Acalabrutinib plus Obinutuzumab in Treatment-Naïve and Relapsed/Refractory CLL

[Jm954]

Overall response rates were 95% (treatment-naïve) and 92% (relapsed/refractory). Thirty-two percent of treatment-naïve and 8% of relapsed/refractory patients achieved complete remission. At 36 months, 94% (treatment-naïve) and 88% (relapsed/refractory) were progression free. Acalabrutinib plus obinutuzumab was well tolerated, producing high and durable responses in treatment-naïve and relapsed/refractory CLL.

At 12 months, 5 of 19 patients (26%) in the treatment-naïve cohort and 4 of 26 patients (15%) in the relapsed/refractory cohort had achieved MRD negativity in bone marrow assessed by 10-color flow cytometry using 10−4 CLL cells/leukocyte as cutoff.

One treatment-naïve patient developed a BTKC481S mutation (0.2% variant allele frequency) 48 months after the initiation of therapy but has no sign of clinical progression. In the relapsed/refractory cohort, 1 patient who progressed with CLL developed a BTKC481S mutation 3 months before clinical progression, and 1 patient who developed Richter transformation developed a BTKC481S mutation at progression.

This regimen appears quite tolerable, with a low rate of discontinuation due to AEs, despite the long follow-up. Toxicities that generally led to discontinuation of ibrutinib, such as atrial fibrillation and arthralgias, did not lead to acalabrutinib discontinuation in this study. Moreover, the overall rate of atrial fibrillation in this study was low, with only 1 patient experiencing an atrial fibrillation event. This also suggests that patients who develop or are at high risk for developing these specific adverse effects might benefit from acalabrutinib if BTK inhibitor treatment is indicated.

Rituximab plus the less selective BTK inhibitor ibrutinib has not shown benefit in CLL; however, the selective BTK inhibitor acalabrutinib plus the antibody-dependent cellular cytotoxicity–enhanced antibody obinutuzumab yielded durable responses that deepened over time in treatment-naïve and relapsed/refractory CLL.

More here: cancerdiscovery.aacrjournal...

Jackie

[cartwheels]

Thanks Jackie

[cajunjeff]

Very interesting. This raises a few questions. Ibrutinib (I) and acalabrutinib (A) are both btk inhibitors. Rituximab(R) and Obinutuzumab(O) are both CD20 monoclonal antibodies.

In head to head tests comparing I plus R to I, they found R didn't add much to the end result. So you would think A plus O would be the same as A alone.

But here you have people on A plus O getting to mrd negativity. We know O is more effective than R, but I have not heard that A is better than I in terms of efficacy, only side effects.

I guess if we wanted to find out who was pulling the weight, they need to compare A plus O to I plus O.

This study is not good news for ibrutinib. I would definitely consider A plus O if I was starting treatment today.

[Jm954 Administrator in reply to cajunjeff]

I think that O might be the difference if everything else is equal.

Acalabrutinib appears definitely better safety profile for cardiovascular side effects but interesting to see that, sadly, resistance is still a problem.

Jackie

[SethB34]

Interesting and encouraging results. And yes, not great news for Ibrutinib. One question--I'm 99 percent sure this study is not a fixed duration study, in that the participants are still on the medicines? It would be nice if they did have a time limited study on acalabrutinib / obinutuzumab like there is on venetoclax/obinutuzumab (in which the treatment was stopped after 1 year and despite that, PFS rates remained high after discontinuation.

ascopost.com/issues/june-25...

Lastly, I have heard that ibrutinib and acalabrutinib is being compared head to head, and the study is either completed or nearing completion, with results estimated to be out in 2022. I'm wondering if this is the trial that was being alluded to in the CLL conference I just attended:

clinicaltrials.gov/ct2/show...

As a young person to be diagnosed , I'm more interested in those treatments that allow for as few long term toxicities as possible, and it seems acalabrutinib is better tolerated than ibrutinib.

[Jm954 Administrator in reply to SethB34]

Thanks for those comments.

It will be interesting to see the head to head results but it could be 10 years before there is a clear difference, depending on how the trial is powered (number of patients).

I think that after less than 5 years it would be difficult to see a difference in efficacy but the side effect profile and QOL issues would be the critical factors

Jackie

[bhayes84]

Maybe in the future we'll find that A + O + Venetoclax is the silver bullet to wipe out CLL.