Plenary Lecture 1:

-Present status and future view of molecular targeting therapy for cancer -Viewpoint of individualized cancer therapy-

Phase I Trials at a Crossroads: Proof of Antitumor Activity as Primary Objective,

Bruce A. Chabner, MD

Director of Clinical Research
Massachusetts General Hospital Cancer Center, USA

In former times, Phase I trials in oncology sought to establish a safe dose and schedule for new compounds. Pharmacokinetic studies established a rational basis for changing schedule and understanding the relationship of dose to exposure (Area under the curve: AUC). The patients for such trials were selected primarily on the basis of performance status and normal organ function, i.e. good “physiological” subjects for the study of a new drug. Their tumors were secondary considerations. Clinical responses were rare (less than 5% of patients), but did provide clues for further directions in drug development. With the rapid expansion of targeted drug discovery and development, the paradigm for Phase I trials has shifted signifi cantly. These trials are now regarded as an early opportunity to validate the concept that inhibition of the target will slow tumor growth or lead to tumor regression. While the basic elements of the trial (dose escalation in a “physiologically intact” population, coupled with PK studies) has not changed, the assessment of clinical response in a highly selected patient population, enriched for tumors that carry the target of interest, has become a primary goal. If the tumor contains the target, and the drug levels are achievable, then the tumor should respond to treatment.

In this lecture, I will illustrate the strength of this new approach by comparing the development of two targeted compounds: inhibitors of the epidermal growth factor receptor (EGFR), and inhibitors of c-met/alk kinase. In the former instance, gefi tinib and erlotinib were developed in broad-based, unselected patient populations, with a small number of responses, primarily in non-small cell lung cancer (NSCLC). Further development in Phase II and III trials established erlotinib as a modestly active drug in a general lung cancer population. Only in retrospect was it appreciated that a distinct subset of NSCLC patients with activating mutations in EGFR were highly responsive to both of these drugs. Six years after its initial approval, and then withdrawal for lack of activity, gefi tinib was won a new life as a potent inhibitor of EGFR mutant non-small cell lung cancer.

By contrast, the recent clinical development of inhibitors of the ALK kinase has proceeded rapidly in a highly selected patient population. In a carefully planned Phase I trial, with expansion at the maximum tolerated dose to include 60 patients with EML4/ALK activating translocations, the Pfi zer c-met/alk inhibitor proved to be highly active (65% response rate, 20% stable disease) in these selected patients. Without the need for a Phase II study, a Phase III randomized trial comparing the new drug against standard therapy will start shortly. Patients with other kinds of tumors that contain activating mutations in ALK, including neuroblastoma, and colon cancer will also be included in other Phase II trials.

The alk inhibitor study, as well as others recently reported with inhibitors of b-RAF and c-kit in melanoma, and a hedgehog pathway inhibitor in basal cell cancer, all support the strategy of selecting patients according to molecular profi ling of tumors in early “proof of concept” trials. The results in Phase I can establish the clear value of new drugs in selected subsets of patients. The implications of this new strategy are significant:

Molecular profi ling of metastatic tumors will be essential to allow appropriate patient selection for early clinical trials, and, as the numbers of approved targeted drugs increases, ultimately for standard therapies.
Early drug trials will require the co-operation of multiple cancer centers, particularly in their expansion phase, to fi nd adequate numbers of appropriate patients, since many of the interesting mutations occur in small subsets of various tumors.
New technology, such as molecular imaging and/or the isolation of circulating tumor cells in large numbers, will be required to establish that drug dose and schedule are optimal for inhibiting the target molecule.
Early studies of mechanisms of drug resistance may inform the design of Phase II trials of drug combinations.
公益財団法人東京生化学研究会 CHAAO事業