In NSCLC, as inmost solid tumors, it is believed that there is multilevel cross-stimulation among targets along several pathways of signal transduction that lead to malignancy. As most first-generation targeted agents act by blocking only one of these pathways, other pathways are allowed to act as salvage or escape mechanisms for cancer cells. Therefore, a logical approach would involve a single agent with multiple targets, which, in combination with chemotherapy, may provide a more complete therapeutic benefit. Such agents include a number of small-molecule tyrosine kinase inhibitors that target several receptor tyrosine kinases associated with NSCLC and activated vascular endothelial cells.
The potential advantages of multitargeted tyrosine kinase inhibitors over single-targeted agents may include convenience of multiactivity in single agent, higher likelihood of single-agent activity, direct targeting of both tumor and blood vessels, and potentially lower costs. These possible benefits must be weighed against potential disadvantages; for instance, the inhibition of each target may not be equally effective at the relevant dose used in patients, and the potential exists for different toxicity profiles for multitargeted agents compared with single-targeted agents.
Preclinical data have shown benefits for combining VEGFR and PDGFR inhibition in terms of tumor regression in the H266 human lung carcinoma model.22
The antitumor activity of single-agent sunitinib in mouse models is similar to that observed with the combination of a PDGFR/kit inhibitor with a selective VEGFR inhibitor and superior to either agent administered alone.22
These data support the importance of dual inhibition of VEGFR and PDGFR for antitumor activity. The importance of these signaling pathways has been further evaluated in patients with NSCLC, where aberrant VEGF and PDGF signal transduction is associated with decreased survival and tumor angiogenesis.2,3
Clinical trials with the anti-VEGF monoclonal antibody bevacizumab have confirmed the importance of VEGF pathways in advanced NSCLC, showing that the addition of an anti-VEGF agent to chemotherapy improves survival when compared with chemotherapy alone.8
However, the importance of PDGF pathways is increasingly recognized.3–5
In the present study, sunitinib, an inhibitor of both VEGFR and PDGFR, has demonstrated single-agent activity in patients with previously treated, advanced NSCLC with an ORR of 11.1%. Similar response rates in this disease setting have not been previously reported for an antiangiogenic agent, suggesting that the broader and/or more complete inhibition of angiogenic pathways of sunitinib can effect greater antitumor activity.
As shown in , the majority of patients demonstrated some reduction in the target lesion measurements while enrolled onto the study. However, the activity of sunitinib and other antiangiogenic agents may still be underestimated by RECIST criteria. Some patients who showed small changes in tumor measurements demonstrated tumor cavitation, suggesting clinical efficacy might not always result in decreases in target lesion measurements.
Docetaxel, pemetrexed, and erlotinib are approved for patients with recurrent NSCLC.23–25
Single-agent treatment with docetaxel results in an ORR of 6.7% to 10.8% and a median OS of 5.5 to 7.5 months.23,26
Pemetrexed and erlotinib have shown similar response rates.24,25
The clinical activity of sunitinib observed in the current study seems similar to the currently approved agents despite the evaluation of sunitinib in a more heavily pretreated patient population, with the majority (60%) of the sunitinib-treated patients having received two or more prior systemic treatment regimens.
The AEs observed in this study were either expected for this patient population or similar to those reported in other trials of sunitinib.15–17
Sunitinib was generally well tolerated, with the majority of AEs being grade 1 or 2 in nature. Preliminary analysis of the additional patients (n = 47) treated on the continuous schedule of sunitinib at 37.5 mg/d suggest a lower rate of severe fatigue.27,28
In addition, evidence suggests that hemorrhage seems to occur with antiangiogenic agents in NSCLC,29
as described in this study. Hematologic toxicity was minimal, but careful phase I/II trials of sunitinib combined with standard cytotoxic agents must be undertaken to be sure sunitinib does not worsen hematologic toxicity, as has previously been observed with bevacizumab.8
In conclusion, this study shows that sunitinib has promising single-agent activity and a manageable tolerability profile in patients with recurrent NSCLC. The clinical activity of sunitinib in this heavily pretreated population of patients was similar to that of currently approved agents. This study has been amended to evaluate an alternative sunitinib treatment schedule comprising continuous once-daily dosing at 37.5 mg/d.27
Given the preliminary evidence of sunitinib activity in NSCLC, additional studies are currently underway, including trials of sunitinib in combination with chemotherapy or molecularly targeted agents and trials evaluating sunitinib as maintenance therapy in those patients who derive clinical benefit from first-line platinum-based chemotherapy.