New targets, therapies, and toxicities: lessons to be learned.

The article in this issue by Faivre et al describing a phase I trial of sunitinib is an important contribution to the literature, and reflects some of the new opportunities and challenges in oncology for both researchers and clinicians. Sunitinib is an oral tyrosine kinase inhibitor targeting predominantly the vascular endothelial growth factor (VEGFR) and platelet-derived growth factor (PDGFR) receptors. The article reports that sunitinib is reasonably well tolerated, with asthenia, hypertension, dermatitis, and mild myelosuppression as the major toxicities. Of greatest interest for the clinician (and the sponsor) is the observation of tumor shrinkages (including responses as defined by standard Response Evaluation Criteria in Solid Tumors Group [RECIST] criteria) among the enrolled refractory solid tumor patients. This has already led to a number of phase II studies, as well as a phase III study in GI stromal tumor patients demonstrating that sunitinib has dramatic activity in renal cell cancer, and that it is effective in refractory GI stromal tumor. As a result, sunitinib will almost certainly enter the standard therapeutic armamentarium. Given that sunitinib is only one of several broad-spectrum kinase inhibitors preferentially targeting VEGFR and PDGFR in clinical trials, the lessons illustrated here are critical for practicing clinicians and clinical researchers. Many editorialists could have or perhaps would have written about the triumph of molecular-targeted therapy as the most important lesson to be learned. It is, however, perhaps instructive to recall that many if not most of our current effective therapies are also targeted. The taxanes, for example, are targeted to betatubulin, the fluoropyrimidines are targeted to thymidylate synthase, and doxorubicin is targeted to topoisomerase-II. Like sunitinib, which affects kinases other than just VEGFR and PDGFR, these older targeted therapies are not necessarily specific to their primary target and instead are somewhat promiscuous in their molecular targeting, and certainly affect a variety of critical cellular mechanisms. The first lesson may well then be that “dirty drugs,” rather than a drug with high specificity toward a single target, may be needed to overcome the heterogeneity and genetic instability that characterize human solid tumor cancer cells. As might be expected, changing the class of targets inhibited from those that are critical to DNA division and cellular proliferation to those that are critical to intracellular signaling and angiogenesis also changes the observed toxicity profiles to ones that most oncologists may not be used to seeing. Hypertension, for example, was one of the most common toxicities observed in the study by Faivre et al, and has been seen in trials of other similar agents as well. Importantly, this may contribute to some of the rare cardiovascular toxicities that were also observed. As has been seen with the epidermal growth factor receptor inhibitors, skin toxicities including effects on hair follicles, were also common but rarely serious. The lesson for practicing clinicians is that antihypertensive and skin care regimens must be learned, especially because these drugs may need to be given for prolonged periods of time. The lesson for clinical researchers is that new standardized toxicity criteria may need to be developed because the current criteria were designed for intermittently administered agents and acute toxicities. Perhaps more importantly, restricting the definition of doselimiting toxicities in phase I trials to those serious toxicities that occur during the first cycle may no longer be appropriate. The authors of the current trial also describe tumor shrinkages that do not meet the usual standard RECIST criteria for response, but that probably still reflect true antitumor activity. The authors suggest that some of the changes in tumor perfusion characteristics on computed tomography scan or ultrasound may be a better way of assessing the effect of sunitinib or other similar agents on tumors. Here there are important lessons as well. A recent editorial in this journal discussed the fact that the RECIST criteria for response are arbitrary and correlate rather poorly with measures of true patient benefit such as survival, especially for agents targeting signaling and/or angiogenesis mechanisms. Nevertheless, substituting another radiologic biomarker before validation studies have been completed is even more illogical. At this point, it is simply not known whether the observed changes are a simple pharmacodynamic effect (similar to the neutropenia observed with taxanes), or whether they truly reflect a beneficial effect on the tumor and for the patient (such as complete response on standard radiologic examinations). Standardized approaches for these newer radiologic markers and studies describing within-patient (intrapatient) variability have also not been published. These markers obviously need to be investigated, but broad application before the appropriate validation studies have been conducted would mean that we have not learned the lessons from the past. Even without fancy radiologic markers, it is clear that sunitinib has rather dramatic antitumor effects in certain individuals insomuch as fistulas and a lethal peritoneal hemorrhage in association with apparent tumor necrosis were observed. Although these were disastrous toxicities for the affected patients, they reflect perhaps the expected outcome with an effective drug against a solid JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 24 NUMBER 1 JANUARY 1 2006