QUASAR 2 Findings End Adjuvant Bevacizumab Use In Stage II/III CRC

Negative disease-free survival results for stage III or high-risk stage II colorectal cancer add to evidence against adjuvant bevacizumab in this setting

medwireNews: The QUASAR 2 trial rules out a role for bevacizumab in the treatment of unselected patients after potentially curative surgery for high-risk stage II or stage III colorectal cancer (CRC), finding no improvement in disease-free survival (DFS).

Three-year DFS was achieved by a comparable 75.4% of the 973 patients who were randomly assigned to receive eight 3-week cycles of capecitabine (1250 mg/m2 twice daily for 14 days) plus 16 cycles of bevacizumab (7.5 mg/kg for 90 min on day 1) and 78.4% of the 968 patients given capecitabine alone.

Leonard Saltz, from Memorial Sloan Kettering Cancer Center in New York, USA, says the QUASAR 2 findings follow negative survival results for adjuvant bevacizumab in two other large randomised trials – the NSABP C08 study of FOLFOX6 and the AVANT study of bevacizumab plus FOLFOX4 versus capecitabine plus oxaliplatin.

These results “force us to accept that just because an agent has antitumour activity against macroscopic metastatic cancer does not mean that it has activity against that same cancer in the microscopic metastatic setting”, he writes in a comment accompanying the study in The Lancet Oncology.

Patients given bevacizumab plus capecitabine were more likely than those given capecitabine alone to require a dose reduction in either agent (69 vs 52%), although total capecitabine dose given was similar in the two groups.

Serious adverse events, mostly gastrointestinal or cardiovascular, were reported in 350 patients given bevacizumab plus capecitabine versus 221 patients given only capecitabine, with a significant increase in the risk of venous thromboembolism. Fifteen patients given combined treatment died within the first 6 months versus eight patients given capecitabine alone.

Bevacizumab was also associated with a significant increase in the risk of all grades of hypertension and proteinuria, and a trend towards more grade 1 or more severe wound healing problems. The vascular endothelial growth factor inhibitor was also linked to a significant increase in the rate of grade 1–2 epistaxis and stomatitis, and grade 3 or 4 hand–foot syndrome.

Rachel Kerr, from the University of Oxford in the UK, and fellow QUASAR 2 investigators observe that DFS did not significantly differ with patient age, gender, country of origin or disease site or stage.

Analysis of tumour DNA from 1187 patients, however, suggested that DFS was significantly longer with bevacizumab than capecitabine monotherapy for patients with microsatellite-unstable tumours and patients with microsatellite-stable tumours who also had high levels of free CD31.

By contrast, patients with microsatellite-stable disease with low expression of free CD31 had poorer DFS with the addition of bevacizumab.

“These exploratory analyses were not preplanned, but rather were driven by our knowledge of the biology of bevacizumab and, therefore, the results need to be interpreted with caution”, the authors emphasize.

Discussing these possible indicators of bevacizumab response, however, they conclude: “Since no new drugs have been introduced for the adjuvant treatment of colorectal cancer for more than a decade, perhaps bevacizumab will be worth investigating in prospective studies with clearly defined populations of patients who have been specifically selected on the basis of biomarker profiles.”

References

Kerr RS, Love S, Segelov E, et al. Adjuvant capecitabine plus bevacizumab versus capecitabine alone in patients with colorectal cancer (QUASAR 2): an open-label, randomised phase 3 trial. Lancet Oncol; Advance online publication 19 September 2016. DOI: http://dx.doi.org/10.1016/S1470-2045(16)30172-3

Saltz LB. Bevacizumab in colorectal cancer: it should have worked. Lancet Oncol; Advance online publication 19 September 2016. DOI: http://dx.doi.org/10.1016/S1470-2045(16)30213-3

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