- © 2011 by American Society of Clinical Oncology
Vatalanib in Advanced Colorectal Cancer: Two Studies With Identical Results
Because of biologic variability, limited impact of treatment, chance, and sometimes bias, the results of clinical trials in oncology are often divergent and occasionally fully contradictory. The two studies in advanced colorectal cancer on the antiangiogenic drug vatalanib (PTK/ZK) in first-1 and second-line treatment,2 called Colorectal Oral Novel Therapy for the Inhibition of Angiogenesis and Retarding of Metastases (CONFIRM) 1 and 2, respectively, are a striking exception because their results are truly identical.
The studies showed the same hazard ratio (HR) for progression-free survival (PFS; 0.88 and 0.83) and for overall survival (OS; 1.08 and 1.00), the same increased efficacy in the subgroup with high lactate dehydrogenase (HR for PFS = 0.67 and 0.63) and the same lack of effect on the rate of objective responses (data not shown). The exposure to PTK/ZK or placebo and to the component drugs of infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) were similarly reduced (10% to 20%) compared with the controls. The increased incidence of serious adverse events (SAEs) in the experimental arms over the control arms was identical (9% and 10%) as was the increased treatment discontinuation proportion due to SAEs (14% and 17%). Even the time to deterioration of performance status (HR = 1.55 and 2.23), and the time to more than 5% weight loss (HR = 1.91 and 1.83) were similarly decreased in the PTK/ZK arms. From every viewpoint the results are superimposable, to an extent that is not usually observed even when the same trial is replicated in the same target population.
The implications of these unusual similarities are two-fold. First, the results of either study represent strong, independent confirmation by each other; as a consequence, bias and chance can be reasonably ruled out as possible explanations for these findings. Indeed, the results can be considered a reliable picture of the effects of PTK/ZK plus FOLFOX in advanced colorectal cancer. Second, notwithstanding the differences between the studies, their results can be discussed together.
Taken together, the message is clear: PTK/ZK, when used in combination with FOLFOX in metastatic colorectal cancer, has but a marginal effect on PFS, and no detectable effect on OS. Considering the non-negligible added toxicity, these results do not support the clinical use of this drug. Even if one ignores OS and accepts the effect on PFS as the main criterion on which to base clinical decisions in advanced colorectal cancer, the size of the effect observed in both studies is too small to justify the use of PTK/ZK instead of standard regimens. In addition, just because of the strong internal validity of these trials, further studies on this drug do not seem warranted in this disease, at least in unselected populations of patients.
Along this line, the other consistent message is that the effect of PTK/ZK appears to be stronger in the subgroup of patients with high lactate dehydrogenase at diagnosis (HR for PFS = 0.67 and 0.63 in CONFIRM 1 and CONFIRM 2, respectively). However, the size of the benefit observed even in this subgroup of patients is not outstanding from a clinical perspective: the increase in median PFS was less than 2 months in both studies, tempering the enthusiasm to pursue this further.
One wonders why the results have been so limited in the face of a strong theoretical rationale: complete blockade of the vascular endothelial growth factor receptor (VEGFR) pathways through inhibition of the three receptors should affect both angiogenesis and lymphangiogenesis. A number of reasons may be considered.
First, the rationale itself. The relevance of triple VEGFR inhibition in colorectal cancer is unknown, as evidenced by the absence of strong data on experimental colon tumor systems. In addition, no formal phase II or randomized phase II trial suggesting substantial activity in colorectal cancer was done before these large phase III studies. Empiric evidence indicates that demonstration of activity in phase II trials is a prerequisite for success.3,4
Second, pharmacokinetic reasons. With a half-life of 4 to 6 hours, the once-daily schedule may have been inappropriate. Easy to speak after the facts: two observations, in fact, mitigate what now sounds like a mistake. First, an attempt was made to pursue the theoretically more appropriate twice-daily schedule,5 but the toxicity was higher. Second, with the once-daily regimen, chemotherapy had to be reduced by 15% to 20% in the CONFIRM studies. Thus, if the twice-daily schedule of PTK ZK was to be used, either its dose should have been cut drastically below that of biologic activity, or an unacceptably low chemotherapy dose intensity should have been used.
