BEAM Trial: Lighting the Way Ahead?

Antiangiogenic therapy in cancer is at a crossroad. Recent clinical trial data have led to better understanding of this therapy but have raised many questions that require additional research. Cancers can induce or recruit vascular supply by producing diffusible vascular growth factors. Inhibiting the action of these growth factors by binding the ligand or inhibiting its receptor is the basis of antiangiogenic therapy. Bevacizumab, the paradigmatic antivascular endothelial growth factor (VEGF) monoclonal antibody, was first explored in a phase I clinical trial in 1997. Although only modestly active as a single agent, bevacizumab showed consistent and relatively nontoxic activity in combination with chemotherapy in preclinical models. By the mid2000s, the excitement after positive trials in colon, lung, and breast cancers led to the thought that many or most solid cancer chemotherapy regimens in any disease site could be improved by the addition of an antiangiogenic agent. Several tumor types, however, have proved insensitive to bevacizumab combination therapy. Adding bevacizumab to gemcitabine did not improve the response rate, progression-free survival (PFS), or overall survival (OS) of pancreatic adenocarcinoma. In gastric cancer, bevacizumab did not prolong OS and only added one month to PFS with a modestly improved response rate. In metastatic castration-resistant prostate cancer, PFS was improved by about 2 months, but OS was not significantly improved. Even in tumor types sensitive to bevacizumab, such as colorectal cancer, there are different effects depending on the chemotherapy backbone. Whereas irinotecan-based regimens seem to benefit from bevacizumab, oxaliplatin-based regimens did not seem to benefit in terms of OS in the same setting. It is not clear why this difference of chemotherapy regimen should affect the added benefit of antiangiogenic therapy. Small molecule VEGF receptor (VEGFR) tyrosine kinase inhibitors, such as sunitinib and sorafenib, have an entirely different spectrum of clinical activity; they are effective in renal cancer and hepatocellular cancer. Given this complicated data set, no clear pattern emerges of an antiangiogenic inhibitor–sensitive tumor type. Melanoma is a highly vascularized tumor with an early and aggressive pattern of hematogenous metastatic spread. Given these characteristics, it should be an ideal target for clinical trials using VEGFR kinase inhibitors and anti-VEGF monoclonal antibodies. So far the results have been underwhelming. Sorafenib, a multikinase inhibitor that inhibits VEGFR and RAF, has been tested extensively in melanoma and is minimally active. Axitinib, a more potent and targeted VEGFR inhibitor, seems more active as a single agent in melanoma, but no randomized trial to confirm its activity has yet been completed. The randomized phase II clinical trial by Kim et al is an important contribution, because it aims to estimate the benefit of adding bevacizumab (B) to a carboplatin/paclitaxel (CP) backbone in melanoma (the BEAM [Bevacizumab in Advanced Melanoma] Trial). The primary end point of this large (for a phase II trial) randomized multicenter trial was median PFS; the trial was adequately powered to detect a 2-month improvement for the bevacizumab arm. Secondary end points included OS and response rate. A total of 214 patients were accrued over 18 months and randomly assigned 2:1 favoring the CPB arm. This primary efficacy end point, PFS, was numerically superior by 1.4 months in the CPB arm but statistically negative (logrank P .1414). The objective response rate was 25% in the CPB arm and 16% in the CP arm, which was also not significantly different. Surprisingly, given the lack of benefit for PFS, the secondary OS end point at the prespecified time point 8 months after the last patient was enrolled showed a 3.7 month improvement for the CPB arm (CPB, 12.3 months; CP, 8.6 months), which was statistically significant (logrank P .0366) in an initial evaluation; however, a later reanalysis at 16 months showed a smaller benefit (3.1 months) that was no longer statistically significant. Response rate, another secondary end point, was not significantly different (CPB, 25%; CP, 16%; P .1577). Putting this data in the context of other bevacizumab data, PFS and OS benefits closely parallel each other in colon cancer. In non–small-cell lung cancer, this is also true. In breast cancer, PFS benefit exceeds OS benefit. Outside of immunotherapy agents, there is no precedent for improving OS without also improving disease control. Taking the cumulative data gathered to date with antiangiogenic agents, it is probable that the significant OS difference seen at 8 months is an outlier rather than an early signal; indeed the fact that the benefit is receding in the subsequent 16-month analysis seems to confirm this. Given the expense and risk of bevacizumab, this trial does not support using bevacizumab in melanoma in routine clinical practice. The subset analyses performed by the authors are interesting. The greatest magnitude of benefit seems to be for those with elevated lactate dehydrogenase, which may correlate with tumor hypoxia. This may represent a group of patients to be targeted for antiangiogenic therapy trials. Given the recent developments with BRAF inhibitors in melanoma another subset analysis of interest would have been BRAF mutation status, which may affect the sensitivity of melanoma to antiangiogenic agents. This trial raises issues with the randomized phase II design, which have been proposed to reduce selection bias in phase II testing contributing to failure in phase III trials. Given the small size of these trials, it is easy for a positive randomized phase II trial to still lead to a negative phase III trial. Indeed, that is exactly what has happened in two recent high-profile trials of the redox inhibitor eseclamol in melanoma and the PARP inhibitor iniparib in triplenegative breast cancer. It is equally easy to imagine that negative phase II results such as those of the BEAM trial could show a smaller but real difference in a large phase III trial. A more nuanced understanding of antiangiogenic agents in cancer therapy is emerging. These agents are clearly effective in some tumor types, but they are certainly not universally effective and, even within a sensitive tumor, not additive with many common regimens. In this sense, they are a reminder of the tremendous heterogeneity and Editorials