ASH 2024 | Interim results of AMPLIFY: AV/AVO versus chemoimmunotherapy for first-line treatment of CLL

The AMPLIFY trial is a Phase III randomized trial in fit treatment-naive CLL patients requiring treatment but without 17p deletion or p53, testing the combination of acalabrutinib and venetoclax with or without obinutuzumab compared to chemoimmunotherapy. 

So there were three arms in the trial, the acalabrutinib and venetoclax, the acalabrutinib and venetoclax and obinutuzumab, and then chemoimmunotherapy FCR or BR for six cycles. The regimens included starting with acalabrutinib in the first month, adding obinutuzumab in the second month if it was given, and then ramping up venetoclax in the third month. The acalabrutinib and venetoclax then continued through the end of 14 cycles. 

The primary endpoint was IRC assessed progression-free survival of AV compared to chemoimmunotherapy, which was met, with an estimated three-year progression-free survival of 76% for AV compared to 66% for chemo. The first key secondary endpoint was IRC-assessed progression-free survival for AVO compared to chemo, and that was also met at 83% compared to 66%. 

We looked at undetectable MRD, which was highest in the AVO regimen. That was about 66% in the intention-to-treat population and 95% in the evaluable population. With AV at end of treatment, it was about 35% in the intention-to-treat and 45% in the evaluable population. Overall survival was prolonged in the AV arm compared to chemoimmunotherapy. And in an analysis that was pre-planned centering for COVID deaths, overall survival was improved with both AV and AVO compared to chemoimmunotherapy. 

The safety was pretty good. The most common adverse event was neutropenia. Cardiac events of hypertension and atrial fibrillation were rare. There were more infections and neutropenia with AVO compared to AV. 

So this trial is designed to lead to approval registration for the acalabrutinib and venetoclax with or without obinutuzumab combination. And it shows that the AV combination is really very well tolerated, time-limited therapy potentially suitable for most of our CLL patients. And then the addition of obinutuzumab was not a planned comparison, but looking at that arm, we can see that probably depth of remission in PFS is somewhat improved, but with a little bit more toxicity, infectious and neutropenia. So we did notice that the unmutated IGHV patients receiving AVO had a similar three-year PFS to the mutated patients, which is unusual and favorable. So I would consider the addition of the obinutuzumab particularly for the fitter, younger patients with unmutated IGHV or higher risk disease.

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