The investigation of novel agents in SCCHN is of major interest. Although the incorporation of cetuximab into platinum and FU has improved overall survival and other efficacy parameters in recurrent or metastatic SCCHN,9
prognosis remains poor, and treatment-related toxicities are frequently considerable. We studied a novel regimen with pemetrexed and bevacizumab in patients with recurrent or metastatic SCCHN. Our central hypothesis was that bevacizumab can potentiate the antitumor activity of pemetrexed as has been shown for other chemotherapy agents in solid malignancies. Using a non-platinum doublet, we report efficacy results (median TTP of 5 months and median overall survival of 11.3 months) that are at least comparable with those achieved with the combination of platinum, FU, and cetuximab.9
However, we acknowledge the limitations of a comparison between results of a single-arm phase II trial and a large multicenter phase III trial. Furthermore, it is of interest that although pemetrexed has poor activity in SCC of the lung, it appears to be active in SCCHN. Nevertheless, pemetrexed did not improve survival (P
= .08) or progression-free survival (P
= .166) when added to cisplatin in a phase III trial in recurrent or metastatic SCCHN.15
Subset analysis demonstrated survival benefit in patients with good performance status or oropharyngeal primaries.15
In our study, half the patients had oropharyngeal primaries, which is a favorable prognostic factor in recurrent or metastatic SCCHN3
and may have favorably influenced efficacy results.
Two other clinical trials, one presented in abstract form,30,31
have investigated the combination of an epidermal growth factor receptor inhibitor with bevacizumab. A phase I/II trial of erlotinib and bevacizumab in patients with recurrent or metastatic SCCHN showed promising results; median overall survival was 7.1 months and progression-free survival was 4.1 months.30
Three bleeding events (one of which was fatal) were reported in 48 patients. In our study, bleeding events were frequent, and six patients had serious bleeding of grade 3 or higher. However, hemorrhagic complications were rare in a phase II trial with cetuximab and bevacizumab in patients with recurrent or metastatic SCCHN.31
In patients with SCC of the lung, bevacizumab results in unacceptable rates of serious and fatal bleeding complications, and thus bevacizumab use has been restricted to nonsquamous non–small-cell lung cancer.32
We observed frequent serious bleeding events in patients treated with pemetrexed and bevacizumab in our study (15%), including two deaths, which is a potential concern for the safety of the regimen. However, this rate of serious bleeding events may not be prohibitive for further evaluation of the pemetrexed/bevacizumab combination in SCCHN, especially given the rarity of other serious adverse events. Hemorrhagic complications are not uncommon in the natural history of SCCHN, and it is sometimes difficult to discern the contribution of study drugs to these events. The application of careful eligibility and re-treatment criteria regarding tumor-related bleeding can potentially reduce the incidence of these events. Ultimately, a randomized comparison of chemotherapy with or without bevacizumab will be able to accurately evaluate the added toxicities and benefits with bevacizumab in recurrent or metastatic SCCHN. A phase III trial with cisplatin-based chemotherapy with or without bevacizumab is currently ongoing in the ECOG E1305 trial.
One challenge in the incorporation of new agents into cancer therapeutics has been the identification of reliable and easily reproducible predictive factors. In this study, we conducted an exploratory analysis of MTHFR
, and VEGF
polymorphisms and their association with efficacy of bevacizumab and pemetrexed combination. Altered reduced folate pools that relate to MTHFR activity may modulate response to antifolates. Here, we observed a significant association between the MTHFR
A1298C allele and survival, with homozygous carriers of the common allele (AA) having reduced survival (P
= .034). Previously, MTHFR
SNPs have been found to be associated with survival in patients with colon cancer,33,34
non–small-cell lung cancer,36
and other malignant tumors25
; however, some of these studies reported a significant association of the reduced activity of the variant C allele with poorer prognosis. Prospective clinical studies should be performed to validate MTHFR
polymorphisms as a predictive or prognostic marker in patients with SCCHN who have been treated with pemetrexed. Biomarkers for antiangiogenesis therapy in SCCHN are also under investigation.30
In our study, we examined several VEGF
SNPs, some of which were previously shown to relate to the outcome of patients with breast cancer who had been treated with bevacizumab-containing therapy26
; however, our exploratory analysis did not reveal any clinically significant associations.
In conclusion, the addition of bevacizumab to pemetrexed showed promising efficacy results in recurrent or metastatic SCCHN. Bleeding events were frequent in this study, but some may have been related to the natural history of the disease. The use of MTHFR polymorphisms for treatment individualization warrants further investigation in this setting. Bevacizumab-containing regimens should be further investigated in SCCHN.