Thank you, good morning. Thank you for attending, for showing an interest in the data I’m actually presenting later today. These are my disclosures here.

We investigated the effect of fixed duration targeted treatment with venetoclax combination as compared with fixed duration standard chemo-immunotherapy in previously untreated patients with CLL and with co-existing comorbidities within this phase III trial of the German CLL Study Group that is called CLL14 following the systematic approach of the German CLL Study group here. You may know that already the vast majority of patients really are older than 70 years of age and have clinically relevant coexisting comorbidities. Now, such unfit patients, as we loosely call them, then would require less toxic regimens. If we look at the current standard of care for these patients then it is really as simple as that, it is either fixed duration chemo-immunotherapy or, since more recently, continuous indefinite targeted therapy. That was the reason why we decided to develop a new treatment regimen that is a fixed duration targeted therapy and that was the purpose we wanted to address with this unmet medical need. We wanted to evaluate fixed duration targeted treatment with venetoclax and obinutuzumab. In fact, we wanted to replace chemotherapy by venetoclax and combine this with another strong compound with obinutuzumab and compare this against the standard therapy in this patient population, which is obinutuzumab and chlorambucil. By doing so we wanted to introduce now a new therapy for poor patients with previously untreated CLL and with coexisting conditions.

What we did, we designed CLL14 as a multicentre open-label phase III trial where patients were centrally reviewed in order to confirm their eligibility, including their coexisting medical conditions here with a CIRS greater than 6 and/or calculated creatinine clearance below 70ml/min. We then randomised the patients, 432 patients, to receive either venetoclax obinutuzumab for twelve cycles or chlorambucil obinutuzumab for twelve cycles and 216 patients got randomised in each treatment group, making up the intention to treat population here. No cross over was allowed, the primary endpoint was progression free survival.
At the time of data cut-off all patients had completed treatment for at least a year and these are the efficacy results. The overall complete rates were significantly higher with venetoclax obinutuzumab with a complete remission rate of 50% as compared to a complete remission rate of 23% for chlorambucil obinutuzumab. These excellent response rates translated then into an improved progression free survival. The progression free survival was significantly higher for venetoclax obinutuzumab as compared to chlorambucil obinutuzumab, median progression free survival has not been reached in either group, a hazard ratio of 0.35. Additionally, that was defined as a secondary endpoint and an independent review committee assessed the data and confirmed these results. Accordingly, the 24 months progression free survival was 88% in the venetoclax obinutuzumab group as compared to 64% in the chlorambucil obinutuzumab group.

The analysis of the median MRD levels over time, this is the minimal residual disease, they show that MRD negativity occurred very early and was sustained, that’s the most important thing, they were sustained after completion of therapy in most patients treated with venetoclax obinutuzumab whereas a rapid increase in MRD was noted in four patients treated with chlorambucil obinutuzumab, actually starting right after completion of treatment, as you can see here. Accordingly, the MRD negativity rates in the intention to treat population assessed by ASO-PCR assay were significantly higher with venetoclax obinutuzumab in both peripheral blood, and that was 76% versus 35%, but also in bone marrow and I’m not showing the data here.
Now, I would like to conclude that we showed that fixed duration venetoclax plus obinutuzumab can be safely administered to elderly patients with CLL with relevant comorbidities with no new toxicities identified and no increase in known toxicities. I do apologise for not showing this data here but I will be showing that later today. This regimen provides a superior outcome compared to chlorambucil and obinutuzumab regarding progression free survival, overall response rates, complete response rates and MRD negative responses. This benefit has been observed in all relevant subgroups including patients with unmutated Ig3 mutation status or patients with TP53 mutation and/or deletion. To me, what is most important and remarkable, this is a fixed duration therapy for twelve months only and hence it achieves the highest rate of MRD negative responses observed in a randomised clinical study so far.
Based on these results, the combination venetoclax obinutuzumab has been approved by the FDA on May 15th in the Real-Time Oncology Program and also the full manuscript went online actually last week. Thank you very much for your attention.

