Transcript: 

I am Dr. Con Tam from the University of Melbourne and Peter MacCallum Cancer Centre. I am a professor of medicine and a consulting hematologist.

Our presentation is on Phase 3 study called the SYMPATICO study, which looks at the combination of ibrutinib plus venetoclax in patients with mantle cell lymphoma.

This is a Phase 3 study which compares ibrutinib monotherapy against the combination of ibrutinib plus venetoclax in patients with relapsed/refractory mantle cell lymphoma.

The presentation itself is actually not concerned about the randomized portion, which is still in progress. The presentation is regarding the safety run-in portion.

Now the background to this is that we knew that both ibrutinib and venetoclax are active in mantle cell lymphoma, and individually, those two drugs give about a 20 percent complete remission rate.

We have previously shown, in a Phase 2 study, that when you combine the two drugs together, you get a far higher complete remission rate of 71 percent, as well as a clearance of minimal residual disease, which is what led to the Phase 3 study to compare the combination against ibrutinib monotherapy.

However, what we did in the previous study is that we gave patients one month of ibrutinib to reduce the risk of tumor lysis syndrome before starting venetoclax.

This has both advantages and disadvantages. The advantage is that, theoretically, there may be a lower risk of tumor lysis syndrome, but the disadvantage is that in patients with aggressive mantle cell lymphoma, one month of ibrutinib monotherapy may give the chance for a tumor to develop resistance.

In the SYMPATICO study, a question arose as to whether you can give the two drugs simultaneously from day one. We did what we call a safety run-in cohort, which is nonrandomized portion and the subject of today's report, where the two drugs were given simultaneously from day one.

In this cohort, we treated 21 patients, 15 of which were at high risk for tumor lysis syndrome due to tumor burden or impaired renal function.

Essentially, these patients got, from day one, the combination of ibrutinib plus venetoclax. They all had relapsed/refractory mantle cell lymphoma.

One of the most pleasing findings was that despite this fairly at-risk, tumor lysis population and the simultaneous start of the two drugs day one, of the 21 patients, we only had 1 patient develop laboratory tumor lysis syndrome, which lasted five days, and no patient developed clinical tumor lysis syndrome.

Based on this, we concluded that the combination, starting with the two drugs from day one, is feasible in the randomized portion, which is fully enrolled. The patients are now being treated and being analyzed using the simultaneous start of both drugs together.

There were not any unusual adverse events or any other toxicities that we did not expect. The combination seems to be quite tolerable. This cohort of 21 patients also allowed us to look into the early efficacy of this combination to see if our earlier Phase 2 study data can be reproduced.

Indeed, in this international study, where we had patients in a safety run-in, our previous data was reproduced. The overall response rate to this combination was very high, 81 percent. The complete remission rate, if you remember is only about 20 percent for ibrutinib or venetoclax monotherapy.

With the combination here, the complete remission rate is now 62 percent, and all the patients with detectable MRD at baseline had achieved MRD clearance.

We also had a readout of progression-free survival, which is looking fairly promising. 75 percent progression-free survival at 18 months, which, once again is higher than you would expect for patients receiving either venetoclax or ibrutinib monotherapy.

Our conclusion from the safety run-in of the SYMPATICO study is that the combination is safe to be given from day one together. The data from this nonrandomized portion looks very promising, with high complete remission rates, high MRD clearance, and a very robust progression-free survival, suggesting that this combination may in fact be better than ibrutinib monotherapy.

Of course, the randomized portion, which will hopefully readout in the next year or two, will tell us whether that is true or not.