Adding Venetoclax to Obinutuzumab Prolongs Progression-Free Survival in Previously Untreated CLL

[Jm954]

Dated 1st September 2019

In a phase III trial of patients with previously untreated CLL and co-existing comorbidities, a fixed-duration regimen of obinutuzumab plus venetoclax reduced the risk of disease progression and death by 65%, compared with obinutuzumab plus chlorambucil.

The findings were presented at the 2019 American Society of Clinical Oncology annual meeting by lead author Kirsten Fischer, MD, of the University Hospital of Cologne in Germany.

After a median follow-up of 28.1 months, the investigators found that patients who received obinutuzumab plus venetoclax had significantly higher rates of progression-free survival (PFS) at 24 months, compared with patients who received obinutuzumab plus chlorambucil: 88% vs. 64%. Overall response rates also were higher in the venetoclax group (85% vs. 71%).

The PFS benefit was observed in the venetoclax group, regardless of TP53 and IGHV status, the investigators added. In addition, more patients in the venetoclax group achieved measurable residual disease (MRD) negativity, measured via polymerase chain reaction assay and next-generation sequencing, at three months following treatment: MRD in peripheral blood: 76% vs. 35% (p<0.0001) and MRD in bone marrow: 57% vs. 17% (p<0.0001).

WOW, just WOW for this group of patients!!

More here: ashclinicalnews.org/on-loca...

Jackie

[cartwheels]

So many good options coming online it really is pleasing to see how far we have moved in ten years not so long ago I was one of the new kids on the block with 17p and getting access to ibrutinib which I'm pleased to say is still working fine 2.5 years on that decision was easy as consultants seemed to be going away from STC what would have been my other option at the time and now more novel agents are giving greater choices for patients we are luck to be in this era .

[Mldeterm]

Venetoclax is such a game changer! I do wish the study was V+O vs V to get a definitive answer that the O is helping but it appears to not really hurt anything to assume it is. I do wonder who gets in the comparator arm of these studies and doesn't know they are getting setup for a raw deal. I am grateful for all data though and the people who do them. Husband is currently on I+O+V study which is being studied against I+O (both arms fantastic CLL options).

[Jm954 Administrator in reply to Mldeterm]

The O is definitley helping Mideterm. It helps in obtaining deeper responses much more quickly and, in doing so, is partly enabling the fixed term for treatment.

Jackie

[avzuclav in reply to Jm954]

TBD.

"We demonstrate comparable efficacy between VENmono and VEN plus CD20-directed therapy in a heavily pretreated, high-risk cohort, in terms of both response data and survival outcomes. In adjusted and unadjusted models, there were no differences in PFS and OS between these cohorts. "

ncbi.nlm.nih.gov/pmc/articl...

[Justasheet1 in reply to avzuclav]

Keep reading,

“Finally, although a few patients treated with VEN plus obinutuzumab were included, we note this comparison did not include enough patients to make conclusions about specific anti-CD20 antibodies or use of VEN plus obinutuzumab in the front-line setting.”

I wish I saved the post from the other day but it shows that obinutuzamab and ibrutinib may be a good combo whereas rituxin is out. Apparently, there are differences between the two that we weren’t aware of.

Great post. Thanks!

Jeff

[Justasheet1 in reply to Justasheet1]

Avs,

I just found the post and it’s yours. 😂

“avzuclav

avzuclavJm954

7 days ago

Obinutuzumab (GA101) Is Less Prone to Antagonism of Immune Effector Function By Ibrutinib Than Rituximab in Vitro and in Vivo:

healthunlocked.com/api/redi...

Conclusions: Surprisingly, we found that the inhibitory effect of ibrutinib on the immune effector mediated activity of obinutuzumab is not observed when compared to rituximab.”

[Motoli in reply to avzuclav]

The heavily pretreated description is key: intensive treatment with ibrutinib may reduce the efficacy of obinituzimab or rituximab. Actually Dr Mato argued that a randomized comparison between V and V+O is needed.

It may be that O helps to debulk and reduce the TLS rate. Whether it increases PFS or OS over V monotherapy is unknown.

[Smakwater in reply to Mldeterm]

It was explained to me that much of the reason for the O is to prevent tumorlysis when V is added. Same with I plus V, and R + V etc...

JM

[avzuclav in reply to Mldeterm]

Around the three minute mark in this video, Dr. Ghia describes a new trial for R/R where they will give venetoclax monotherapy for up to a year. If you reach UMRD, stop drugs. If you don't reach UMRD they will add ibrutinib to venetoclax for up to a year.

Nice to see the I+V combo in reverse order - results should be very interesting.

youtube.com/watch?v=2e3VROq...(Not working as expected?)

[Jm954 Administrator in reply to avzuclav]

I heard this Dr speak at the CLL meeting over the weekend. He was very impressive.

Jackie

[avzuclav in reply to avzuclav]

Dr. Mato tweeted a few photos of the presentation of the Italian IMPROVE study. Results are looking good so far: ~50% reached U-MRD4 after 12 months on venetoclax. Rates of U-MRD4 increase after they add ibrutinib to venetoclax, though it's a small number of patients.

twitter.com/anthonymatomd/s...

[AdrianUK in reply to Mldeterm]

The comparator arm of this study was standard treatment at the time. To be honest it now seems clear to me that chlorambucil and bendamustine should probably be shelved for CLL. If you want chemo go for FCR. And if you can’t tolerate that go for one of the newer combinations. It will be fascinating to see if VO manages to make it as a first line treatment. In the uk NICE has committed to examine this option which must mean it is being looked at by the EMA (let’s hope they approve it before Brexit as who knows if we will get new drugs very quickly outside the EU...).

This could be the combo that finally kills FCR.

And since it seems that CD20 antibodies are a good feature Early on in the disease it could also delay ibrutinib meaning that for the first X relapses (each of which might be ten years or more apart) you go for VO or VR and then only when that stops working or the gap gets too short do you switch to ibrutinib as an admission that you can no longer come close to erradicafing the CLL.

I think the ultimate landing place may well be VO first line, unless that is it turns out AVO is even better...!

[lorna222]

Thanks for posting these results! I have seen them elsewhere concerning the German study. I am about to begin V and O vs FCR. My Dr. gave me the choice and we will see what happens. I am very hopeful - fingers crossed!

Lorna

[AdrianUK]

Yes it really does look like V plus O may actually be a cure for at least some of these people. This is truly the best set of results we’ve seen for any treatment combination so far. Will be fascinating to see how first line V plus I compares to these kinds of results. I also wonder if V plus O is better second line than V plus R but don’t suppose we will ever have a trial to prove that.