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In Reply

Department of Medical Oncology, Erasmus University Medical Center, Daniel den Hoed Cancer Center, Rotterdam, the Netherlands

In our editorial, "Dose Selection in Phase I Studies: Why We Should Always Go for the Top,"¹ we wanted to stress the importance of identifying the maximum tolerated dose (MTD) during phase I studies with molecularly targeted compounds. We believe this is essential as long as we are not sure about the right way to select the optimal biologic dose and, in particular, because it has been shown that certain subpopulations of patients benefit from high-dose treatment with molecularly targeted compounds. Evidence for the latter is derived from two phase III studies conducted in patients with advanced GI stromal tumors (GISTs). In these studies, the efficacy of imatinib given at the MTD (400 mg twice daily) was compared with that of imatinib administered at 400 mg once daily.^2,3 To the best of our knowledge, these two trials are the only phase III studies reported so far in which the MTD of a molecularly targeted drug has been randomly compared with a lower dose. As mentioned in our editorial and also extensively described by Haines, there is no benefit for imatinib treatment at the MTD over the lower imatinib dose at 400 mg for the majority of patients. However, there are subgroups of patients that definitely benefit from imatinib given at the MTD. The first group, not mentioned in the letter by Haines, consists of patients with a GIST harboring an exon-9 c-KIT mutation. This group accounts for approximately 15% of all advanced GIST patients.⁴ In a meta-analysis of the two randomized GIST trials comprising 1640 patients, the only factor that predicted benefit from high-dose therapy compared with the lower dose was the presence of an exon 9 c-KIT mutation in the tumor.⁵ In patients with c-KIT exon-9–mutated tumors, the median progression-free survival for patients treated at MTD was more than three-fold increased compared with that reached by the lower dose (19 v 6 months; P = .017).⁵ There was no difference in terms of overall survival,⁵ probably because of the availability of active second-line and subsequent therapies.

One of the second-line therapies, which is only available for patients experiencing disease progression during imatinib therapy with 400 mg, is escalation of the dose to the MTD. Haines questions in his letter the benefit of this approach. He assumes that a significant number of patients in whom dose-escalation is applied because of progression during therapy with 400 mg imatinib may actually not have experienced disease progression. In these patients, RECIST criteria were used for tumor evaluation, whereas the criteria as proposed by Choi et al⁶ are believed to be more appropriate in imatinib-treated GIST patients. Indeed, response evaluation in imatinib-treated GIST patients can sometimes be quite difficult. Imatinib can induce solid tumor masses to become more viscous, which is reflected as an alteration in tumor density or a cystic appearance on radiologic assessment. These cystic lesions, which are a sign of antitumor activity, can have a larger size than the initial solid lesion, thereby meeting the definition of progressive disease (PD) according to standard criteria such as RECIST. On the other hand, the appearance or growth of a solid nodule in a cystic lesion with a stable size, the so-called nodule in a nodule, is a sign of progression.⁶ Given these difficulties in response assessment of imatinib-treated GIST patients, Choi et al proposed to use other criteria based on changes in tumor size and density instead of RECIST.⁶ We are not aware of studies investigating what proportion of patients with PD according to RECIST has stable disease or a response according to Choi's criteria. However, considering the criteria for PD of both evaluation methods, it is our impression that such cases are rare. PD according to RECIST requires the total tumor size to increase with 20% or more, whereas according to Choi's criteria, an increase in tumor size of only 10% or more is enough to meet the definition of PD, as long as tumor density has not decreased with more than 15%. Appearance of new lesions is PD according to both methods, whereas new intratumoral nodules or growth of such nodules is a sign of PD only according to Choi's criteria.⁶ As a result, we think that the vast majority of patients who have PD according to RECIST will have PD according to Choi's as well.

In the two randomized studies, patients who experienced progression during therapy with 400 mg imatinib were allowed to cross over to the higher dose. This approach yielded 30% to 33% of these patients who experienced disease progression to achieve either stable disease or partial response,^3,7 and 18% of the patients were still progression free at 1 year.⁷ It seems that in particular, patients with c-KIT exon-9 mutations or wild-type tumors with PD and receive less than 400 mg benefit from dose-escalation.⁴ In addition, imatinib at the MTD, which per definition is a dose deemed to have an acceptable toxicity profile, seems to be better tolerated in patients who have initially been treated with 400 mg.³ Collectively, there are precisely defined subpopulations of GIST patients benefiting from imatinib treatment at the MTD.