Third, companion chemotherapy. It is possible that FOLFOX is not the ideal partner chemotherapy for this class of agents. The recently reported Horizon II study in first-line advanced colorectal cancer6 compared FOLFOX with or without cediranib, a multikinase VEGFR inhibitor, similar to PTK/ZK. The results mirror those of CONFIRM 1. Incidentally, some evidence is also emerging that FOLFOX may not be the appropriate chemotherapy partner for the anti–epidermal growth factor receptor (EGFR) antibody cetuximab.7,8 One would thus be tempted to generalize the negative interaction of FOLFOX with both anti-EGFR and VEGF-VEGFR pathway inhibitors. But the initial data on panitumumab9 are against this generalization as are the mature data on bevacizumab. In fact, although the initial report by Saltz10 showed that the benefit of bevacizumab added to FOLFOX or capecitabine plus oxaliplatin (XELOX) was limited, possibly due to inappropriate early discontinuation of the antibody,10 three pieces of evidence indicate the opposite. The strong second-line results with this combination compared with chemotherapy alone showed significant enhancement of every efficacy parameter, including OS.11 The control arms of four large-scale phase III trials using FOLFOX or XELOX plus bevacizumab given appropriately until progression produced the longest PFS ever reported in this setting, ranging from 10.3 to 11.7 months.12–15 Finally, the head-to-head comparison of cediranib plus FOLFOX versus bevacizumab plus FOLFOX (Horizon III study) demonstrated that the antibody is better than the small molecule when combined with FOLFOX.15 A negative interaction between bevacizumab and FOLFOX is thus unlikely. All these data taken together do not allow to rule out a role of partner chemotherapy as the explanation for the disappointing efficacy of PTK/ZK in the two CONFIRM studies, but suggest an intrinsically low efficacy of PTK/ZK in advanced colorectal cancer.
A final contribution of these two well-conducted studies can be recognized. A rebound effect has been described in vitro following discontinuation of treatment with the antiangiogenic small molecules16; if this phenomenon occurs in the clinic, it might provide an additional explanation for the limited results observed in the studies on PTK/ZK. Furthermore, the postulated rebound effect has been considered as a possible explanation for the reversal of the initial efficacy of bevacizumab plus FOLFOX as adjuvant treatment of stage III colon cancer.17 The results of the CONFIRM 1 and 2 actually fail to provide support to such a hypothesis: in the experimental and the control arms of both studies, the median PFS was almost exactly one third that of the median OS. This means that the survival after progression was twice as long as the time from randomization to progression. The reliability of this finding is reinforced by the observation that postprogression survival in CONFIRM 1 (first-line patients), was almost identical to the median OS in CONFIRM 2 (previously treated patients), as if the patients in the second study had come from the first one, which of course was not possible. If the rebound effect actually took place, one would expect that the time from progression to death of the PTK/ZK population would be shorter than in the control arms in both studies, which apparently was not the case. These results suggest instead that metastatic colorectal cancer, once a usually aggressive and rapidly lethal disease, has now a more chronic behavior even after progression, with more than 40% of the advanced cases alive at 2 years, and about one fourth still alive at 3 years. This change occurred already in association with the widespread use of the doublets FOLFOX and fluorouracil, leucovorin, and irinotecan. And the use of biologics has enhanced this permanent impact of medical treatment on the clinical behavior of the disease in the advanced setting.18
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: Alberto F. Sobrero, Bayer (C), Amgen (C), Roche (C), Merck Serono (C), Astra Zeneca (C), sanofi-aventis (C) Stock Ownership: None Honoraria: Alberto F. Sobrero, Roche, Merck Serono, sanofi-aventis Research Funding: None Expert Testimony: None Other Remuneration:None
AUTHOR CONTRIBUTIONS
Manuscript writing: Alberto F. Sobrero, Paolo Bruzzi
Final approval of manuscript: Alberto F. Sobrero, Paolo Bruzzi
