This was a large phase III trial, an investigator initiated trial so an academic trial, that evaluated different venetoclax-based combinations, so venetoclax-obinutuzumab, venetoclax-rituximab and venetoclax-obinutuzumab-ibrutinib, for the first-line treatment of patients with CLL.

What is the study design?

The study design was a four-arm trial with three experimental arms, the three arms I just mentioned, and the control arm that was a systemic chemoimmunotherapy arm with FCR for the younger patients and BR for the older patients. Then patients, in total 926, were randomised in a 1:1:1:1 fashion to these four arms. Then the primary endpoints, there were two of them in this trial, were on the one hand the undetectable MRD rate two months after the end of treatment, so at month 15, and progression free survival comparisons between the treatment arms.

What were the results of this study?

The main results that we’ve already published before as well were that the venetoclax-obinutuzumab arm, so venetoclax-obinutuzumab and the triple combination of venetoclax, obinutuzumab and ibrutinib, they were both superior in terms of PFS when compared to both the venetoclax-rituximab arm and the chemoimmunotherapy arm. What was new now with this longer follow-up was that also the triple combination with venetoclax, obinutuzumab plus ibrutinib showed a significantly longer progression free survival compared with the doublet of venetoclax-obinutuzumab which is one of our standard treatments in Europe. This was quite a big PFS difference – at five years I think it was around 80% for the venetoclax-obinutuzumab- ibrutinib arm and around 70% for the venetoclax-obinutuzumab arm.

This was the main PFS result, this difference was driven by very distinct differences between the IgHV unmutated patients, so patients with unmutated IgHV status benefitted very much from the triple combination whereas in patients with mutated IgHV we didn’t see any differences between these two treatment arms.

Then we had some overall survival data and this overall survival data confirmed what we’ve seen before, that there is no difference in overall survival between the treatment arms and safety-wise there were also no new safety signals. We did see a little bit of excess cardiac adverse events and a little bit of extra incidence rate, or a high incidence rate, in infectious adverse events in the triple combination when compared to the doublet but in general the safety profile was very well tolerated, the drugs were very well tolerated.

What is the clinical significance of these results?

That’s a good question we’ve also discussed a lot in the consortium that led this study. Because, on the one hand, we see a PFS benefit for the triplet arm and we somehow have to do something with it but on the other hand we are all very hesitant to use the triple combination in the first line setting due to the excess toxicities due to an impaired quality of life of the patients under treatment. That’s something I didn’t mention before but we did see impaired quality of life with the triple combination compared with the doublet and also we don’t see any overall survival difference. Also the problem if you already give all three different drugs in the first line is that it’s not as easy to treat these patients again in the second line and that’s why the clinical significance of this PFS difference is maybe not as big as it might seem when you see the PFS curves.