It is unlikely that only in GIST, subgroups of patients exist that benefit from high-dose therapy with molecularly targeted compounds. Hints supporting this statement include the finding of a relationship between area under the curve levels of sunitinib and outcome in renal cell carcinoma patients.⁸ Furthermore, high-dose sorafenib produces a 55% response rate in patients with renal cell carcinoma previously treated with no more than one prior regimen,⁹ whereas in other studies, sorafenib at standard dose yields a 5% and 2% response rate in first¹⁰ and second line therapies,¹¹ respectively.

With respect to molecularly targeted compounds, we are only in the beginning of the learning curve. A one-size-fits-all, or in this case, a one-dose-fits-all approach, is unlikely to be the most optimal way to use these novel compounds. For some patient populations the most effective dose will be the MTD. Identification of such populations benefiting from high-dose therapy can only be made by treating patients with these high doses. Identification of the MTD therefore remains an important component of early clinical drug development.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description 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.

Employment or Leadership Position: None Consultant or Advisory Role: Stefan Sleijfer, Wyeth Pharmaceuticals (U) Stock Ownership: None Honoraria: None Research Funding: Stefan Sleijfer, Novartis Expert Testimony: None Other Remuneration: None

REFERENCES

1. Sleijfer S, Wiemer E: Dose selection in phase I studies: Why we should always go for the top. J Clin Oncol 26:1576-1578, 2008[Free Full Text]

2. Verweij J, Casali PG, Zalcberg J, et al: Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: A randomised trial. Lancet 364:1127-1134, 2004[CrossRef][Medline]

3. Blanke CD, Rankin C, Demetri G, et al: Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol 26:626-632, 2008[Abstract/Free Full Text]

4. Debiec-Rychter M, Sciot R, Le Cesne A, et al: KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours. Eur J Cancer 42:1093-1103, 2006[CrossRef][Medline]

5. Van Glabbeke MM, Owzar K, Rankin C, et al: Comparison of two doses of imatinib for the treatment of gastrointestinal stromal tumors (GIST): A meta-analysis based on 1640 patients. J Clin Oncol 25:546s, 2007 (suppl; abstr 10004)

6. Choi H, Charnsangavej C, Faria SC, et al: Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: Proposal of new computed tomography response criteria. J Clin Oncol 25:1753-1759, 2007[Abstract/Free Full Text]

7. Zalcberg JR, Verweij J, Casali PG, et al: Outcome of patients with advanced gastro-intestinal stromal tumours crossing over to a daily imatinib dose of 800 mg after progression on 400 mg. Eur J Cancer 41:1751-1757, 2005[CrossRef][Medline]

8. Houk BE, Bello CL, Michaelson MD, et al: Exposure-response of sunitinib in metastatic renal cell carcinoma (mRCC): A population pharmacokinetic/pharmacodynamic (PKPD) approach. J Clin Oncol 25:241s, 2007 (suppl; abstr 5027)[CrossRef]

9. Amato RJ, Harris P, Dalton M, et al: A phase II trial of intra-patient dose-escalated sorafenib in patients (pts) with metastatic renal cell cancer (MRCC). J Clin Oncol J Clin Oncol 25:241s, 2007 (suppl; abstr 5026)

10. Szczylik C, Demkow T, Staehler M, et al: Randomized phase II trial of first-line treatment with sorafenib versus interferon in patients with advanced renal cell carcinoma: Final results. J Clin Oncol 25:241s, 2007 (suppl; abstr 5025)[CrossRef]

11. Escudier B, Eisen T, Stadler WM, et al: Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356:125-134, 2007[Abstract/Free Full Text]

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Related Correspondence

• Dose Selection in Phase I Studies: Why We Should Always Go for the Most Effective
  Ian E. Haines
  JCO 2008 26: 3650-3652 [Full Text]

This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Sleijfer, S. Articles by Wiemer, E. Search for Related Content PubMed Articles by Sleijfer, S. Articles by Wiemer, E. Related Articles Related Correspondence Social Bookmarking                            What's this?