
Journal: Journal of Clinical Oncology (2004)

There is no question that the treatment of cancer 10 years from now will be very different from that employed 10 years ago. Are we at the beginning of a series of rapid breakthroughs, or are we making slow progress? Only time will tell. We have many new “druggable” targets, and maybe the results really will be different from the past, with major advances in the treatment of traditionally refractory malignancies. Let us first briefly recapitulate the history of anticancer agents, to understand that the more things change, the more they stay the same. The pharmacologic management of cancer can be traced back to the Manhattan Project (1945), with a number of laboratories developing alkylating agents. These were clearly targeted agents, directed toward alkylating DNA, albeit in a diffuse manner. The next drugs were the antimetabolites, including the antifols, such as methotrexate, and the purine and pyrimidine analogs, such as 6-mercaptopurine and fluorouracil. Again, these drugs were clearly targeted against specific pathways and even specific enzymes, such as dihydrofolate reductase for methotrexate. Even then, we implicitly understood the concept of biomarkers, and myelosuppression was considered to be pharmacodynamic evidence of effects on the target—DNA. Now, approximately a half century (and hundreds of drugs) later, we are engrossed in a new era of oncology therapeutics, that many call “targeted therapies.” To paraphrase one perennially asked question, why are these drugs different from all other drugs? They are meant to be different because we believe that we can preferentially target the tumor rather than normal tissue. This belief is partially supportable, as particularly exemplified by the fantastic results achieved in chronic myelogenous leukemia with imatinib. The drugs are different because we have identified new signaling pathways and tumor biology, which we must learn and understand. They are different because we can’t remember or spell the generic names. They are not different, however, in that we have always had targets, and we have generally known that we have hit a target (which may be different from the intended target). As one example, estramustine was developed as an estrogen-receptor targeted–alkylating agent. However, it was subsequently demonstrated to be an antimitotic agent with activity in prostate cancer independent of the estrogen receptor. Furthermore, we have demonstrated that targeted agents, both old and new, can exhibit mechanism-based effects on normal tissue (myelosuppression, skin rash, diarrhea) that may or may not be associated with a beneficial effect on the patient. With a plethora of new targets, we also have a plethora of new drugs and sponsors, some of whom only have one drug to develop. There is immense competition among companies for patient resources, particularly in the United States and Europe, though many investigators in Asia and South America are equally inundated with requests for trials. Thus, many sponsors and investigators have attempted to minimize the number of patients treated in early clinical trials because of concerns relating to imbalances in patient resources, and financial incentives to move quickly toward phase III trials. Phase I trials have become smaller, in large part because of the recognition that newer targeted agents are less toxic, and are therefore less likely to result in serious toxic effects. This has led to the widespread adaptation of a variety of accelerated titration designs, which have in common, aggressive dose escalations and small patient cohorts, in the absence of toxicity. Such designs are very efficient for defining the maximum-tolerated dose, but are less useful for obtaining a full understanding of a new agent’s clinical pharmacology. In JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 22 NUMBER 22 NOVEMBER 15 2004