Prof Anton Hagenbeek
Thank you. Thank you for sharing these ground-breaking results with us and congratulations with the New England Journal paper and with the Presidential Symposium this afternoon.

Dr Kirsten Fischer
Thank you very much.

Prof Anton Hagenbeek
So, who wants to comment? Who has questions? Yes, please.

Audience member
Doris in Germany. If a patient has a relapse can you start the fixed combination again and get you good results?

Dr Kirsten Fischer
That’s a really good question indeed, thank you very much. Unfortunately this is the thing. Unfortunately we do not have so many progressions so far so we don’t have any data on this. It’s just 14 progessors in this one group but, on the other hand this is crucial. We need to look into this, how these patients may respond but we have no data within this trial so far. Thank you.

Prof Anton Hagenbeek
Further questions? I think you did not really discuss toxicity profiles, are there any differences between the conventional arm with the doublets of chlorambucil plus the antibody versus the experimental arm?

Dr Kirsten Fischer
Thank you for bringing this up.  The toxicity effects were similar in severity in both treatment arms and that is important to mention. It’s an important measurement because normally we see this is a chemotherapy free regimen but still they are equal but there were no added toxicities or no new toxicities identified, which is a good thing. Also patients really did finish treatment duration, it was just around 10% that had to discontinue treatment.

Prof Anton Hagenbeek
And another question because patients are most interested in whether they live longer. I think it’s too premature to say something about overall survival, are you expecting any difference there between the two arms?

Dr Kirsten Fischer
This is again a very good question.

Prof Anton Hagenbeek
Thank you.

Dr Kirsten Fischer
It’s very tricky, overall survival is, indeed, very important but in this study we went for the progression free survival as the primary endpoint. Overall survival is actually defined as a secondary endpoint and, in fact, the last one in the hierarchical order so we didn’t really expect. We wanted to have a very soon primary endpoint and what happened is we have not seen any difference in overall survival so far, hence, we have a relatively short follow-up of 28 months and also there is a very limited number of events so far. The all-cause mortality is around 7% and 9% so that might be just too early to detect any difference in overall survival. Then there is the MRD data and that would be really interesting to see what happens with a longer follow-up to see if these really negative MRD data will eventually translate into an improved overall survival.

Prof Anton Hagenbeek
Right, that’s exactly what would have been my next question, yes. So suppose if there’s no difference in overall survival, would this be the new standard of care?

Dr Kirsten Fischer
Normally the one who is presenting the data is not claiming this but what we did is we presented the data last week at ASCO and then there was a commentary afterwards from Matthew Davids from Boston and he said, ‘Well, this is the new standard therapy. Patients will be treated with this right now.’ The same goes for the German CLL Study Group, we would recommend that but we will have to wait, of course, for the approval of the EMA.

Prof Anton Hagenbeek
Right, it has been submitted to EMA as well?

Dr Kirsten Fischer
Yes, I can confirm that.

Prof Anton Hagenbeek
Okay. Final question to Kirsten?

Audience member
I have a question. I normally think of these targeted therapies as really not having these responses that go on beyond treatment; that is really something you see more in immunotherapy. Do you understand why this seems to be long-term or even permanent?

Dr Kirsten Fischer
Thank you very much. Yes, that was our thinking. We wanted to combine, as I said, we wanted to combine venetoclax, a BCL-2 inhibitor, with another strong compound, with obinutuzumab. There is some preclinical data suggesting an additive effect of these two which is most beneficial when combined with obinutuzumab so that is what we were thinking. But actually we don’t know yet, we will see what longer follow-up brings. But, yes, it is remarkable after completion of treatment these response rates are still so durable right now. Yes, I would agree with you, thank you.

Audience member
But do you have any idea why that is at the cellular level?

Dr Kirsten Fischer
We don’t know yet, no. We’ll see.

Prof Anton Hagenbeek
Further questions? If not, thank you again.