Indifferently Pursued or Unowned Drugs: Who Should Lead Where Companies Do Not Tread?

Abstract

The essence of a successful drug development program for cancer is the demonstration of safety and efficacy (defined as clinical benefit) in the intended population. As others have observed, molecularly targeted agents having potential noncytotoxic end points have, for the most part, proceeded through fairly standard decision-making algorithms, in which responses early in an agent’s development serve as an important signal of potential clinical benefit and form the basis for subsequent development. With even a hint of such responses, it is possible to map out a strategy that may lead to expeditious regulatory approval. Recent good examples of agents of this type vigorously pursued by industry include bortezomib in multiple myeloma and gefitinib in lung cancer. In the case of agents that modulate tumor-cell resistance to chemotherapy or biologics that act in concert with cytotoxic agents, such as cetuximab and bevacizumab, more complicated strategies, including randomized approaches in precisely defined study populations, are necessary and appropriate. Such studies clearly benefit from industry-based organizational drive and expertise for their expeditious design and completion. Pharmaceutical companies tend to want such post– phase I programs to proceed expeditiously and generally demonstrate a lessening of ardor if the plan for definitive registrational trials lasts beyond a 3to 5-year time frame; that latter number would be considered generous by many. The problem is that this time table ill serves the cause of agents that have a development strategy that arises from academic investigators working with hypothesis-directed, rather than market-oriented, goals. The compounds studied may not actually belong to a particular company, or the relevant company may not see the basis for facile regulatory approval, even with interesting clinical results from such small investigator-driven trials. Therefore, are we risking the loss of useful opportunities? How can such agents, which might lie at the fringe or indeed outside the envelope of corporate sponsorship, be usefully pursued? Is all oncology drug discovery and development to be driven by a corporate timetable, potentially not benefiting from informed maturation of a drug’s intellectual and practical basis for use that might come from study in academically oriented laboratory programs and their derivative clinical trials? In this issue, Kortmansky et al report a phase I trial of escalating doses of fluorouracil (FU) in conjunction with the protein kinase antagonist 7-hydroxystaurosporine (UCN-01; NSC 638850). The rationale for this study came from prior laboratory investigations from this group, which demonstrated that UCN-01 caused downregulation of thymidylate synthase (TS), potentially as the result of UCN-01–induced decline in the activity of the E2F transcription factor. Because the level of TS expression has been linked by a number of (but not all) prior studies to the ultimate efficacy of FU-based therapies, with low levels of TS correlating with increased evidence of drug efficacy, a molecular basis for favorable modulation of FU efficacy by UCN-01 could be imagined. The results of the phase I study are encouraging. The study by Kortmansky et al clearly shows that a full dose of 24-hour infusional FU can be administered with the previously identified maximumtolerated dose of UCN-01 without exacerbating either FUrelated toxicities or the expected toxicities of UCN-01. Although no formal responses were observed in this generally heavily pretreated population, interesting oncophenomena occurred, including the perception of stable disease beyond 2 months in approximately one quarter of the assessable patients, which mirrors a prior suggestion of disease stabilization in a fraction of refractory lung cancer patients treated with UCN-01 and carboplatin. An effort in Kortmansky et al’s study to discern modulation of TS mRNA in peripheral-blood mononuclear cells was not informative, although the authors themselves note that these JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 9 MARCH 2