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Originally published as JCO Early Release 10.1200/JCO.2005.04.2408 on November 28 2005 © 2006 American Society of Clinical Oncology.
New Targets, Therapies, and Toxicities: Lessons to Be LearnedDepartment of Medicine, Section Hematology/Oncology, University of Chicago, Chicago, IL The article in this issue by Faivre et al1 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.2 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,3 and that it is effective in refractory GI stromal tumor.4 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 beta-tubulin, 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,1 and has been seen in trials of other similar agents as well.5,6 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 dose-limiting 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.7 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 tumor. So, just as we have learned to manage tumor lysis syndrome as a consequence of effective antileukemic therapy, we will have to learn how to anticipate and manage the complications of effective solid tumor therapy, as well. An effective oral antitumor agent with modest toxicity that may have to be given over prolonged periods of time raises additional issues familiar to other medical specialties, but perhaps less well appreciated by oncologists. First, drug absorption problems, which can obviously be ignored with intravenously administered drugs, now become critical, and the effects of various foods, diets, and GI pathologies on drug pharmacokinetics need to be investigated and considered. Second, patient compliance may become more important. One could imagine that the drug-associated asthenia observed with sunitinib could become a greater issue for patients once adverse effects from the tumor lessen due to effective treatment. It will thus become important to learn how long patients should be treated with these drugs, whether intermittent treatment is better than continuous treatment, and whether lower doses and/or different schedules are better tolerated and equally efficacious. The one unexpected advantage of oral medications is that the body-surface area (BSA) –based dosing, which has risen to iconic status in oncology with little evidence for its value, may reach a timely demise more rapidly with the necessary fixed pill sizes. Faivre et al1 demonstrated that BSA-based dosing did not decrease pharmacokinetic variability of sunitinib; investigating whether a relationship exists between BSA-based dosing and decreased pharmacokinetic variability is a lesson that clinical researchers studying other oral agents should emulate. In summary, the phase I study of sunitinib described in this issue of the Journal is a triumph of modern oncologic research, not so much in the value of molecular targeting per se, but as an example of the development of a whole new class of targets for oncologic therapy. This will, and should, force us to rethink how we develop anticancer drugs and whether the paradigms used previously still apply. It will also force us to learn not only the specifics of the new therapies but to relearn treatments for a whole new set of toxicities, such as hypertension, that we had previously thought we could ignore. It may well also force us to manage complications of truly effective therapy. All this will not only be fun, but will be appreciated by our patients. Author’s Disclosures of Potential Conflicts of Interest
The author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed discription of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000–99,000 (C)
Author Contributions
REFERENCES
1. Faivre S, Delbaldo C, Vera K, et al: Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol 24:25-35, 2006 2. Mendel DB, Laird AD, Xin X, et al: In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: Determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res 9:327-337, 2003 3. Motzer RJ, Rini BI, Michaelson MD, et al: Phase 2 trials of SU11248 show antitumor activity in second-line therapy for patients with metastatic renal cell carcinoma. J Clin Oncol 24:380, 2005 (suppl; abstr 4508) 4. Demetri GD, van Oosterom AT, Blackstein M, et al: Phase 3, multicenter, randomized, double-blind, placebo-controlled trial of SU11248 in patients (pts) following failure of imatinib for metastatic GIST. J Clin Oncol 24:308, 2005 (suppl; abstr 4000) 5. Strumberg D, Richly H, Hilger RA, et al: Phase I clinical and pharmacokinetic study of the novel Raf kinase and vascular endothelial growth factor receptor inhibitor BAY 43-9006 in patients with advanced refractory solid tumors. J Clin Oncol 23:965-972, 2005 6. Yang JC, Haworth L, Sherry RM, et al: A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 349:427-434, 2003 7. Ratain MJ, Eckhardt SG: Phase II studies of modern drugs directed against new targets: If you are fazed, too, then resist RECIST. J Clin Oncol 22:4442-4445, 2004 Related Article
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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$100,000 (N/R) Not Required
