Avastin and PhIII results

After mention of Avastin during the conference call, I didn't know whether this was a red herring or not.  So I thought I'd check out what the literature says.

Avastin (bevacizumab) in combination with 5-FU treatment is now a standard therapy for 1st line treatment.

When added to 1st-line FOLFIRI treatment, Hurwitz et al showed a lift in median PFS from 6.2mths (FOLFIRI) to 10.6mths (FOLFIRI/bev).  First line median OS went from 15.6mths to 20.3mths.

When added to 1st line oxaliplatin-based treatment (XELOX or FOLFOX-4), Saltz et al showed a lift in median PFS from 8.0mths to 9.4mths and no significant OS change.

Bennouna et al then looked at what happened with continued use of bevacizumab with 2nd line 5-FU based chemo (FOLFIRI or FOLFOX depending on 1st line treatment) after use during 1st line (ML18147 trial).  They showed (p25) median PFS increased from 4.0mths to 5.7mths and median OS increased from 9.8mths to 11.2mths.

Note that when bevacizumab was used for 1st-line, then not 2nd line, the expected outcome for chemo alone was 4.0mths median PFS and median 9.8mths OS.  This is similar to previous 2nd line FOLFIRI trial outcomes and significantly lower than the 5.5mth PFS and 14mth OS in the ACL PhIII baseline results.  So I don't think the anomolous PhIII FOLFIRI results can be attributed to 1st line Avastin use.

In 2013, the ML18147 data was further analysed for KRAS status.  This showed higher PFS and OS benefit for KRAS wild-type than mutant.

There is clearly a problem (or benefit from the pts perspective!) with the baseline FOLFIRI results.  That sort of difference from historical data doesn't just happen for no reason.

As to whether Avastin in 1st line has anything to do with the PhIII outcome, I doubt it.  I would have thought if Avastin in 1st line effected tumour uptake of irinotecan in 2nd line we would see it in ML18147.

Leaving aside the baseline results, there is not much difference between the apparent HA-I outcome and 2nd line FOLFIRI/Avastin from the ML18147 trial.  And Avastin is now FDA-approved with FOLFIRI for 2nd line mCRC treatment based on that trial.  Of course, that doesn't solve the immediate problem, but it does give some hope.