Fluoropyrimidine plus Bevacizumab Strong Maintenance Strategy For Metastatic CRC

AIO 0207 study adds to evidence on the optimal maintenance therapy for metastatic colorectal cancer

medwireNews: Phase III trial results support the use of fluoropyrimidine plus bevacizumab as maintenance therapy for patients with metastatic colorectal cancer after first-line therapy with oxaliplatin, fluoropyrimidine and bevacizumab.

The open-label AIO 0207 study showed that maintenance with bevacizumab alone was not inferior to fluoropyrimidine plus bevacizumab with regard to the primary endpoint of median time to failure of treatment strategy, defined as time from randomisation to second progression after maintenance (and where applicable re-induction), death or initiation of further treatment.

By contrast, no maintenance therapy at all was inferior to fluoropyrimidine plus bevacizumab for this endpoint, say lead author Susanna Hegewisch-Becker, from HOPE–Practice for Oncology in Hamburg, Germany, and team in The Lancet Oncology.

But as just 19% of patients in the combined maintenance therapy group, 43% in the bevacizumab monotherapy group and 46% of those given no maintenance treatment underwent the planned re-induction to the full triple chemotherapy regimen on first progression, the researchers say the outcome of the primary endpoint is “non-informative and clinically irrelevant”.

The most common reasons given for non-receipt of re-induction therapy were investigator decision or patient choice, consent withdrawn or non-compliance. Other reasons included neuropathy, death and tumour resection.

The authors report that overall survival was a median of 21.9 months for the whole study population and did not differ between the groups, although they admit the data have “low power”.

However, progression-free survival significantly differed between the three groups, with a hazard ratio (HR) of 1.34 for bevacizumab alone versus with fluoropyrimidine, and HRs of 2.09 and 1.45, for no maintenance treatment versus bevacizumab plus fluoropyrimidine and bevacizumab alone, respectively.

The median time to first progression was 11.7 months for patients given combined maintenance therapy, 10.0 months for those given bevacizumab alone and 9.0 months for those receiving no treatment.

Further analysis indicated that patient response to induction treatment at randomisation was a significant predictor of both time to first progression and overall survival, with median values of 5.0 and 23.7 months, respectively, for those with a complete or partial response versus 4.0 and 8.5 months for patients with stable disease.

In addition, patients who tested positive for RAS or BRAF mutations had significantly shorter time to first progression than patients with Wild-type tumours (4.3 and 3.9 vs 6.0 months). Overall survival was also significantly different by mutation status (20.3 and 9.4 vs 28.4 months).

And patients with wild-type RAS/Raf tumours who received bevacizumab alone or alongside fluoropyrimidine had longer time to first progression than those who received no treatment, whereas patients with mutated tumours had longer time to first progression if they received bevacizumab plus fluoropyrimidine rather than bevacizumab alone or no therapy.

Writing in an accompanying comment, Riccardo Giampieri and Stefano Cascinu, from Universita Politecnica delle Marche in Ancona, Italy, say that there is no “clear biological explanation” for the interaction between bevacizumab maintenance and RAS/RAF status but that a similar relationship has previously been reported.

They conclude that “AIO 0207 is the first study to clearly show that treatment holidays from bevacizumab are not indicated in patients receiving a first-line treatment including bevacizumab.

“Furthermore, it suggests that in patients with RAS or RAF mutant tumours the use of bevacizumab alone as maintenance therapy is associated with a worse outcome, whereas it might be a reasonable choice for patients with RAS or RAF wild-type tumours.”

References

Hegewisch-Becker S, Graeven U, Lerchenmüller CA, et al. Maintenance strategies after first-line oxaliplatin plus fluoropyrimidine plus bevacizumab for patients with metastatic colorectal cancer (AI) 0207): a randomised, non-inferiority, open-label, phase 3 trial. Lancet Oncol 2015; Advance online publication 8 September. DOI: dx.doi.org/10.1016/S1470-2045(15)00042-X

Giampieri R, Cascinu S. Maintenance therapy for metastatic colorectal cancer. Lancet Oncol 2015; Advance online publication 8 September. DOI: dx.doi.org/10.1016/S1470-2045(15)00125-4k

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